# ent

id: cord-000137-idffrnac
type: GGP
entity:
  PMN activation 80 Administration of rapamycin an inhibitor of mTORC1 decreased the severity of lung injury after intratracheal LPS


id: cord-000137-idffrnac
type: ORG
entity:
  the National Institutes of Health Grant R01 HL 079669 National Institutes of Health Center Grant P50 GM


id: cord-006605-tsk3pakb
type: CL
entity:
  alveolar and vascular spaces Both the endothelium and alveolar epithelium are known to play important roles in the pathogenesis of ALI The co localization of the key procoagulant molecules


id: cord-005812-hx6lkuj0
type: GGP
entity:
  EGF epidermal growth factor ENaC epithelial sodium channel KGF keratinocyte growth factor Na K ATPase Na K


id: cord-023890-z346hh2c
type: CELL_LINE
entity:
  A549 cell membranes Fatty acid C14 0 saturated 3 7 C16 0 saturated 31 9 C16 1 monounsaturated 9 6 C18 0 saturated 16 8 C18 1 monounsaturated 27 3 C18 2 linoleic acid n 6 2 8 C20 4 arachidonic acid AA n 6 6 2 C22 6 docosahexaenoic acid DHA n 3 1 7 n 3 n 6


id: cord-023890-z346hh2c
type: CL
entity:
  pneumocytes alveolar type I and II Fig 1 Anteroposterior chest radiograph from a patient with the acute respiratory distress syndrome who was receiving mechanical ventilation Irregular and asymmetric infiltrates are present throughout both lung fields pulmonary capillary endothelial cells alveolar macrophages


id: cord-023890-z346hh2c
type: ORG
entity:
  the European Society for Clinical Nutrition and Metabolism American Society of Parenteral and Enteral Nutrition Society of Critical Care Medicine


id: cord-023890-z346hh2c
type: ORG
entity:
  The European Society for Clinical Nutrition and Metabolism Guidelines on Enteral Nutrition Intensive Care Kreymann


id: cord-023890-z346hh2c
type: ORG
entity:
  The American Society for Parenteral and Enteral Nutrition Guidelines for the Provision and Assessment of Nutrition Support Therapy


id: cord-023890-z346hh2c
type: CHEMICAL
entity:
  linoleic acid n 6 2 8 C20 4 arachidonic acid AA n 6 6 2 C22 6 docosahexaenoic acid DHA n 3 1 7 n 3 n 6 PUFA


id: cord-255440-ls1l2mlg
type: PROTEIN
entity:
  human COVID 19 no severe illness associated with mortality was observed suggesting a wide gap between COVID 19


id: cord-255440-ls1l2mlg
type: CELL_LINE
entity:
  Human Transport Media HTM Advanced DMEM F 12 10 mM HEPES 1X Glutamax 1X penicillin streptomycin 5 M Y 27632


id: cord-255440-ls1l2mlg
type: DNA
entity:
  lung BRCA2 CYBB KRT5 C1QB FCGR1A IL10 IL6 CD44 CD276 XAGE1B CCR5 CCR2 ALOX15B CMKLR1 MX1 TNFRSF17 CCR1 CXCR3 CDK1 GBP1 HLA G IDO1 ISG20 LAG3 MAD2L1 CXCL9 MKI67 SNAI2 IFITM1 GZMB CD163 CD38 BST2 BUB1 CCL20 CCNB2 CXCL11 IFI27 IFI35 TDO2 GZMA OAS3 POU2AF1 CXCL13 GNLY DMBT1 DDX58 TNFAIP8 LAMP3 KIAA0101 MELK SLAMF8 IL21 FOXM1 IFIH1 IFI6 PDCD1LG2 IFIT2 IFIT1 CXCL10 IRF4 PSMB9 CCL18 TNFSF18 ISG15 CDKN3 C1QA OAS1 OAS2 IFIT3 TOP2A LILRB1 HERC6 TNFSF13B IFI44L STAT1 Collection


id: cord-255440-ls1l2mlg
type: GGP
entity:
  IFIT2 IFIT1 CXCL10 IRF4 PSMB9 CCL18 TNFSF18 ISG15 CDKN3 C1QA OAS1 OAS2 IFIT3 TOP2A LILRB1 HERC6 TNFSF13B IFI44L STAT1


id: cord-005832-p1joajvn
type: GGP
entity:
  Gossypol 2 5 5 10 20 and 40 mg kg was given by intraperitoneal injection i p 8 h after injection of gossypol 20 ll of peripheral blood


id: cord-005832-p1joajvn
type: GGP
entity:
  gossypol 2 5 5 10 20 and 40 mg kg and DEX 0 5 mg kg was found to significantly decrease the number of total


id: cord-005832-p1joajvn
type: GGP
entity:
  Gossypol 2 5 5 10 20 and 40 mg kg and DEX significantly reduced TNF a p 0 05 IL 6 p 0 05 and IL 1b p 0 05 production compared to those in the LPS


id: cord-005832-p1joajvn
type: GGP
entity:
  gossypol 2 5 5 10 20 and 40 mg kg p 0 05 or DEX p 0 05 Lung tissues harvested at 7 h after injection of LPS


id: cord-103496-8tq78p2z
type: ORG
entity:
  SRLF Collaborative Group on Mechanical Ventilation Société de Réanimation de Langue Française Spontaneous Breathing


id: cord-015384-bz7ui5a0
type: PROTEIN
entity:
  geradezu einen explosionsartigen Wissenszuwachs zur Pathophysiologie und Differenzialtherapie von MODS bis hin zur Aufdeckung molekularer Mechanismen Neben Untersuchungen zu akuten Krankheitsstadien von ALI und ARDS zeichnen sich


id: cord-015384-bz7ui5a0
type: CHEMICAL
entity:
  sich zwischen 25 bis 50 7 43 In einer konsiliarpsychiatrischen Perspektive überwiegen Angststörungen


id: cord-006507-amo8e81h
type: GGP
entity:
  rat HMGB1 5 0 TCCCCTACTAAAGAC CTGAGAATG 3 0 sense and 5 0 TTTATCCGCTTTCCTTGT ATCTG 3 0 antisense rat TLR4 5 0 CAGGGAGCACGAGG CTTCTAACC 3 0 sense and 5 0 CTTGTGCCCTGTGAGGTC GTTGA 3 0 antisense


id: cord-006507-amo8e81h
type: CHEMICAL
entity:
  5 0 AACCTAGAACATGTGGATCTT 3 0 and 5 0 TTCTCCGAA CGTGTCACGT 3 0 respectively Then the recombinant virus


id: cord-001945-ueccexxc
type: PROTEIN
entity:
  vascular endothelial growth factor granulocyte colonystimulating factor G CSF hepatocyte growth factor HGF


id: cord-001945-ueccexxc
type: CELL_TYPE
entity:
  fetal membrane derived MSCs umbilical cord MSCs umbilical cord blood derived MSCs amniotic fluid stem cells


id: cord-001945-ueccexxc
type: CELL_TYPE
entity:
  Pulmonary stem progenitor cells trachea and bronchial stem cells bronchiolar stem cells bronchioloalveolar stem cells alveolar stem cells


id: cord-012045-1cqqj84n
type: DNA
entity:
  MPND myb like SWIRM and MPN domains 1 MYSM1 eukaryotic translation initiation factor 3 subunit EIF3 H CSN6 26S proteasome non ATPase regulatory subunit 7 PSMD7 EIF3F anti Müllerian hormone AMSH AMSH LP


id: cord-012045-1cqqj84n
type: PROTEIN
entity:
  ATPase regulatory subunit 7 RIG 1 Retinoic acid inducible gene I RIPK1 Receptor interacting protein kinase 1


id: cord-012045-1cqqj84n
type: GGP
entity:
  interferon β TNF α Tumor necrosis factor α TRAF Tumor necrosis factor receptor associated factor UBA


id: cord-331887-kagggou1
type: PROTEIN
entity:
  170 BCL2A1 CXCL1 CXCL2 CXCL6 DNAJC5 FADD KIT IFNG IL1R1 IL6 IL17A IL17F 171 IL17C ITGA5 MMP9 NFKBIA NPLOC4 PPP1R15A THBS1 TNFAIP3 TRADD


id: cord-282336-zvc04s39
type: CL
entity:
  epithelial endothelial barrier resulting in increased vascular permeability 2 Non cardiogenic pulmonary edema characterized by excessive accumulation of protein


id: cord-007858-1ijxilpb
type: PROTEIN
entity:
  MAP kinase extracellular signal regulated protein kinase ERK1 2 p42 p44 c Jun N terminal protein kinase JNK p38 MAP kinase


id: cord-023928-9a1w174h
type: PROTEIN
entity:
  TNF tumor necrosis factor LT lymphotoxin IL 1ra interleukin 1 receptor antagonist IL 10 interleukin 10 IRAK 1 interleukin receptor


id: cord-023928-9a1w174h
type: GGP
entity:
  TNF tumor necrosis factor LT lymphotoxin IL 1ra interleukin 1 receptor antagonist IL 10 interleukin 10 IRAK 1 interleukin receptor associated kinase 1 HSP


id: cord-258087-93yfs7ve
type: PROTEIN
entity:
  MIF macrophage migration inhibitory factor MYLK myosin light chain kinase NFKB1 nuclear factor kappa light polypeptide gene enhancer


id: cord-258087-93yfs7ve
type: PROTEIN
entity:
  B cell enhancing factor PLAU plasminogen activator urokinase SFTPB surfactant pulmonary associated protein B TNF tumor necrosis factor VEGF vascular endothelial growth factor


id: cord-258087-93yfs7ve
type: GGP
entity:
  ACE angiotensin converting enzyme CXCL2 chemokine CXC motif ligand 2 F5 coagulation factor V IL 6 interleukin 6 IL 10 interleukin 10 MBL2 mannose binding lectin 2 MIF


id: cord-258087-93yfs7ve
type: GGP
entity:
  CXC motif ligand 2 F5 coagulation factor V IL 6 interleukin 6 IL 10 interleukin 10 MBL2 mannose binding lectin 2 MIF


id: cord-309301-ai84el0j
type: CELL_TYPE
entity:
  tumor associated macrophages CTLs Cytotoxic T lymphocyte T H cells T helper cells B cells natural killer NK cells


id: cord-309301-ai84el0j
type: PROTEIN
entity:
  EGFR Epidermal growth factor receptor PRMT5 Protein Arginine Methyltransferase 5 MTAP Methylthioadenosine phosphorylase ERK Extracellular regulated protein kinases AR Androgen receptor


id: cord-309301-ai84el0j
type: CELL_LINE
entity:
  human ESCs Coppes RP Purification and ex vivo expansion of fully functional salivary gland stem cells


id: cord-309301-ai84el0j
type: CL
entity:
  epithelial and endothelial components Because differentiation protocols recapitulate development in vitro iPSCs derived organoids are excellent models for studying development Takasato et al 2015 genetic


id: cord-309301-ai84el0j
type: GGP
entity:
  Interferon gamma MHC Major histocompatibility complex NHE3 Sodium Hydrogen Exchanger 3 MUC2 Mucoprotein2 AKT Protein kinase B MAPK Mitogen activated protein kinase EIF3E Eukaryotic


id: cord-309301-ai84el0j
type: WORK_OF_ART
entity:
  A Colorectal Tumor Organoid Library Demonstrates Progressive Loss of Niche Factor Requirements during Tumorigenesis


id: cord-309301-ai84el0j
type: ORG
entity:
  Regeneration of Thyroid Function by Transplantation of Differentiated Pluripotent Stem Cells SARS CoV 2


id: cord-309301-ai84el0j
type: DISEASE
entity:
  prostate breast colorectum esophagus brain pancreas lung small intestine ovary uterus soft tissue bladder ureter and kidney In


id: cord-291076-p350i54m
type: DISEASE
entity:
  influenza A virus H1N1 4 H5N1 5 H7N9 6 severe acute respiratory syndrome coronavirus SARS Cov 7 Middle East respiratory syndrome coronavirus MERS


id: cord-291076-p350i54m
type: DISEASE
entity:
  influenza A H5N1 Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses


id: cord-017853-mgsuwft0
type: PROTEIN
entity:
  phosphatidylinositol 3 kinase Janus kinase signal transducer and activator of transcription Rho p160 Rho kinase


id: cord-016142-7j5cdt1b
type: PROTEIN
entity:
  actin hepatocyte growth factor hydroxy 3 methylglutaryl coenzyme A lipopolysaccharide mitogen activated protein kinase myosin light chain kinase


id: cord-016142-7j5cdt1b
type: GGP
entity:
  protein C endothelial cell endothelial protein C receptor filamentous actin hepatocyte growth factor hydroxy 3 methylglutaryl coenzyme A lipopolysaccharide mitogen activated protein kinase myosin light chain kinase methylnaltrexone mu opioid receptor phosphatidylinositol 3 kinase 1 palmitoyl 2 arachidonoyl


id: cord-016142-7j5cdt1b
type: GGP
entity:
  ICAM 1 intercellular adhesion molecule 1 interleukin PAI 1 plasminogen activator inhibitor 1 sICAM 1 soluble intercellular adhesion molecule 1


id: cord-006778-qnxyhmw5
type: PROTEIN
entity:
  G G A G AT C T T G AT G G A G G G T T T C TCGAGAAACCCTCCATCAAGATCTCC 3 antisense GeneChem Co Ltd Shanghai China


id: cord-317993-012hx4kc
type: WORK_OF_ART
entity:
  A Changing Therapeutic Landscape as Key Patents Expire and Biologics Targeted Therapies and CFTR Modulators for Asthma and Cystic Fibrosis Treatment Emerge


id: cord-317993-012hx4kc
type: ORG
entity:
  Lung Fluid for Simulation of Inhaled Compounds Human Cellular Models for the Investigation of Lung Inflammation and Mucus Production in Cystic Fibrosis Expression


id: cord-354829-god79qzw
type: PROTEIN
entity:
  Ccl7 1 100 Abcam Saa3 1 50 ab231680 Abcam Ly6i 1 2000 Abcam Saa1 1 100 1 200 Thermo lrf7 1 100 Thermo Timp1 1 100


id: cord-340865-sut3nf2a
type: CELL_LINE
entity:
  monocyte macrophage 15 dendritic cells 16 lymphocytes 15 endothelial cells 17 mast cells 18 eosinophils 19


id: cord-340865-sut3nf2a
type: DISEASE
entity:
  influenza A H1N1 virus 34 In our study IL 17A was markedly elevated in the lung tissues and BAL fluids


id: cord-029488-l11ufs6k
type: PROTEIN
entity:
  primary antibodies anti human extracellular signal regulated protein kinase ERK 1 2 mouse monoclonal antibody 1 1000 Cell Signaling Danvers MA


id: cord-029488-l11ufs6k
type: PROTEIN
entity:
  anti human phospho ERK1 2 Thr 202 Tyr 204 rabbit monoclonal antibody 1 1000 Cell Signaling anti human c Jun Nterminal kinase JNK rabbit monoclonal antibody 1 1000 Cell Signaling anti human p38 rabbit monoclonal antibody 1 1000 Cell Signaling anti human phospho p38 Thr 180 Tyr 182 mouse monoclonal antibody 1 1000 Cell Signaling anti human JNK Thr 183 Tyr 185 mouse monoclonal antibody 1 1000 Cell Signaling and


id: cord-349201-d88g5toc
type: CHEBI
entity:
  amino acid 7 80 8 75 also dominates Figure 4A Interestingly RF analysis of lung targeted metabolomics


id: cord-349201-d88g5toc
type: WORK_OF_ART
entity:
  Smarter Splitting Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design Acute


id: cord-349201-d88g5toc
type: EVENT
entity:
  Prevention Open Forum Infect Dis A New Role for the Spleen Aggravation of the Systemic Inflammatory Response in Rats with Severe


id: cord-284332-p4c1fneh
type: CELL_LINE
entity:
  M1 007 ClinicalTrials gov identifier NCT00074906 Effect of exogenous surfactant calfactant in pediatric acute lung injury a randomized controlled trial A trial of antioxidants N acetylcysteine and procysteine in ARDS the Antioxidant in ARDS Study Group N acetylcysteine


id: cord-284332-p4c1fneh
type: GGP
entity:
  angiotensin receptor antagonist blocker FA fatty acid GM CSF granulocyte macrophage colonystimulating factor HNE human neutrophil elastase ICAM 1 intercellular adhesion molecule 1 IL 8 interleukin 8 MMPs matrix metalloproteinases NF kB


id: cord-284332-p4c1fneh
type: GGP
entity:
  peroxisome proliferator activated receptor g rhPAF recombinant human PAF TNFa tumour necrosis factor


id: cord-284332-p4c1fneh
type: GGP
entity:
  Peroxisome proliferator activated receptors PPARs are ligand activated transcription factors related to thyroid hormone steroid


id: cord-333520-v2sb90rc
type: PROTEIN
entity:
  hepatocyte growth factor HGF leukemia inhibitory factor LIF fibroblast growth factor FGF vascular endothelial growth factor VEGF epidermal growth factor EGF


id: cord-333520-v2sb90rc
type: GGP
entity:
  angiotensin 1 7 AT1R ang II type 1 receptor ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin receptor blockers


id: cord-333520-v2sb90rc
type: GGP
entity:
  ang I angiotensin I ang II angiotensin II ang 1 7 angiotensin 1 7 AT1R ang II type 1 receptor ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin receptor blockers


id: cord-333520-v2sb90rc
type: GGP
entity:
  LIF fibroblast growth factor FGF vascular endothelial growth factor VEGF epidermal growth factor EGF


id: cord-333520-v2sb90rc
type: WORK_OF_ART
entity:
  Akt Modified Human Umbilical Cord Mesenchymal Stem Cells Improve Cardiac Regeneration and Promote Angiogenesis


id: cord-333520-v2sb90rc
type: WORK_OF_ART
entity:
  Activating Platelet Derived Growth Factor D Stem Cells Transl Extracellular Vesicles From Notch Activated Cardiac Mesenchymal Stem Cells Promote Myocyte Proliferation and


id: cord-333520-v2sb90rc
type: WORK_OF_ART
entity:
  Mesenchymal Stem Cell Derived Exosomes Improve the Microenvironment of Infarcted Myocardium Contributing to Angiogenesis and Anti Inflammation


id: cord-306835-juitltpi
type: PROTEIN
entity:
  IL1RA IL 7 IL 8 IL 9 IL 10 basic fibroblast growth factors FGF granulocyte colony stimulating factor GCSF granulocyte macrophage colony stimulating factor GM


id: cord-306835-juitltpi
type: CELL_TYPE
entity:
  activated B cells MAPK mitogen activated protein kinase PAI 1 plasminogen activator inhibitor 1 PLA2


id: cord-306835-juitltpi
type: GGP
entity:
  Cas 3 caspase 3 COX cyclooxygenase CXCL chemokine C X C motif ligand 12 HPETE 12 hydroperoxyeicosatetraenoic acid JNK c Jun N terminal kinase 12


id: cord-306835-juitltpi
type: DISEASE
entity:
  acute respiratory distress syndrome ARDS chronic obstructive pulmonary disease COPD pulmonary hypertension ALI


id: cord-306835-juitltpi
type: DISEASE
entity:
  pulmonary or extrapulmonary infectious or noninfectious insult Matthay Ware Zimmerman 2012 Major inflammatory


id: cord-014996-p6q0f37c
type: DNA
entity:
  colloids 4 gelatin 6 HES 130 0 4 or 5 albumin 250 ml in 20 min Hemodynamic and extravascular lung water index EVLWI GEDVI


id: cord-014996-p6q0f37c
type: DNA
entity:
  S pneumoniae positive bacteriological sample pulmonary quantitative culture pleural fluid blood culture


id: cord-014996-p6q0f37c
type: DNA
entity:
  APACHE II scores 12 1 4 1 and 11 4 4 4 vs 15 0 4 5 p 0 02 and MODS scores 3 58 1 73 and 3 25 2 12 vs 4 75 3 06 p 0 027


id: cord-014996-p6q0f37c
type: GGP
entity:
  V t ScaW p 0 002 CONCLUSIONS Our data show that there is no gold standard method for estimate or calculate body weight


id: cord-014996-p6q0f37c
type: GGP
entity:
  SCS 3 15 for the GCS and 5 16 for the FOUR Beyond this threshold only the SCS provides a highly significant correlation with the risk of death Spearman 0 907 p 0 0001 A


id: cord-014996-p6q0f37c
type: WORK_OF_ART
entity:
  Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis Procalcitonin


id: cord-014996-p6q0f37c
type: DISEASE
entity:
  type 1 diabetes mellitus A Shono 1 T Mihara 1 Y Murakami 1 J Ota 1 F Kono 1 Y Saito 1 1 Shimane Universiy


# bib

id: cord-000137-idffrnac
title: Pattern Recognition Receptor–Dependent Mechanisms of Acute Lung Injury
author: Xiang, Meng
date: 2009-11-02
txt: ./txt/cord-000137-idffrnac.txt
cache: ./cache/cord-000137-idffrnac.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785474/
doi: 10.2119/molmed.2009.00097
summary:
  The study further found that the induction of the negative regulators of TLR signaling IL-1R-associated kinase-M, Toll-interacting protein and A20 by intratracheal LPS in vivo and in macrophages in vitro was significantly reduced in CD44 -/mice. Thus, the study demonstrates a novel mechanism underlying HS-augmented lung inflammation, namely that induction of increased TLR2 surface expression in lung endothelial cells, which is induced by HS/R and mediated by HMGB1 activation of TLR4 signaling, is an important mechanism responsible for EC-mediated inflammation and organ injury following HS (122) . These results provide evidence for direct activation of the NLRP3 inflammasome by biglycan and suggest a fundamental paradigm of how tissue stress and injury are monitored by innate immune receptors detecting the release of the extracellular matrix components and turning such a signal into a robust inflammatory response (147) .

abstract:
  Acute lung injury (ALI) that clinically manifests as acute respiratory distress syndrome is caused by an uncontrolled systemic inflammatory response resulting from clinical events including sepsis, major surgery and trauma. Innate immunity activation plays a central role in the development of ALI. Innate immunity is activated through families of related pattern recognition receptors (PRRs), which recognize conserved microbial motifs or pathogen-associated molecular patterns (PAMPs). Toll-like receptors were the first major family of PRRs discovered in mammals. Recently, NACHT–leucine-rich repeat (LRR) receptors and retinoic acid–inducible gene–like receptors have been added to the list. It is now understood that in addition to recognizing infectious stimuli, both Toll-like receptors and NACHT-LRR receptors can also respond to endogenous molecules released in response to stress, trauma and cell damage. These molecules have been termed damage-associated molecular patterns (DAMPs). It has been clinically observed for a long time that infectious and noninfectious insults initiate inflammation, so confirmation of overlapping receptor-signal pathways of activation between PAMPs and DAMPs is no surprise. This review provides an overview of the PRR-dependent mechanisms of ALI and clinical implication. Modification of PRR pathways is likely to be a logical therapeutic target for ALI/acute respiratory distress syndrome.


id: cord-000492-ec5qzurk
title: Clinical Review: Gene-based therapies for ALI/ARDS: where are we now?
author: Devaney, James
date: 2011-06-20
txt: ./txt/cord-000492-ec5qzurk.txt
cache: ./cache/cord-000492-ec5qzurk.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218971/
doi: 10.1186/cc10216
summary:
  Plasmid transfer (closed Easily produced at low cost No specifi c cell targeting Electroporation-mediated gene transfer of the dsDNA circles) Very ineffi cient Na + ,K + -ATPase rescues endotoxin-induced lung injury [60] Nonviral DNA complexes Complexes protect DNA Less effi cient than viral vectors Cationic lipid-mediated transfer of the Na + ,K + -(lipoplexes or polyplexes) Modifying transgene DNA to eliminate bacterial motifs [75, 76] Development of high-effi ciency tissue-specifi c promoters [77] [78] [79] [80] Development of promoters that regulate gene expression [83] Enhanced therapeutic targeting Nebulization technologies [9] Strategies to target the pulmonary endothelium [10] Improved cellular uptake of vector Surface active agents to enhance vector spread [84] Reduce ubiquitination of viral capsid proteins [85] Better therapeutic targets Enhancement or restoration of lung epithelial and/or endothelial cell function [86] Strengthening lung defense mechanisms against injury [87] Speeding clearance of infl ammation and infection Enhancement of the repair process following ALI/ARDS [88] .

abstract:
  Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) confer substantial morbidity and mortality, and have no specific therapy. The accessibility of the distal lung epithelium via the airway route, and the relatively transient nature of ALI/ARDS, suggest that the disease may be amenable to gene-based therapies. Ongoing advances in our understanding of the pathophysiology of ALI/ARDS have revealed multiple therapeutic targets for gene-based approaches. Strategies to enhance or restore lung epithelial and/or endothelial cell function, to strengthen lung defense mechanisms against injury, to speed clearance of infection and to enhance the repair process following ALI/ARDS have all demonstrated promise in preclinical models. Despite three decades of gene therapy research, however, the clinical potential for gene-based approaches to lung diseases including ALI/ARDS remains to be realized. Multiple barriers to effective pulmonary gene therapy exist, including the pulmonary architecture, pulmonary defense mechanisms against inhaled particles, the immunogenicity of viral vectors and the poor transfection efficiency of nonviral delivery methods. Deficits remain in our knowledge regarding the optimal molecular targets for gene-based approaches. Encouragingly, recent progress in overcoming these barriers offers hope for the successful translation of gene-based approaches for ALI/ARDS to the clinical setting.


id: cord-000812-mu5u5bvj
author: Wiesen, Jonathan
date: 2012-08-28
txt: ./txt/cord-000812-mu5u5bvj.txt
cache: ./cache/cord-000812-mu5u5bvj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503790/
doi: 10.1186/2110-5820-2-41
summary:
  Based on clinical bedside observations and published reports [4, 5, 8] , we hypothesize that ALI/ARDS secondary to pandemic influenza is associated with similar ICU outcomes but increased resource utilization and higher hospital charges due to the frequent need for rescue interventions and prolonged ventilatory assistance. A Research Electronic Data Capture (REDCap) database was constructed with a complete listing of the patient''s demographic and clinical information, including age, gender, height, weight, body mass index (BMI), presenting symptoms, past medical history, primary reason for admission to the ICU, vital signs, presence of vasopressors, laboratory values, ventilator settings and respiratory parameters, Acute Physiology and Chronic Health Evaluation (APACHE) III and Sequential Organ Failure Assessment (SOFA) scores on admission to the MICU, number of intubated days, duration of ICU and hospital stay, mortality, and rescue therapies (namely inhaled nitric oxide, proning, high-frequency oscillatory ventilation, and extracorporeal membrane oxygenation [ECMO]) [22] .

title:
  Relative cost and outcomes in the intensive care unit of acute lung injury (ALI) due to pandemic influenza compared with other etiologies: a single-center study

abstract:
  BACKGROUND: Critical illness due to 2009 H1N1 influenza has been characterized by respiratory complications, including acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), and associated with high mortality. We studied the severity, outcomes, and hospital charges of patients with ALI/ARDS secondary to pandemic influenza A infection compared with ALI and ARDS from other etiologies. METHODS: A retrospective review was conducted that included patients admitted to the Cleveland Clinic MICU with ALI/ARDS and confirmed influenza A infection, and all patients admitted with ALI/ARDS from any other etiology from September 2009 to March 2010. An itemized list of individual hospital charges was obtained for each patient from the hospital billing office and organized by billing code into a database. Continuous data that were normally distributed are presented as the mean ± SD and were analyzed by the Student’s t test. The chi-square and Fisher exact tests were used to evaluate differences in proportions between patient subgroups. Data that were not normally distributed were compared with the Wilcoxon rank-sum test. RESULTS: Forty-five patients were studied: 23 in the H1N1 group and 22 in the noninfluenza group. Mean ± SD age was similar (44 ± 13 and 51 ± 17 years, respectively, p = 0.15). H1N1 patients had lower APACHE III scores (66 ± 20 vs. 89 ± 32, p = 0.015) and had higher Pplat and PEEP on days 1, 3, and 14. Hospital and ICU length of stay and duration of mechanical ventilation were comparable. SOFA scores over the first 2 weeks in the ICU indicate more severe organ failure in the noninfluenza group (p = 0.017). Hospital mortality was significantly higher in the noninfluenza group (77 vs. 39%, p = 0.016). The noninfluenza group tended to have higher overall charges, including significantly higher cost of blood products in the ICU. CONCLUSIONS: ALI/ARDS secondary to pandemic influenza infection is associated with more severe respiratory compromise but has lower overall acuity and better survival rates than ALI/ARDS due to other causes. Higher absolute charges in the noninfluenza group are likely due to underlying comorbid medical conditions.


id: cord-001020-2iwsx727
title: Adipose-derived stem cells weigh in as novel therapeutics for acute lung injury
author: Gupta, Kushagra
date: 2013-02-28
txt: ./txt/cord-001020-2iwsx727.txt
cache: ./cache/cord-001020-2iwsx727.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706912/
doi: 10.1186/scrt167
summary:
  Herein, we discuss the advantages and potential limitations of using adipose-derived stem cells as therapeutics for human acute lung injury. A strength of the paper is its novel focus on ASCs as a therapy for ALI, and its approach to test ASCs therapeutically (rather than prophylactically) in an ALI model Abstract Acute lung injury is characterized by intense neutrophilic lung infl ammation and increased alveolar-capillary barrier permeability leading to severe hypoxemia, and is associated with high mortality despite improvements in supportive care. Zhang and colleagues tested the effi cacy of adipose-derived stem cells in acute lung injury in mice. While the LPS model studied by Zhang and coworkers induces robust neutrophilic lung infl ammation, it causes only modest alveolar-capillary barrier injury, which is a hallmark of ALI/ARDS. Comparison of the therapeutic eff ects of human and mouse adipose-derived stem cells in a murine model of lipopolysaccharide-induced acute lung injury

abstract:
  Acute lung injury is characterized by intense neutrophilic lung inflammation and increased alveolar-capillary barrier permeability leading to severe hypoxemia, and is associated with high mortality despite improvements in supportive care. There is an urgent need for effective therapies for acute lung injury. Zhang and colleagues tested the efficacy of adipose-derived stem cells in acute lung injury in mice. When adipose-derived stem cells were delivered to mice that had been challenged with lipopolysaccharide, they potently limited acute lung inflammation and injury in the mice, indicating that adipose-derived stem cells have therapeutic potential in acute lung injury in humans. Herein, we discuss the advantages and potential limitations of using adipose-derived stem cells as therapeutics for human acute lung injury.


id: cord-001473-aki28lhp
title: Silencing airway epithelial cell-derived hepcidin exacerbates sepsis-induced acute lung injury
author: Chen, Qi Xing
date: 2014-08-06
txt: ./txt/cord-001473-aki28lhp.txt
cache: ./cache/cord-001473-aki28lhp.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243715/
doi: 10.1186/s13054-014-0470-8
summary:
  The knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased mortality (53.33% in Ad-shHepc1-treated mice versus 12.5% in Ad-shNeg-treated mice, P <0.05). The severe lung injury in the airway epithelial cell-derived hepcidin knockdown mice is at least partially related to the altered intracellular iron level and function of alveolar macrophages. These results demonstrated that in the current study the intratracheal administration of Ad-shHepc1 only silenced the hepcidin gene transcription in AECs, which was in accordance with previous studies that adenovirus-mediated intratracheal gene delivery specifically inhibited targeted gene expression in lung epithelial cells but not in alveolar macrophages and other organs [29, 30] . The current study explored the role of AEC-derived hepcidin in polymicrobial sepsis-induced ALI, which is at least partially related to the altered intracellular iron level and function of alveolar macrophages.

abstract:
  INTRODUCTION: The production of antimicrobial peptides by airway epithelial cells is an important component of the innate immune response to pulmonary infection and inflammation. Hepcidin is a β-defensin-like antimicrobial peptide and acts as a principal iron regulatory hormone. Hepcidin is mostly produced by hepatocytes, but is also expressed by other cells, such as airway epithelial cells. However, nothing is known about its function in lung infections and inflammatory diseases. We therefore sought to investigate the role of airway epithelial cell-derived hepcidin in sepsis-induced acute lung injury. METHODS: Acute lung injury was induced by polymicrobial sepsis via cecal ligation and puncture (CLP) surgery. Adenovirus-mediated short hairpin RNA specific for the mouse hepcidin gene hepc1 and control adenovirus were intratracheally injected into mice. The adenovirus-mediated knockdown of hepcidin in airway epithelial cells was evaluated in vivo. Lung injury and the seven-day survival rate were assessed. The levels of hepcidin-related iron export protein ferroportin were measured, and the iron content and function of alveolar macrophages were evaluated. RESULTS: The hepcidin level in airway epithelial cells was upregulated during polymicrobial sepsis. The knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased mortality (53.33% in Ad-shHepc1-treated mice versus 12.5% in Ad-shNeg-treated mice, P <0.05). The knockdown of hepcidin in airway epithelial cells also led to reduced ferroportin degradation and a low intracellular iron content in alveolar macrophages. Moreover, alveolar macrophages form the airway epithelial cell-derived hepcidin knockdown mice showed impaired phagocytic ability than those from the control mice. CONCLUSIONS: Airway epithelial cell-derived hepcidin plays an important role in CLP-induced acute lung injury. The severe lung injury in the airway epithelial cell-derived hepcidin knockdown mice is at least partially related to the altered intracellular iron level and function of alveolar macrophages.


id: cord-001945-ueccexxc
author: Yang, Ce
date: 2016-02-11
txt: ./txt/cord-001945-ueccexxc.txt
cache: ./cache/cord-001945-ueccexxc.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4750219/
doi: 10.1186/s12967-016-0804-1
summary:
  All these findings indicate Fig. 1 Schematic illustration of the exogenous and endogenous stem/progenitor cells as well as the regular delivery routes in the repair and regeneration in acute lung injury that the bone marrow-derived stem/progenitor cells exhibit the mobilizing courses, and play a substantial role in the regression of excessive inflammatory responses and repair in injured lungs. Concerning the protective roles of bone marrow-and peripheral blood-derived EPCs in ALI, recent studies showed that their peripheral infusion could lead to homing in injured lung tissues [24] , relieving the inflammatory injury [25, 26] and promote the endothelial repair and recovery of immune function dissonance [26, 27] , which may be enhanced by the treatment of simvastatin [28] .

title:
  Stem/progenitor cells in endogenous repairing responses: new toolbox for the treatment of acute lung injury

abstract:
  The repair of organs and tissues has stepped into a prospective era of regenerative medicine. However, basic research and clinical practice in the lung regeneration remains crawling. Owing to the complicated three dimensional structures and above 40 types of pulmonary cells, the regeneration of lung tissues becomes a great challenge. Compelling evidence has showed that distinct populations of intrapulmonary and extrapulmonary stem/progenitor cells can regenerate epithelia as well as endothelia in various parts of the respiratory tract. Recently, the discovery of human lung stem cells and their relevant studies has opened the door of hope again, which might put us on the path to repair our injured body parts, lungs on demand. Herein, we emphasized the role of endogenous and exogenous stem/progenitor cells in lungs as well as artificial tissue repair for the injured lungs, which constitute a marvelous toolbox for the treatment of acute lung injury. Finally, we further discussed the potential problems in the pulmonary remodeling and regeneration.


id: cord-002329-7s0ytfed
author: Zeng, Ling
date: 2016-12-07
txt: ./txt/cord-002329-7s0ytfed.txt
cache: ./cache/cord-002329-7s0ytfed.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141641/
doi: 10.1186/s12931-016-0480-y
summary:
  CONCLUSIONS: AEC2s are damage resistant during acute lung injury and the HGF/c-Met signaling pathway is of vital importance in the proliferation of AEC2s after ALI. Using a microfluidic magnetic activated cell sorting system, our previous study has isolated mouse lung multipotent stem cells (MLSCs) which play an important role in bronchiolar and alveolar epithelial cells injury repair [8] . The rat whole lung cell suspensions were incubated with FITC conjugated to anti-proSPC antibody, the percentage of AEC2s was analyzed by flow cytometry analysis (Fig. 1e) , in sham-operated mice, there were no differences in numbers of AEC2s at various time points. It can significantly accelerate AEC2 cell cycle in vitro, indicating that the proliferation of AEC2 after acute lung injury may be induced by the elevated HGF. HGF/c-Met signaling is likely a major factor responsible for the pulmonary epithelial cell proliferation after acute lung injury.

title:
  The cellular kinetics of lung alveolar epithelial cells and its relationship with lung tissue repair after acute lung injury

abstract:
  BACKGROUND: Organ regeneration in mammals is hypothesized to require a functional pool of stem or progenitor cells, but the role of these cells in lung regeneration is unknown. METHODS: Based on the fact that postnatal regeneration of alveolar tissue has been attributed to alveolar epithelial cells, we established a hemorrhagic shock and Lipopolysaccharide (LPS) lung injury model. Using this model, we analyzed the cellular kinetics of lung alveolar epithelial cells. RESULTS: The results showed that alveolar epithelium type 2 cells (AEC2s) are damage resistant during acute lung injury, they might be the main cells involved in lung injury and repair. Then we observed the relationship between the expression of HGF, c-Met following ALI in rat lung and proliferation of AEC2s. The proliferation of AEC2s was inhibited when isolated primary AEC2s were co-cultured with c-Met inhibitor SU11274. Furthermore, the numbers of AEC2s was significantly decreased when ALI rats were administrated with SU11274 in vivo. It provided further evidence that the HGF/c-Met signaling plays a vital role in ALI-induced AEC2s proliferation. CONCLUSIONS: AEC2s are damage resistant during acute lung injury and the HGF/c-Met signaling pathway is of vital importance in the proliferation of AEC2s after ALI.


id: cord-005812-hx6lkuj0
author: Morty, Rory E.
date: 2007-05-25
txt: ./txt/cord-005812-hx6lkuj0.txt
cache: ./cache/cord-005812-hx6lkuj0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095514/
doi: 10.1007/s00134-007-0662-7
summary:
  To complement that report this review focuses on how intact organ and animal models and clinical studies have facilitated our understanding of alveolar edema fluid clearance in acute lung injury and acute respiratory distress syndrome. Given the established importance of the type II cell in AFC [6] and the emerging importance of the type I cell in AFC with the recent discovery that type I cells also contain functional sodium and chloride channels [12] , this epithelial damage Fig. 1 Factors that cause impaired alveolar fluid clearance in ALI/ARDS that have been investigated in animal and organ models and in clinical studies. This idea was further supported by the observations that adenovirus-mediated transfer of β-adrenergic receptor genes to live rats improved AFC due to increased sensitivity to endogenous catecholamines and consequent upregulation of Na,K-ATPase activity and ENaC protein expression the lung [73] .

title:
  Alveolar fluid clearance in acute lung injury: what have we learned from animal models and clinical studies?

abstract:
  BACKGROUND: Acute lung injury and the acute respiratory distress syndrome continue to be significant causes of morbidity and mortality in the intensive care setting. The failure of patients to resolve the alveolar edema associated with these conditions is a major contributing factor to mortality; hence there is continued interest to understand the mechanisms of alveolar edema fluid clearance. DISCUSSION: The accompanying review by Vadász et al. details our current understanding of the signaling mechanisms and cellular processes that facilitate clearance of edema fluid from the alveolar compartment, and how these signaling processes may be exploited in the development of novel therapeutic strategies. To complement that report this review focuses on how intact organ and animal models and clinical studies have facilitated our understanding of alveolar edema fluid clearance in acute lung injury and acute respiratory distress syndrome. Furthermore, it considers how what we have learned from these animal and organ models and clinical studies has suggested novel therapeutic avenues to pursue.


id: cord-005832-p1joajvn
title: Protective effect of gossypol on lipopolysaccharide-induced acute lung injury in mice
author: Liu, Zhicheng
date: 2013-02-23
txt: ./txt/cord-005832-p1joajvn.txt
cache: ./cache/cord-005832-p1joajvn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095812/
doi: 10.1007/s00011-013-0603-6
summary:
  The purpose of this study was to evaluate the effect of gossypol on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice. Additionally, gossypol reduced the inflammatory cells in BALF, decreased the wet/dry ratio of lungs and inhibited the phosphorylation of IκB-α, p65 NF-κB, p46–p54 JNK, p42–p44 ERK, and p38 caused by LPS. CONCLUSION: The data suggest that anti-inflammatory effects of gossypol against the LPS-induced ALI may be due to its ability of inhibition of the NF-κB and MAPKs signaling pathways. The results showed that pretreatment with gossypol attenuated lung damage induced by LPS and decreased the W/D ratio, proinflammatory cytokine production, inflammatory cell migration into the lung, protein leakage, the activation of NF-jB and MAPK. In conclusion, the present study demonstrated that gossypol has a protective effect against LPS-induced ALI, which may be related to its suppression of NF-jB and MAPKs activation, and subsequently leads to the reduction the inflammatory cell infiltration and proinflammatory cytokine expression in lung tissues.

abstract:
  OBJECTIVE: Gossypol has been reported to have anti-inflammatory properties. The purpose of this study was to evaluate the effect of gossypol on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice. METHODS: Male BALB/c mice were pretreated with gossypol 1 h before intranasal instillation of LPS. Then, 7 h after LPS administration, the myeloperoxidase in histology of lungs, lung wet/dry ratio and inflammatory cells in the bronchoalveolar lavage fluid (BALF) were determined. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in the BALF were measured by ELISA. The extent of phosphorylation of IκB-α, p65 NF-κB, p46–p54 JNK, p42–p44 ERK, and p38 were detected by western blot. RESULTS: Gossypol markedly attenuated the LPS-induced histological alterations in the lung and inhibited the production of TNF-α, IL-1β and IL-6. Additionally, gossypol reduced the inflammatory cells in BALF, decreased the wet/dry ratio of lungs and inhibited the phosphorylation of IκB-α, p65 NF-κB, p46–p54 JNK, p42–p44 ERK, and p38 caused by LPS. CONCLUSION: The data suggest that anti-inflammatory effects of gossypol against the LPS-induced ALI may be due to its ability of inhibition of the NF-κB and MAPKs signaling pathways. Gossypol may be a promising potential therapeutic reagent for ALI treatment.


id: cord-005980-e2s0racp
title: TIPE2 ameliorates lipopolysaccharide-induced apoptosis and inflammation in acute lung injury
author: Wu, Xiaojing
date: 2019-09-05
txt: ./txt/cord-005980-e2s0racp.txt
cache: ./cache/cord-005980-e2s0racp.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096061/
doi: 10.1007/s00011-019-01280-6
summary:
  Twenty-four hours later, lung bronchoalveolar lavage fluid (BALF) was acquired to analyse cells and protein, arterial blood was collected for arterial blood gas analysis and the determination of pro-inflammatory factor levels, and lung issues were collected for histologic examination, transmission electron microscopy (TEM), TUNEL staining, wet/dry (W/D) weight ratio analysis, myeloperoxidase (MPO) activity analysis and blot analysis of protein expression. RESULTS: We found that TIPE2 overexpression markedly mitigated LPS-induced lung injury, which was evaluated by the deterioration of histopathology, histologic scores, the W/D weight ratio, and total protein expression in the BALF. CONCLUSIONS: Our study shows that the increased expression of AAV-mediated TIPE2 in the lungs of mice inhibits acute inflammation and apoptosis and suppresses the activation of NF-κB and JNK in a murine model of ALI. Compared with those in the control group, the PMN/total cell ratio in the BALF (Fig. 4c) and lung MPO activity (Fig. 4d) in LPS-challenged mice were dramatically increased, and these levels were inhibited by AAV-TIPE2 treatment.

abstract:
  OBJECTIVE: Tumour necrosis factor-α-induced protein 8-like 2 (TIPE2) has strong anti-inflammatory properties. However, it is unknown whether increased TIPE2 is protective against lipopolysaccharide (LPS)-induced ALI. In the current study, we aimed to investigate whether increased TIPE2 can exert protective effects in a mouse model of ALI induced by LPS. METHODS: We administered TIPE2 adeno-associated virus (AAV-TIPE2) intratracheally into the lungs of mice. Three weeks later, ALI was induced by intratracheal injection of LPS into BALB/c mice. Twenty-four hours later, lung bronchoalveolar lavage fluid (BALF) was acquired to analyse cells and protein, arterial blood was collected for arterial blood gas analysis and the determination of pro-inflammatory factor levels, and lung issues were collected for histologic examination, transmission electron microscopy (TEM), TUNEL staining, wet/dry (W/D) weight ratio analysis, myeloperoxidase (MPO) activity analysis and blot analysis of protein expression. RESULTS: We found that TIPE2 overexpression markedly mitigated LPS-induced lung injury, which was evaluated by the deterioration of histopathology, histologic scores, the W/D weight ratio, and total protein expression in the BALF. Moreover, TIPE2 overexpression markedly attenuated lung inflammation, as evidenced by the downregulation of polymorphonuclear neutrophils (PMNs) in the BALF, lung MPO activity, and pro-inflammatory cytokine levels in the serum. Moreover, TIPE2 overexpression not only dramatically prevented LPS-induced pulmonary cell apoptosis in mice but also blocked LPS-activated JNK phosphorylation and NF-κB p65 nuclear translocation. CONCLUSIONS: Our study shows that the increased expression of AAV-mediated TIPE2 in the lungs of mice inhibits acute inflammation and apoptosis and suppresses the activation of NF-κB and JNK in a murine model of ALI.


id: cord-006507-amo8e81h
title: TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury
author: Yang, Zhongwei
date: 2013-04-29
txt: ./txt/cord-006507-amo8e81h.txt
cache: ./cache/cord-006507-amo8e81h.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101938/
doi: 10.1038/labinvest.2013.66
summary:
  This study investigated whether HMGB1 was involved as a stimulating factor, and whether its downstream Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (p38MAPK), and activator protein-1 (AP-1) signaling pathways act as mediators in the development of liver I/R injury-induced ALI. To study the role of TLR4 and its downstream p38MAPK and AP-1 signaling pathways in the pathogenesis of liver I/R injury-induced ALI, TLR4-small hairpin RNA (shRNA) lentivirus were used to inhibit TLR4 expression in rat lung tissue. As is shown in Figure 3b , relative levels of HMGB1 mRNA in the lung tissue from I/R, shNT þ I/R, and shTLR4 þ I/R groups increased significantly at 18 h after liver I/R injury when compared to the control group, respectively. TLR4-mediated ALI after liver I/R injury Z Yang et al Figure 3 Expression of high-mobility group box protein 1 (HMGB1) in serum and lung tissue from rats at 18 h after liver ischemia/reperfusion (I/R) injury or sham operation.

abstract:
  Acute lung injury (ALI) frequently occurs after liver transplantation and major liver surgery. Proinflammatory mediators released by damaged liver after liver ischemia/reperfusion (I/R) injury might contribute to this form of ALI, but the underlying mechanisms have not been well characterized. High-mobility group box protein 1 (HMGB1), a recently identified proinflammatory cytokine, was found to be significantly higher in the serum after liver I/R injury. This study investigated whether HMGB1 was involved as a stimulating factor, and whether its downstream Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (p38MAPK), and activator protein-1 (AP-1) signaling pathways act as mediators in the development of liver I/R injury-induced ALI. Extensive ALI and lung inflammation was induced in a rat model of liver I/R injury. Serum HMGB1 was significantly higher after liver I/R injury, and more importantly, expression of HMGB1 mRNA and protein in the lung tissue was also significantly increased. We further found that liver I/R injury enhanced the expression of TLR4 mRNA and protein, and the activity of p38MAPK and AP-1 in the lung tissue. Inhibition of TLR4 expression in the lung tissue by infection with pGCSIL-GFP-lentivirus-expressing small hairpin RNAs targeting the TLR4 gene (TLR4-shRNA lentivirus) significantly attenuated ALI, lung inflammation, and activity of p38MAPK and AP-1 in the lung tissue. These findings indicate that HMGB1 might contribute to the underlying mechanism for liver I/R injury-induced ALI and that its downstream TLR4, p38MAPK, and AP-1 signaling pathways are potentially important mediators in the development of ALI.


id: cord-006573-mwtqxwbw
author: Zhang, Leifang
date: 2018-06-16
txt: ./txt/cord-006573-mwtqxwbw.txt
cache: ./cache/cord-006573-mwtqxwbw.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102050/
doi: 10.1007/s10753-018-0802-y
summary:
  title: SOCS-1 Suppresses Inflammation Through Inhibition of NALP3 Inflammasome Formation in Smoke Inhalation-Induced Acute Lung Injury Similar to oxidized ATP, high protein level of SOCS-1 dampened the formation of NALP3 inflammasome and the activation of caspase-1 and IL-1β induced by smoke exposure in mouse alveolar macrophages. In conclusion, SOCS-1 relieves smoke inhalation-induced pulmonary inflammation and injury by inhibiting NALP3 inflammasome formation. To test whether SOCS-1 exerts anti-inflammatory effect through inhibition of NALP3 inflammasome formation and consequent activation of caspase-1 and IL-1β, Ad-GFP, or Ad-SOCS-1-adminstered mice were exposed to smoke for 15 min and euthanized 1 day later to collect alveolar macrophages. Alveolar macrophages were isolated from C57BL/6 mice, treated with or without oxATP, exposed to smoke for 30 min, and then analyzed for a ATP release, b extracellular, and c intracellular K + levels, d expression of inflammasome components NALP3, ASC, and caspase-1, and e the complex formed by NALP3 and ASC.

title:
  SOCS-1 Suppresses Inflammation Through Inhibition of NALP3 Inflammasome Formation in Smoke Inhalation-Induced Acute Lung Injury

abstract:
  Smoke inhalation leads to acute lung injury (ALI), a devastating clinical problem associated with high mortality rates. Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of proinflammatory cytokine signaling. We have found that adenoviral gene transfer of SOCS-1 ameliorates smoke inhalation-induced lung injury in C57BL/6 mice. We also found that the release of adenosine triphosphate (ATP) was increased post smoke exposure, while oxidized ATP, an inhibitor of purinergic P2X7 receptor, suppressed smoke-induced NALP3 inflammasome assembly, caspase-1 activation, and K(+) efflux. Similar to oxidized ATP, high protein level of SOCS-1 dampened the formation of NALP3 inflammasome and the activation of caspase-1 and IL-1β induced by smoke exposure in mouse alveolar macrophages. In conclusion, SOCS-1 relieves smoke inhalation-induced pulmonary inflammation and injury by inhibiting NALP3 inflammasome formation.


id: cord-006605-tsk3pakb
author: Jesmin, Subrina
date: 2006-11-30
txt: ./txt/cord-006605-tsk3pakb.txt
cache: ./cache/cord-006605-tsk3pakb.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102102/
doi: 10.1007/s10753-006-9017-8
summary:
  The hypothesis that the expression of protease-activated receptors (PARs) protein is regulated at the level of transcription and that PAR isoforms, PAR-1, PAR-2, PAR-3, and PAR-4, in lung tissue show different patterns of expression in lipopolysaccharide (LPS)-induced acute lung injury (ALI) was tested. LPS administration induced significant increases in the expression of PAR isoforms (protein) at the level of transcription in ALI. We conclude that LPS induces increase in protein expression of PAR isoforms at the level of transcription in rats with ALI. Here, we also found that LPS induces increases in the protein expression of PARs isoforms 1 to 4 in the lung of rats. While our previous study demonstrated the immunolocalization of PAR-1 in these cells and tissues in LPS-treated rabbits, the present study showed strong immunoreactivities for all isoforms of PARs in the endothelium, alveolar epithelium, and lung macrophages using a rat model of ALI [10] .

title:
  Differential Expression, Time Course and Distribution of Four PARs in Rats with Endotoxin-induced Acute Lung Injury

abstract:
  The hypothesis that the expression of protease-activated receptors (PARs) protein is regulated at the level of transcription and that PAR isoforms, PAR-1, PAR-2, PAR-3, and PAR-4, in lung tissue show different patterns of expression in lipopolysaccharide (LPS)-induced acute lung injury (ALI) was tested. Male Wistar rats were rendered endotoxemic by intra-peritoneal injection of LPS (15 mg/kg body weight). We examined the expression of protein and mRNA and the immunohistochemical localization of PAR isoforms in lung tissues 1, 3, 6, and 10 h after LPS administration. Induction of ALI by LPS was confirmed based on histopathological changes. LPS administration induced significant increases in the expression of PAR isoforms (protein) at the level of transcription in ALI. While the time course of PAR-1 and -2 expressions were different, those of PAR-3 and -4 were almost similar. An immunohistochemical analysis showed localization of PAR isoforms in the vascular endothelium, alveolar epithelium, and alveolar macrophages. However, the cellular distribution patterns of PAR isoforms were different. We conclude that LPS induces increase in protein expression of PAR isoforms at the level of transcription in rats with ALI. The differential expression patterns (over a time course) and distribution of PAR isoforms suggests a distinct role for each isoform in the pathogenesis of LPS-induced ALI.


id: cord-006778-qnxyhmw5
author: Chen, Xuxin
date: 2017-08-12
txt: ./txt/cord-006778-qnxyhmw5.txt
cache: ./cache/cord-006778-qnxyhmw5.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102376/
doi: 10.1007/s10753-017-0639-9
summary:
  Results showed that downregulation of PALM3 improved the survival rate, attenuated lung pathological changes, alleviated pulmonary edema, lung vascular leakage and neutrophil infiltration, inhibited the production of proinflammatory cytokines and activation of nuclear factor κB and interferon β regulatory factor 3, and promoted the secretion of anti-inflammatory cytokine interleukin-10 and expression of suppressor of cytokine signaling-3 in the ALI rat model. Adult Wistar rats (n = 6 per group) were treated as described in the BMaterials and Methods^section BEstablishment of ALI Rat Model and Experimental Design.^At 24 h after LPS challenge, the right lungs were harvested and stored in liquid nitrogen for the analysis of NF-κB phospho-p65, phospho-IRF3, TLR4, MyD88, TRIF, suppressor of cytokine signaling 3 (SOCS3) protein levels and coimmunoprecipitation assay, and the left lungs were harvested for the analysis of lung wet/dry weight ratio.

title:
  Downregulation of Paralemmin-3 Ameliorates Lipopolysaccharide-Induced Acute Lung Injury in Rats by Regulating Inflammatory Response and Inhibiting Formation of TLR4/MyD88 and TLR4/TRIF Complexes

abstract:
  Previous studies have demonstrated paralemmin-3 (PALM3) participates in Toll-like receptor (TLR) signaling. This study investigated the effect of PALM3 knockdown on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and its underlying mechanisms. We constructed a recombinant adenoviral vector containing short hairpin RNA for PALM3 to knockdown PALM3 expression. A transgene-free adenoviral vector was used as a negative control. The ALI rat model was established by LPS peritoneal injection at 48-h post-transfection. Results showed that downregulation of PALM3 improved the survival rate, attenuated lung pathological changes, alleviated pulmonary edema, lung vascular leakage and neutrophil infiltration, inhibited the production of proinflammatory cytokines and activation of nuclear factor κB and interferon β regulatory factor 3, and promoted the secretion of anti-inflammatory cytokine interleukin-10 and expression of suppressor of cytokine signaling-3 in the ALI rat model. However, PALM3 knockdown had no effect on TLR4, myeloid differentiation factor 88 (MyD88), and Toll-interleukin-1 receptor domain-containing adaptor inducing interferon β (TRIF) expression. Moreover, PALM3 knockdown reduced the interaction of TLR4 with MyD88 or TRIF induced by LPS in rat lungs. Therefore, the downregulation of PALM3 protected rats from LPS-induced ALI and its mechanisms were partially associated with the modulation of inflammatory responses and inhibition of TLR4/MyD88 and TLR4/TRIF complex formation.


id: cord-007858-1ijxilpb
author: Xu, G.L.
date: 2005-04-08
txt: ./txt/cord-007858-1ijxilpb.txt
cache: ./cache/cord-007858-1ijxilpb.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125571/
doi: 10.1016/j.jep.2005.01.026
summary:
  Furthermore, pretreatment with oxymatrine significantly alleviated oleic acid-induced lung injury accompanied by reduction of lung index and wet-to-dry weight ratio, decreases in serum TNF-α level and inhibition of phosphorylated p38 MAPK. These findings suggest that oxymatrine has a beneficial effect on acute lung injury induced by oleic acid in mice and may inhibit the production of proinflammatory cytokine, TNF-α, by means of the inhibition of p38 MAPK. Light microscopic findings in the lung at 6 h after oleic acid injection demonstrated a marked lung injury resembling those seen in lung of patients with ALI/ARDS, represented by prominent atelectasis, intraalveolar and interstitial patchy hemorrhage, edema, thickened alveolar septum, formation of hyaline membranes and the existence of inflammatory cells in alveolar spaces (Fig. 1A) , which were not observed in the control group (Fig. 1B) . Effect of oxymatrine on serum TNF-␣ level in mice with lung injury induced by oleic acid.

title:
  Attenuation of acute lung injury in mice by oxymatrine is associated with inhibition of phosphorylated p38 mitogen-activated protein kinase

abstract:
  Oxymatrine is one of the alkaloids extracted from Chinese herb Sophora japonica (Sophora flavescens Ait.) with activities of anti-inflammation, inhibiting immune reaction, antivirus, protecting hepatocytes and antihepatic fibrosis. However, the effect of oxymatrine on acute lung injury (ALI) has not been known yet. In this study, the effect of oxymatrine on ALI was investigated using an oleic acid-induced ALI mouse model. Morphological findings showed that the oleic acid group demonstrated a marked lung injury represented by prominent atelectasis, intraalveolar and interstitial patchy hemorrhage, edema, thickened alveolar septum, formation of hyaline membranes and the existence of inflammatory cells in alveolar spaces. While in the oxymatrine/dexamethasone group, these changes were less severe and in the vicinity of the control group. Furthermore, pretreatment with oxymatrine significantly alleviated oleic acid-induced lung injury accompanied by reduction of lung index and wet-to-dry weight ratio, decreases in serum TNF-α level and inhibition of phosphorylated p38 MAPK. These findings suggest that oxymatrine has a beneficial effect on acute lung injury induced by oleic acid in mice and may inhibit the production of proinflammatory cytokine, TNF-α, by means of the inhibition of p38 MAPK.


id: cord-010983-2bzllo0n
title: Programmed ‘disarming’ of the neutrophil proteome reduces the magnitude of inflammation
author: Adrover, Jose M.
date: 2020-01-13
txt: ./txt/cord-010983-2bzllo0n.txt
cache: ./cache/cord-010983-2bzllo0n.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223223/
doi: 10.1038/s41590-019-0571-2
summary:
  MRP8 CRE Arntl fl/fl mice, which have a neutrophil-specific deletion of Arntl (which encodes Bmal1, referred hereafter as Bmal1 ΔN ) showed no circadian differences in MPO + granule content between ZT5 and ZT13 (Extended Data Fig. 4a ) and NET formation (Extended Data Fig. 4b ) in blood Ly6G + neutrophils compared to neutrophils from wild-type controls, suggesting that Bmal1 controlled the changes in the neutrophil proteome. Proteome analysis in Ly6G + neutrophils purified at ZT5 (day) or ZT13 (night) from the blood of Bmal1 ΔN mice (Extended Data Fig. 4c and Supplementary Table 5) indicated that Bmal1 ΔN neutrophils did not show circadian changes in granule proteins or in NET-associated proteins (Extended Data Fig. 4d,e) . We measured neutrophil counts in blood and performed proteomic analysis, granule content and NET-formation assays in neutrophils isolated at 8:00, 14:00 and 17:00 (Extended Data Fig. 9a ), when diurnal patterns in neutrophil number and phenotype are prominent in humans 12 , from ten healthy volunteers.

abstract:
  The antimicrobial functions of neutrophils are facilitated by a defensive armamentarium of proteins stored in granules, and by the formation of neutrophil extracellular traps (NETs). However, the toxic nature of these structures poses a threat to highly vascularized tissues, such as the lungs. Here, we identified a cell-intrinsic program that modified the neutrophil proteome in the circulation and caused the progressive loss of granule content and reduction of the NET-forming capacity. This program was driven by the receptor CXCR2 and by regulators of circadian cycles. As a consequence, lungs were protected from inflammatory injury at times of day or in mouse mutants in which granule content was low. Changes in the proteome, granule content and NET formation also occurred in human neutrophils, and correlated with the incidence and severity of respiratory distress in pneumonia patients. Our findings unveil a ‘disarming’ strategy of neutrophils that depletes protein stores to reduce the magnitude of inflammation.


id: cord-012045-1cqqj84n
title: The Role of Deubiquitinating Enzymes in Acute Lung Injury and Acute Respiratory Distress Syndrome
author: Li, Tiao
date: 2020-07-08
txt: ./txt/cord-012045-1cqqj84n.txt
cache: ./cache/cord-012045-1cqqj84n.txt
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url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402294/
doi: 10.3390/ijms21144842
summary:
  IL-1R8/Sigirr [40] Suppresses lung inflammation [40] PTEN [41] Regulates cell apoptosis [41] MCL1 [42] Regulates transformation of fibroblasts [42] STAT1 [55] Regulates IFN Signaling [55] STING [56] Negatively regulates antiviral responses [56] USP-14 I-kB [31] Increases cytokine release [31] CBP [32] Lung inflammation [32] USP-15 IκBα [57] NF-κB activation [57] USP-17 HDAC2 [58] Reverses glucocorticoid resistance [58] TRAF2/TRAF3 [59] Lung inflammation [59] [92] Inhibits type I IFN signaling and antiviral response [92] POH1 pro-IL-1β [93] Negatively regulates the immune response [93] BRCC3 NLRP3 [94] Promotes the inflammasome activation [94] STAMBP NALP7 [95] Reduces pro-inflammatory stress [95] Alveolar residential macrophages are central to the development of the inflammatory response by recruiting neutrophils and circulating macrophages to the site of injury, their functions are modulated by deubiquitinating enzymes [96, 97] .

abstract:
  Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are characterized by an inflammatory response, alveolar edema, and hypoxemia. ARDS occurs most often in the settings of pneumonia, sepsis, aspiration of gastric contents, or severe trauma. The prevalence of ARDS is approximately 10% in patients of intensive care. There is no effective remedy with mortality high at 30–40%. Most functional proteins are dynamic and stringently governed by ubiquitin proteasomal degradation. Protein ubiquitination is reversible, the covalently attached monoubiquitin or polyubiquitin moieties within the targeted protein can be removed by a group of enzymes called deubiquitinating enzymes (DUBs). Deubiquitination plays an important role in the pathobiology of ALI/ARDS as it regulates proteins critical in engagement of the alveolo-capillary barrier and in the inflammatory response. In this review, we provide an overview of how DUBs emerge in pathogen-induced pulmonary inflammation and related aspects in ALI/ARDS. Better understanding of deubiquitination-relatedsignaling may lead to novel therapeutic approaches by targeting specific elements of the deubiquitination pathways.


id: cord-014996-p6q0f37c
title: Posters_Monday_12 October 2009
author: nan
date: 2009-08-06
txt: ./txt/cord-014996-p6q0f37c.txt
cache: ./cache/cord-014996-p6q0f37c.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094934/
doi: 10.1007/s00134-009-1593-2
abstract: nan
summary:
  Data recorded on admission were the patient demographics with, acute physiology and chronic health evaluation II score (APACHE II), and type of admission; during intensive care stay, sepsis-related organ failure assessment score (SOFA) and clinical concomitant factors and conditions. For each severe septic patient the following data was registered: time delay, APACHE II and SOFA scores at ICU admission, diagnosis, the rate of compliance with the resucitation and management bundles, microbiological data, evolution of levels of serum lactate, empiric antibiotic therapy, length of stay and mortality in ICU. Sepsis and septic shock remain the most important causes of acute kidney injury (AKI) in critically ill patients and account for more than 50% of cases of acute renal failure (ARF) in intensive care units (ICU). There were no significant differences between the demographic data (sex, age) or the data on admission to intensive care (APACHE II score, ratio of medical to surgical patients) and duration of mechanical ventilation between the two groups.


id: cord-015384-bz7ui5a0
author: Hans-Peter, Kapfhammer
date: 2008-11-27
txt: ./txt/cord-015384-bz7ui5a0.txt
cache: ./cache/cord-015384-bz7ui5a0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104133/
doi: 10.1007/s11800-008-0129-x
summary:
  From a perspective of C/L psychiatry persisting cognitive dysfunctions, anxiety and mood disorders, posttraumatic stress disorders (PTSD) in their negative impact on healthIn the etiopathogenesis of PTSD associated with ALI/ ARDS, many influences have to be discussed, e.g., increases in CO 2 triggering panic affects, a mismatch of norepinephric overstimulation and cortisol insufficiency, negative effects of high doses of benzodiazepines resulting in oversedation, prolonged phases of weaning and more frequent states of delirium. Social support during intensive care unit stay might improve mental impairment and consequently health-related quality of life in survivors of severe acute respiratory distress syndrome Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: A prospective cohort study Post-traumatic stress disorder and posttraumatic stress symptoms following critical illness in medical intensive care unit patients: Assessing the magnitude of the problem Health-related quality of life and posttrauamtic stress disorder in survivors of the acute respiratory distress syndrome

title:
  Posttraumatic stress disorder in survivors of acute respiratory distress syndrome (ARDS) and septic shock

abstract:
  Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) define medical conditions of acute respiratory insufficiency deriving from direct and indirect damage of the alveolar parenchyma and often associated with multiorgan dysfunction (MODS). As a rule, intensive care is based on mechanical ventilation often requiring high doses of sedatives and narcotics. Despite major progress in intensive care medicine the rate of mortality is still very high. Whereas in the past the level of medical progress has been rated based on the mortality rate alone, the many negative somatic and psychological sequelae in long-term-survivors of ARDS are only now being appreciated. From a perspective of C/L psychiatry persisting cognitive dysfunctions, anxiety and mood disorders, posttraumatic stress disorders (PTSD) in their negative impact on health-related quality of life are intensively investigated. In the etiopathogenesis of PTSD associated with ALI/ARDS, many influences have to be discussed, e.g., increases in CO(2) triggering panic affects, a mismatch of norepinephric overstimulation and cortisol insufficiency, negative effects of high doses of benzodiazepines resulting in oversedation, prolonged phases of weaning and more frequent states of delirium. Consolidation and retrieval of traumatic memories of the ICU stay are influenced by complex factors. From a clinical point of view prophylactic stress doses of hydrocortisone may reduce the major risk of PTSD associated with ALI / ARDS.


id: cord-016142-7j5cdt1b
author: Chiang, Eddie T.
date: 2010-06-28
txt: ./txt/cord-016142-7j5cdt1b.txt
cache: ./cache/cord-016142-7j5cdt1b.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7120335/
doi: 10.1007/978-0-387-87429-6_12
summary:
  In this chapter, we will (1) address the role of cytoskeletal rearrangement in mechanistic regulation of pulmonary vascular barrier function and permeability, (2) define current strategies designed to enhance the integrity of the lung vascular endothelium, and (3) identify vascular biomarkers and potential prognostic determinants of acute inflammation. Phosphorylation of the substrate myosin light chain (MLC) by nmMLCK is central to paracellular gap formation and increased permeability by many edemagenic agents, including thrombin [18] and vascular endothelial growth factor (VEGF) [19] , both in vitro and in preclinical models of inflammatory lung injury. Protein kinase C (PKC)-mediated pathways exert a prominent effect on barrier regulation in a time-and speciesspecific manner without significantly increasing MLC phosphorylation and without inducing formation of actin stress fibers, but with alterations in other components of the endothelial cytoskeleton [18, 83, 84] .

title:
  Acute Lung Injury: The Injured Lung Endothelium, Therapeutic Strategies for Barrier Protection, and Vascular Biomarkers

abstract:
  The vascular endothelium can be considered as an organ/tissue which comprises a monolayer of endothelial cells which serve as a semipermeable cellular barrier separating the inner space of blood vessels from its surrounding tissue and to control the exchange of fluids and cells between the two compartments. Since the pulmonary circulation receives the entire cardiac output, the large surface area of the lung microvasculature is well suited for sensing mechanical, chemical, and cellular injury by inhaled or circulating substances. This endothelial barrier is dynamically regulated through exposure to these various stimuli of physiological and pathological origin and serves to regulate multiple key biological processes (including lung fluid balance and solute transport between vascular compartments). For example, an increase in vascular permeability is a necessary feature of the body’s defense mechanism to provide injured tissues with access to leucocytes, resulting in tissue edema due to fluid extravasation. However, during conditions of intense lung inflammation such as observed in acute lung injury or its severer form of acute respiratory distress syndrome, the large surface area becomes a liability and provides the opportunity for profound vascular permeability resulting in massive fluid accumulation in the alveolar space and progressively leading to pulmonary failure. Alterations in vascular permeability occur not only in acute inflammatory lung disorders primarily caused by sepsis, pneumonia, and trauma which result in high rates of patient morbidity and mortality, but are an attractive target for therapeutic intervention in subacute lung inflammatory disorders such as ischemia–reperfusion injury, radiation lung injury, and asthma. Thus, understanding the mechanisms of endothelial barrier dysfunction is vital for the management and treatment of key and enigmatic pulmonary disorders.


id: cord-017107-sg8n12hs
title: Epidemiology of Acute Respiratory Failure and Mechanical Ventilation
author: Suri, H. S.
date: 2008
txt: ./txt/cord-017107-sg8n12hs.txt
cache: ./cache/cord-017107-sg8n12hs.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7121586/
doi: 10.1007/978-0-387-77383-4_18
summary:
  A recently completed, retrospective, community cohort study in Olmsted County, Minnesota included patients treated with NIV and found an even higher incidence of ALI, 156 per 100,000 person-years (personal communication, Rodrigo Cartin -Ceba), Mortality from ALI varies greatly depending upon the age of the patient, underlying chronic illnesses, ALI risk factors, and non-pulmonary organ dysfunctions [15] . In an international cohort study [4] , acute exacerbation of COPD was a principal indication for initiating mechanical ventilation in 13 % of patients with acute respiratory failure. The majority of patients with interstitial lung disease and acute respiratory failure admitted to the ICU require invasive mechanical ventilation . In a retrospective review [39] of 75 patients with interstitial lung disease who were mechanically ventilated at Mayo Clinic from 2003 to 2005, acute respiratory failure was the most common cause of ICU admiss ion (77 %), followed by sepsis (11 %) and cardiopulmonary arrest (4 %).

abstract:
  Acute respiratory failure, and the need for mechanical ventilation, remains one of the most common reasons for admission to the intensive care unit (ICU). The burden of acute respiratory failure is high in terms of mortality and morbidity as well as the cost of its principal treatment, mechanical ventilation. Very few epidemiologic studies have evaluated the prevalence and outcome of acute respiratory failure and mechanical ventilation in general. Most of the published literature has focused on specific forms of acute respiratory failure, particularly acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In this chapter, we provide a brief review of the pathophysiology of acute respiratory failure, its definition and classification, and then present the incidence and outcomes of specific forms of acute respiratory failure from epidemiologic studies.


id: cord-017217-zjab7o2o
title: Self Assessment Questions
author: Ali, Yousaf
date: 2008-01-08
txt: ./txt/cord-017217-zjab7o2o.txt
cache: ./cache/cord-017217-zjab7o2o.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7121721/
doi: 10.1007/978-1-59745-497-1_1
abstract: nan
summary:
  A 47-year-old patient with Crohn''s disease presents for evaluation of new onset arthritis. Although the patient has not had prior thromboses she is at high risk for developing antiphospholipid antibody syndrome in view of these blood tests. A 19-year-old previously healthy student is evaluated for new onset fever, joint pain, and rash. Her lab work reveals leukocytosis with lymphocytic predominance, normal renal function, mild transaminitis, and low serum albumin. Yousaf Ali, Self Assessment Questions in Rheumatology, DOI: 10.1007/ 978-1-59745-497-1, Humana Press, a part of Springer Science + Business Media, LLC 2009 A 55-year-old female with chronic renal failure is seen for evaluation of lower extremity edema and ankle pain. This 41-year-old patient presents with a 4-year history of recurrent sinusitis in the setting of a positive P-ANCA, destructive nasopharyngeal mass, and ophthalmoplegia.The differential diagnosis includes infection with a refractory organism, such as mucormycosis or tuberculosis, malignancy, midline granuloma, or vasculitis.


id: cord-017853-mgsuwft0
title: Genomics of Acute Lung Injury and Vascular Barrier Dysfunction
author: Machado, Roberto F.
date: 2010-06-28
txt: ./txt/cord-017853-mgsuwft0.txt
cache: ./cache/cord-017853-mgsuwft0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122529/
doi: 10.1007/978-0-387-87429-6_63
summary:
  In this chapter, we utilize a systems biology approach combining cellular signaling pathway analysis with population-based association studies to review established and suspected candidate genes that contribute to dysfunction of endothelial cell barrier integrity and ALI susceptibility. Genes encoding proinflammatory cytokines, growth factors and mediators, receptors for barrier-regulatory agonists, and mechanical-stress-sensitive genes expressed in endothelium which regulate inflammatory responses also serve as attractive ALI candidate genes and are representative of the diverse but fertile areas of exploration for candidate SNPs affecting ALI susceptibility and severity. Interrogating the prospective pathways involved in endothelial permeability and correlation with these differentially expressed genes in VALI models identified the most putative ALI genes such as myosin light chain kinase (MYLK), sphingosine 1-phosphate receptor 1, cMet, and vascular endothelial growth factor (VEGF) mechanical stress [37, 38] . Role of macrophage migration inhibitory factor (MIF) in human and animal models of acute lung injury (ALI) and sepsis: association of a promoter polymorphism and increased gene expression

abstract:
  Acute lung injury (ALI) is a devastating ­syndrome of diffuse alveolar damage that develops via a variety of local and systemic insults such as sepsis, trauma, ­pneumonia, and aspiration. It is interestingly to note that only a subset of individuals exposed to potential ALI-inciting insults develop the disorder and the severity of the disease varies from complete resolution to death. In addition, ALI susceptibility and severity are also affected by ethnicity as evidenced by the higher mortality rates observed in African-American ALI patients compared with other ethnic groups in the USA. Moreover, marked differences in strain-specific ALI responses to inflammatory and injurious agents are observed in preclinical animal models. Together, these observations strongly indicate genetic components to be involved in the pathogenesis of ALI. The identification of genes contributing to ALI would potentially provide a better understanding of ALI pathobiology, yield novel biomarkers, identify individuals or populations at risk, and prove useful for the development of novel and individualized therapies. Genome-wide searches in animal models have identified a number of quantitative trait loci that associate with ALI susceptibility. In this chapter, we utilize a systems biology approach combining cellular signaling pathway analysis with population- based association studies to review established and suspected candidate genes that contribute to dysfunction of endothelial cell barrier integrity and ALI susceptibility.


id: cord-023890-z346hh2c
title: Polyunsaturated Fatty Acids and Cytokines: Their Relationship in Acute Lung Injury
author: Cotogni, Paolo
date: 2015
txt: ./txt/cord-023890-z346hh2c.txt
cache: ./cache/cord-023890-z346hh2c.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176238/
doi: 10.1007/978-1-4614-7836-2_112
summary:
  However, at present, the issue of lipid therapy in ALI/ARDS is still controversial due, at least in part, to inconclusive or contradicting results in several recent clinical trials using n-3 PUFAs. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are inflammatory diseases whose clinical severity depends on the grade of inflammatory response. The first RCT showed the ability of an enteral formula with a high n-3/n-6 PUFA ratio (1:1) to reduce pulmonary inflammation and improve clinical outcomes, i.e., better oxygenation, shorter requirement for mechanical ventilation, shorter ICU-LOS, and less incidence of new organ failure; however, no difference in mortality was observed in ARDS patients (Gadek et al. The first RCT analyzed the effect of an enteral n-3 PUFA-enriched diet in septic patients with ALI or ARDS showing that the administration of the study formula, compared to a control formula with less lipids than in the previous three studies, was associated to a shorter ICU-LOS but not to an improvement in gas exchange or in a lower incidence of novel organ failures (Grau-Carmona et al.

abstract:
  Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are inflammatory diseases whose clinical severity depends on the grade of inflammatory response. Inflammatory cytokines are key elements in the pathogenesis of ALI/ARDS, and the occurrence of an imbalance between pro- and anti-inflammatory cytokines leads to additional non-pulmonary organ dysfunction which contributes to excess mortality rates. Treatment of these patients includes nutrition support with lipids, usually soybean oil-based lipid emulsions, which are rich in omega (n)-6 polyunsaturated fatty acids (PUFAs) and deficient in n-3 PUFAs; however, too much n-6 PUFAs are detrimental due to their pro-inflammatory effects. Conversely, a large amount of experimental studies and some randomized clinical trials showed the benefits of the n-3 PUFA administration in the context of ALI because of their anti-inflammatory properties. Based on these data, several scientific societies recommended in their guidelines, with an A or B grade of recommendation, the use of n-3 PUFAs in ALI/ARDS patients. However, at present, the issue of lipid therapy in ALI/ARDS is still controversial due, at least in part, to inconclusive or contradicting results in several recent clinical trials using n-3 PUFAs.


id: cord-023928-9a1w174h
title: Genetic Predisposition to Critical Illness in the Pediatric Intensive Care Unit
author: Thomas, Neal J.
date: 2011-12-16
txt: ./txt/cord-023928-9a1w174h.txt
cache: ./cache/cord-023928-9a1w174h.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178837/
doi: 10.1007/978-0-85729-923-9_11
summary:
  authors: Thomas, Neal J.; Dahmer, Mary K.; Quasney, Michael W. Examples of the infl uence of genetic variations in proteins involved in recognition of pathogens on the severity of infections include polymorphisms in the genes coding for mannose binding Individual variability in the susceptibility to and outcome from critical care diseases has long been observed, and advances in genomic medicine now gives an opportunity to understand these differences.

abstract:
  Much progress has been made in the past decade in the understanding of the genetic contribution to the development of human disease in general, and critical care illness specifically. With the mapping of the human genome and on-going mapping of genetic polymorphisms and haplotypes in humans, the field of critical care is now in prime position to study the impact of genetics on common illnesses that affect children who require critical care, to examine how differences of the host defense response lead to variable outcomes in outwardly appearing similar disease states, and to study how genetic differences in response to therapy will help practitioners tailor therapeutic interventions to an individual child’s genetic composition. While we are still years away from true individualized medicine, we are now closer than ever to understanding why two might children respond to the same environmental insult in vastly different ways.


id: cord-029488-l11ufs6k
author: Tomita, Kengo
date: 2020-07-21
txt: ./txt/cord-029488-l11ufs6k.txt
cache: ./cache/cord-029488-l11ufs6k.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371837/
doi: 10.1007/s00210-020-01947-6
summary:
  Expression levels of VEGF were significantly reduced in lung tissues from mice with both intranasal LPS administration and cecal ligation and puncture (CLP)-induced sepsis, which may stem from decreases in non-endothelial cells-dependent VEGF production in the lungs. In support of this assumption, stimulation with LPS and interferon-γ (IFN-γ) significantly increased VEGF in human pulmonary microvascular endothelial cells (HPMECs) at mRNA and protein levels. Taken together, our results indicate that VEGF can contribute to the development of non-cardiogenic lung edema in sepsis-associated ALI due to increased VEGF secretion from pulmonary vascular endothelial cells through multiple MAPK-dependent pathways. We thus examined whether expression of VEGF in human pulmonary microvascular endothelial cells is regulated by MAPKs. When HPMEC-ST1.6R cells were treated with PD98059, an inhibitor of MAPK kinase which is an ERK1/2 upstream activator, or SB203580, which is widely used as a specific inhibitor of p38 MAPK, the LPS/IFN-γinduced increase in VEGF protein levels was strongly blocked (Fig. 4b) .

title:
  Vascular endothelial growth factor contributes to lung vascular hyperpermeability in sepsis-associated acute lung injury

abstract:
  Vascular endothelial growth factor (VEGF) is a prime regulator of vascular permeability. Acute lung injury (ALI) is characterized by high-permeability pulmonary edema in addition to refractory hypoxemia and diffuse pulmonary infiltrates. In this study, we examined whether VEGF can be implicated as a pulmonary vascular permeability factor in sepsis-associated ALI. We found that a great increase in lung vascular leak occurred in mice instilled intranasally with lipopolysaccharide (LPS), as assessed by IgM levels in bronchoalveolar lavage fluid. Treatment with the VEGF-neutralizing monoclonal antibody bevacizumab significantly reduced this hyperpermeability response, suggesting active participation of VEGF in non-cardiogenic lung edema associated with LPS-induced ALI. However, this was not solely attributable to excessive levels of intrapulmonary VEGF. Expression levels of VEGF were significantly reduced in lung tissues from mice with both intranasal LPS administration and cecal ligation and puncture (CLP)-induced sepsis, which may stem from decreases in non-endothelial cells-dependent VEGF production in the lungs. In support of this assumption, stimulation with LPS and interferon-γ (IFN-γ) significantly increased VEGF in human pulmonary microvascular endothelial cells (HPMECs) at mRNA and protein levels. Furthermore, a significant rise in plasma VEGF levels was observed in CLP-induced septic mice. The increase in VEGF released from HPMECs after LPS/IFN-γ challenge was completely blocked by either specific inhibitor of mitogen-activated protein kinase (MAPK) subgroups. Taken together, our results indicate that VEGF can contribute to the development of non-cardiogenic lung edema in sepsis-associated ALI due to increased VEGF secretion from pulmonary vascular endothelial cells through multiple MAPK-dependent pathways.


id: cord-102958-q8jamg07
author: Hahka, Taija M.
date: 2020-09-14
txt: ./txt/cord-102958-q8jamg07.txt
cache: ./cache/cord-102958-q8jamg07.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.09.14.296731
doi: 10.1101/2020.09.14.296731
summary:
  We ablated cardiopulmonary spinal afferents through either epidural T1-T4 dorsal root ganglia (DRG) application or intra-stellate ganglia delivery of a selective afferent neurotoxin, resiniferatoxin (RTX) in rats 3 days post bleomycin-induced lung injury. Our data showed that both epidural and intra-stellate ganglia injection of RTX significantly reduced plasma extravasation and reduced the level of lung pro-inflammatory cytokines providing proof of principle that cardiopulmonary spinal afferents are involved in lung pathology post ALI. Therefore, in the current study we hypothesized that ablation of lung afferent innervation (thoracic spinal) by application of an ultrapotent, selective afferent neurotoxin, resiniferatoxin (RTX) will modify the course of the pathology including lung edema and local pulmonary inflammation associated with progressive ALI. 2 1 Our data suggest that pulmonary spinal afferent ablation by intra-stellate injection of RTX reduces plasma extravasation and local pulmonary inflammation post bleomycininduced lung injury which results in improved blood gas exchange.

title:
  Resiniferatoxin (RTX) ameliorates acute respiratory distress syndrome (ARDS) in a rodent model of lung injury

abstract:
  Acute lung injury (ALI) is associated with cytokine release, pulmonary edema and in the longer term, fibrosis. A severe cytokine storm and pulmonary pathology can cause respiratory failure due to acute respiratory distress syndrome (ARDS), which is one of the major causes of mortality associated with ALI. In this study, we aimed to determine a novel neural component through cardiopulmonary spinal afferents that mediates lung pathology during ALI/ARDS. We ablated cardiopulmonary spinal afferents through either epidural T1-T4 dorsal root ganglia (DRG) application or intra-stellate ganglia delivery of a selective afferent neurotoxin, resiniferatoxin (RTX) in rats 3 days post bleomycin-induced lung injury. Our data showed that both epidural and intra-stellate ganglia injection of RTX significantly reduced plasma extravasation and reduced the level of lung pro-inflammatory cytokines providing proof of principle that cardiopulmonary spinal afferents are involved in lung pathology post ALI. Considering the translational potential of stellate ganglia delivery of RTX, we further examined the effects of stellate RTX on blood gas exchange and lung edema in the ALI rat model. Our data suggest that intra-stellate ganglia injection of RTX improved pO2 and blood acidosis 7 days post ALI. It also reduced wet lung weight in bleomycin treated rats, indicating a reduction in lung edema. Taken together, this study suggests that cardiopulmonary spinal afferents play a critical role in lung inflammation and edema post ALI. This study shows the translational potential for ganglionic administration of RTX in ARDS.


id: cord-103496-8tq78p2z
author: Wang, Ting
date: 2020-11-13
txt: ./txt/cord-103496-8tq78p2z.txt
cache: ./cache/cord-103496-8tq78p2z.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S221323172030999X
doi: 10.1016/j.redox.2020.101794
summary:
  title: RAC1 nitration at Y32 IS involved in the endothelial barrier disruption associated with lipopolysaccharide-mediated acute lung injury Using a molecular modeling approach, we designed a nitration shielding peptide for Rac1, designated NipR2 (nitration inhibitor peptide for the Rho GTPases 2), which attenuated the LPS-induced nitration of Rac1 at Y32, preserves Rac1 activity and attenuates the LPS-mediated disruption of the endothelial barrier in human lung microvascular endothelial cells (HLMVEC). Using a murine model of ALI induced by intratracheal installation of LPS we found that NipR2 successfully prevented Rac1 nitration and Rac1 inhibition, and more importantly attenuated pulmonary inflammation, reduced lung injury and prevented the loss of lung function. We anticipate that a successful clinical efficacy of NipR2 or similar product might require: 1) precision medicine approach to identify patients in the sub-group with satisfactory responsiveness of Rac1 nitration blockade, as not all triggers of ALI (e.g., trauma) will lead to endothelial oxidative stress and peroxynitrite generation; 2) combination therapy with other effective reagents, including suppressor of the cytokine storm and/or neutrophil eliminators; 3)

title:
  RAC1 nitration at Y32 IS involved in the endothelial barrier disruption associated with lipopolysaccharide-mediated acute lung injury

abstract:
  Acute lung injury (ALI), a devastating illness induced by systemic inflammation e.g., sepsis or local lung inflammation e.g., COVID-19 mediated severe pneumonia, has an unacceptably high mortality and has no effective therapy. ALI is associated with increased pulmonary microvascular hyperpermeability and alveolar flooding. The small Rho GTPases, RhoA and Rac1 are central regulators of vascular permeability through cytoskeleton rearrangements. RhoA and Rac1 have opposing functional outcome: RhoA induces an endothelial contractile phenotype and barrier disruption, while Rac1 stabilizes endothelial junctions and increases barrier integrity. In ALI, RhoA activity is increased while Rac1 activity is reduced. We have shown that the activation of RhoA in lipopolysaccharide (LPS)-mediated ALI, is dependent, at least in part, on a single nitration event at tyrosine (Y)34. Thus, the purpose of this study was to determine if the inhibition of Rac1 is also dependent on its nitration. Our data show that Rac1 inhibition by LPS is associated with its nitration that mass spectrometry identified as Y32, within the switch I region adjacent to the nucleotide-binding site. Using a molecular modeling approach, we designed a nitration shielding peptide for Rac1, designated NipR2 (nitration inhibitor peptide for the Rho GTPases 2), which attenuated the LPS-induced nitration of Rac1 at Y32, preserves Rac1 activity and attenuates the LPS-mediated disruption of the endothelial barrier in human lung microvascular endothelial cells (HLMVEC). Using a murine model of ALI induced by intratracheal installation of LPS we found that NipR2 successfully prevented Rac1 nitration and Rac1 inhibition, and more importantly attenuated pulmonary inflammation, reduced lung injury and prevented the loss of lung function. Together, our data identify a new post-translational mechanism of Rac1 inhibition through its nitration at Y32. As NipR2 also reduces sepsis induced ALI in the mouse lung, we conclude that Rac1 nitration is a therapeutic target in ALI.


id: cord-255440-ls1l2mlg
title: Adult Stem Cell-derived Complete Lung Organoid Models Emulate Lung Disease in COVID-19
author: Tindle, Courtney
date: 2020-10-18
txt: ./txt/cord-255440-ls1l2mlg.txt
cache: ./cache/cord-255440-ls1l2mlg.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33106807/
doi: 10.1101/2020.10.17.344002
summary:
  Besides the approaches described so far, there are a few more approaches used for modeling COVID-19-(i) 3D organoids from bronchospheres and tracheospheres have been established before (Hild and Jaffe, 2016; Rock et al., 2009; Tadokoro et al., 2016) and are now used in apical-out cultures for infection with SARS-COV-2 (Suzuki et al., 2020); (ii) the most common model used for drug screening is the air-liquid interphase (ALI model) in which pseudo-stratified primary bronchial or small airway epithelial cells are used to recreate the multilayered mucociliary epithelium (Mou et al., 2016; Randell et al., 2011) ; (iii) several groups have also generated 3D airway models from iPSCs or tissue-resident stem cells (Dye et al., 2015; Ghaedi et al., 2013; Konishi et al., 2016; McCauley et al., 2017; Miller et al., 2019; Wong et al., 2012) ; (iv) others have generated AT2 cells from iPSCs using closely overlapping protocols of sequential differentiation starting with definitive endoderm, anterior foregut endoderm, and distal alveolar expression (Chen et al., 2017; Gotoh et al., 2014; Huang et al., 2014; Jacob et al., 2017; Jacob et al., 2019; Yamamoto et al., 2017) .

abstract:
  SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type-II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19. Infected ALO-monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection, whereas distal alveolar differentiation (AT2→AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both. Findings validate a human lung model of COVID-19, which can be immediately utilized to investigate COVID-19 pathogenesis and vet new therapies and vaccines. GRAPHIC ABSTRACT HIGHLIGHTS Human lung organoids with mixed proximodistal epithelia are created Proximal airway cells are critical for viral infectivity Distal alveolar cells are important for emulating host response Both are required for the overzealous response in severe COVID-19 IN BRIEF An integrated stem cell-based disease modeling and computational approach demonstrate how both proximal airway epithelium is critical for SARS-CoV-2 infectivity, but distal differentiation of alveolar pneumocytes is critical for simulating the overzealous host response in fatal COVID-19.


id: cord-258087-93yfs7ve
author: Flores, Carlos
date: 2008-10-25
txt: ./txt/cord-258087-93yfs7ve.txt
cache: ./cache/cord-258087-93yfs7ve.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/cc7098
doi: 10.1186/cc7098
summary:
  CONCLUSIONS: Although the quality of association studies seems to have improved over the years, more and better designed studies, including the replication of previous findings, with larger sample sizes extended to population groups other than those of European descent, are needed for identifying firm genetic modifiers of ALI. This quality assessment of genetic association studies with positive findings in susceptibility or outcome of ALI and ARDS identified a total of 29 articles and 16 genes. ACE, angiotensin-converting enzyme; ALI, acute lung injury; ARDS, acute respiratory distress syndrome; CAP, community-acquired pneumonia; CXCL2, chemokine CXC motif ligand 2; F5, coagulation factor V; IL-6, interleukin-6; IL-10, interleukin-10; MBL2, mannose-binding lectin-2; MIF, macrophage migration inhibitory factor; MV, mechanical ventilation; MYLK, myosin light-chain kinase; NFKB1, nuclear factor kappa light polypeptide gene enhancer in B cells; NFKBIA, nuclear factor kappa light polypeptide gene enhancer in B cells inhibitor alpha; NRF2, nuclear factor erythroid-derived 2 factor; PBEF, pre-B cell-enhancing factor; PLAU, plasminogen activator urokinase; SARS, severe acute respiratory syndrome; SFTPB, surfactant pulmonaryassociated protein B; SIRS, systemic inflammatory response syndrome; SNP, single-nucleotide polymorphism; TNF, tumor necrosis factor; TR, tandem repeat (polymorphism); VEGF, vascular endothelial growth factor. Positive genetic association studies with acute lung injury/acute respiratory distress syndrome susceptibility and/or outcome (by year of publication)

title:
  A quality assessment of genetic association studies supporting susceptibility and outcome in acute lung injury

abstract:
  INTRODUCTION: Clinical observations and animal models provide evidence that the development of acute lung injury (ALI), a phenomenon of acute diffuse lung inflammation in critically ill patients, is influenced by genetic factors. Association studies are the main tool for exploring common genetic variations underlying ALI susceptibility and/or outcome. We aimed to assess the quality of positive genetic association studies with ALI susceptibility and/or outcome in adults in order to highlight their consistency and major limitations. METHODS: We conducted a broad PubMed literature search from 1996 to June 2008 for original articles in English supporting a positive association (P ≤ 0.05) of genetic variants contributing to all-cause ALI susceptibility and/or outcome. Studies were evaluated based on current recommendations using a 10-point quality scoring system derived from 14 criteria, and the gene was considered as the unit of replication. Genes were also categorized according to biological processes using the Gene Ontology. RESULTS: Our search identified a total of 29 studies reporting positive findings for 16 genes involved mainly in the response to external stimulus and cell signal transduction. The genes encoding for interleukin-6, mannose-binding lectin, surfactant protein B, and angiotensin-converting enzyme were the most replicated across the studies. On average, the studies had an intermediate quality score (median of 4.62 and interquartile range of 3.33 to 6.15). CONCLUSIONS: Although the quality of association studies seems to have improved over the years, more and better designed studies, including the replication of previous findings, with larger sample sizes extended to population groups other than those of European descent, are needed for identifying firm genetic modifiers of ALI.


id: cord-282336-zvc04s39
author: Choudhary, Ishita
date: 2020-09-02
txt: ./txt/cord-282336-zvc04s39.txt
cache: ./cache/cord-282336-zvc04s39.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.02164
doi: 10.3389/fimmu.2020.02164
summary:
  In contrast, the lung injury in LPS-challenged TTP KO mice was characterized by severe consolidation (>90% of total area of lung section) (Figures 1F,G) that included infiltration of neutrophils, edema, fibrin, and airspace hemorrhage within the airway and alveolar lumen, multifocal loss of bronchiolar epithelium with infiltration of neutrophils and red blood cells within the bronchiolar lumen, and moderate to severe perivascular edema and inflammation (Figures 1F-H) . To determine the cell-specific role of TTP levels in ALI, we modulated TTP levels in hematopoietic progenitor cells (HPCs) and non-HPCs. In order to test whether donor HPCs repopulate the recipient mouse lungs, we first made bone marrow chimeras in which total body irradiated WT mice were transplanted with HPCs from a mouse expressing green fluorescent protein (GFP) in their somatic cells.

title:
  Tristetraprolin Overexpression in Non-hematopoietic Cells Protects Against Acute Lung Injury in Mice

abstract:
  Tristetraprolin (TTP) is a mRNA binding protein that binds to adenylate-uridylate-rich elements within the 3′ untranslated regions of certain transcripts, such as tumor necrosis factor (Tnf) mRNA, and increases their rate of decay. Modulation of TTP expression is implicated in inflammation; however, its role in acute lung inflammation remains unknown. Accordingly, we tested the role of TTP in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. LPS-challenged TTP-knockout (TTP(KO)) mice, as well as myeloid cell-specific TTP-deficient (TTP(myeKO)) mice, exhibited significant increases in lung injury, although these responses were more robust in the TTP(KO). Mice with systemic overexpression of TTP (TTP(ΔARE)) were protected from ALI, as indicated by significantly reduced neutrophilic infiltration, reduced levels of neutrophil chemoattractants, and histological parameters of ALI. Interestingly, while irradiated wild-type (WT) mice reconstituted with TTP(KO) hematopoietic progenitor cells (HPCs) showed exaggerated ALI, their reconstitution with the TTP(ΔARE) HPCs mitigated ALI. The reconstitution of irradiated TTP(ΔARE) mice with HPCs from either WT or TTP(ΔARE) donors conferred significant protection against ALI. In contrast, irradiated TTP(ΔARE) mice reconstituted with TTP(KO) HPCs had exaggerated ALI, but the response was milder as compared to WT recipients that received TTP(KO) HPCs. Finally, the reconstitution of irradiated TTP(KO) recipient mice with TTP(ΔARE) HPCs did not confer any protection to the TTP(KO) mice. These data together suggest that non-HPCs-specific overexpression of TTP within the lungs protects against ALI via downregulation of neutrophil chemoattractants and reduction in neutrophilic infiltration.


id: cord-284332-p4c1fneh
author: Bosma, Karen J.
date: 2012-09-19
txt: ./txt/cord-284332-p4c1fneh.txt
cache: ./cache/cord-284332-p4c1fneh.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/20568833/
doi: 10.2165/10898570-000000000-00000
summary:
  [47] Although both of these studies were conducted prior to the 1994 AECC definition, ARDS was strictly defined in the aforementioned studies, including a PaO 2 /FiO 2 ratio <150 or intrapulmonary shunt >20% in patients requiring mechanical ventilation and who had diffuse infiltrates on chest radiograph without clinical evidence of heart failure as pulmonary arterial occlusion pressures were <18 mmHg. Building on the results of these two studies, Sinuff and colleagues [48] developed practice guidelines for prophylactic ketoconazole use, and tested the implementation and efficacy of these guidelines in two ICUs (one control and one active comparator). [119] A phase II study enrolling 98 patients with ALI compared an antioxidant enteral feeding formula containing eicosapentaenoic acid, g-linolenic acid and antioxidant vitamins with placebo, and observed improved oxygenation, reduced pulmonary inflammation, fewer days of mechanical ventilation and fewer non-pulmonary organ failures in the treatment arm, although there was no difference in mortality between this approach and the control group.

title:
  Pharmacotherapy for Prevention and Treatment of Acute Respiratory Distress Syndrome: Current and Experimental Approaches

abstract:
  The acute respiratory distress syndrome (ARDS) arises from direct and indirect injury to the lungs and results in a life-threatening form of respiratory failure in a heterogeneous, critically ill patient population. Critical care technologies used to support patients with ARDS, including strategies for mechanical ventilation, have resulted in improved outcomes in the last decade. However, there is still a need for effective pharmacotherapies to treat ARDS, as mortality rates remain high. To date, no single pharmacotherapy has proven effective in decreasing mortality in adult patients with ARDS, although exogenous surfactant replacement has been shown to reduce mortality in the paediatric population with ARDS from direct causes. Several promising therapies are currently being investigated in preclinical and clinical trials for treatment of ARDS in its acute and subacute, exudative phases. These include exogenous surfactant therapy, β(2)-adrenergic receptor agonists, antioxidants, immunomodulating agents and HMG-CoA reductase inhibitors (statins). Recent research has also focused on prevention of acute lung injury and acute respiratory distress in patients at risk. Drugs such as captopril, rosiglitazone and incyclinide (COL-3), a tetracycline derivative, have shown promising results in animal models, but have not yet been tested clinically. Further research is needed to discover therapies to treat ARDS in its late, fibroproliferative phase. Given the vast number of negative clinical trials to date, it is unlikely that a single pharmacotherapy will effectively treat all patients with ARDS from differing causes. Future randomized controlled trials should target specific, more homogeneous subgroups of patients for single or combination therapy.


id: cord-291076-p350i54m
title: The role of C5a in acute lung injury induced by highly pathogenic viral infections
author: Wang, Renxi
date: 2015-05-06
txt: ./txt/cord-291076-p350i54m.txt
cache: ./cache/cord-291076-p350i54m.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/emi.2015.28
doi: 10.1038/emi.2015.28
summary:
  Unregulated complement activation is likely to play a crucial role in the pathogenesis of acute lung injury (ALI) induced by highly pathogenic virus including influenza A viruses H5N1, H7N9, and severe acute respiratory syndrome (SARS) coronavirus. [1] [2] [3] In addition, the complement system has been implicated in the development of acute lung diseases induced by highly pathogenic viruses including influenza A virus H1N1, 4 H5N1, 5 H7N9, 6 severe acute respiratory syndrome coronavirus (SARS-Cov), 7 Middle East respiratory syndrome coronavirus (MERS-Cov). C5a-mediated release of reactive oxygen species C5a is a strong chemoattractant for neutrophils and monocytes; it then activates these cells to generate oxidative burst with release of 10 A study demonstrated that ROS are primary pathogenic molecules in pneumonia from mice infected with influenza virus. Inhibition of Complement Activation Alleviates Acute Lung Injury Induced by Highly Pathogenic Avian Influenza H5N1 Virus Infection

abstract:
  The complement system, an important part of innate immunity, plays a critical role in pathogen clearance. Unregulated complement activation is likely to play a crucial role in the pathogenesis of acute lung injury (ALI) induced by highly pathogenic virus including influenza A viruses H5N1, H7N9, and severe acute respiratory syndrome (SARS) coronavirus. In highly pathogenic virus-induced acute lung diseases, high levels of chemotactic and anaphylatoxic C5a were produced as a result of excessive complement activaiton. Overproduced C5a displays powerful biological activities in activation of phagocytic cells, generation of oxidants, and inflammatory sequelae named “cytokine storm”, and so on. Blockade of C5a signaling have been implicated in the treatment of ALI induced by highly pathogenic virus. Herein, we review the literature that links C5a and ALI, and review our understanding of the mechanisms by which C5a affects ALI during highly pathogenic viral infection. In particular, we discuss the potential of the blockade of C5a signaling to treat ALI induced by highly pathogenic viruses.


id: cord-305173-95o5z685
title: A TRIFfic Perspective on Acute Lung Injury
author: Martin, Thomas R.
date: 2008-04-18
txt: ./txt/cord-305173-95o5z685.txt
cache: ./cache/cord-305173-95o5z685.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0092867408004546
doi: 10.1016/j.cell.2008.04.006
summary:
  In the complex inflammatory response initiated by HCl in the lungs, one might expect that TLR4 would be activated by several different endogenous stimuli; however, mice lacking TLR4, TRIF, or TRAF6 all resisted HClas well as OxPAPC-induced inflammation, supporting a role for OxPAPC as an important stimulus of TLR4 activation in this model. As in the HCl injury model, immunohistochemical analysis identified OxPAPC in the lungs, but mice lacking TLR4 or TRIF had lung inflammation that was much less severe. Mice lacking the Ncf1 protein, which lack an active NADPH oxidase complex, were protected from viral lung inflammation and did not form OxPAPC in the airspaces, further supporting a key role for oxidation of phospholipids in the pathogenic pathway. OxPAPC activates TLR4 expressed by myeloid cells (an alveolar macrophage is shown), and the intracellular signal is transduced by the adaptor proteins TRIF and TRAF6, leading to interleukin 6 (IL-6) production, inflammation, and alveolar damage.

abstract:
  Acute lung injury (ALI) is a leading cause of death in people infected with H5N1 avian influenza virus or the SARS-coronavirus. Imai et al. (2008) now report that ALI is triggered by the signaling of oxidized phospholipids through Toll-like receptor 4 (TLR4) and the adaptor protein TRIF. These findings provide insight into the molecular pathogenesis of ALI, a condition for which treatment options are currently very limited.


id: cord-306835-juitltpi
title: Curcumin (a constituent of turmeric): New treatment option against COVID‐19
author: Babaei, Fatemeh
date: 2020-09-06
txt: ./txt/cord-306835-juitltpi.txt
cache: ./cache/cord-306835-juitltpi.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33133525/
doi: 10.1002/fsn3.1858
summary:
  The keywords used for the search were as follows: coronavirus-19, COVID-19, SARS-CoV-2, curcumin, Curcuma longa, turmeric, curcumin and antiviral, curcumin and anti-inflammatory, curcumin and antipyretic, curcumin and lung, curcumin and acute lung injury, curcumin and fatigue, curcumin and antioxidant, curcumin and ARDS, curcumin and bradykinin, curcumin and fibrosis, curcumin and Interleukin-6 (IL-6), curcumin and tumor necrosis factor-alpha (TNF-α), curcumin and NF-κB, curcumin and Toll-like receptors (TLRs), curcumin and antiapoptotic. AA: arachidonic acid, ALI: acute lung injury, AP-1: activator protein 1, BK: bradykinin, ACE2: angiotensin-converting enzyme 2, Ang II: angiotensin II, ARDS: acute respiratory distress syndrome, Cas-3: caspase 3, COX: cyclooxygenase, CXCL: chemokine (C-X-C motif) ligand, 12-HPETE: 12-hydroperoxyeicosatetraenoic acid, JNK: c-Jun N-terminal kinase, 12 LOX: 12-lipoxygenase, MMP: matrix metalloproteinase NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, MAPK: mitogen-activated protein kinase, PAI-1: plasminogen activator inhibitor-1, PLA2: phospholipase A2, PG: prostaglandin, SMAD3: mothers against decapentaplegic homolog 3, TGF-β1: transforming growth factor-beta 1, TNF-α: tumor necrosis factor-α, TLR: Toll-like receptor, TRPA1: transient receptor potential channel subfamily vanilloid member 1, TRPV1: transient receptor potential channel subfamily A member 1 mechanisms that curcumin may be useful to prevent or treat the ARDS.

abstract:
  In late December 2019, the outbreak of respiratory illness emerged in Wuhan, China, and spreads worldwide. World Health Organization (WHO) named this disease severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) caused by a new member of beta coronaviruses. Several medications are prescribed to patients, and some clinical trials are underway. Scientists are trying to find a specific drug against this virus. In this review, we summarize the pathogenesis, clinical features, and current treatments of coronavirus disease 2019 (COVID‐19). Then, we describe the possible therapeutic effects of curcumin and its molecular mechanism against coronavirus‐19. Curcumin, as an active constituent of Curcuma longa (turmeric), has been studied in several experimental and clinical trial studies. Curcumin has some useful clinical effects such as antiviral, antinociceptive, anti‐inflammatory, antipyretic, and antifatigue effects that could be effective to manage the symptoms of the infected patient with COVID‐19. It has several molecular mechanisms including antioxidant, antiapoptotic, and antifibrotic properties with inhibitory effects on Toll‐like receptors, NF‐κB, inflammatory cytokines and chemokines, and bradykinin. Scientific evidence suggests that curcumin could have a potential role to treat COVID‐19. Thus, the use of curcumin in the clinical trial, as a new treatment option, should be considered.


id: cord-308892-5gbjdr0u
author: Fu, Lin
date: 2020-04-06
txt: ./txt/cord-308892-5gbjdr0u.txt
cache: ./cache/cord-308892-5gbjdr0u.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.04.02.20050997
doi: 10.1101/2020.04.02.20050997
summary:
  title: Acute liver injury and its association with death risk of patients with COVID-19: a hospital-based prospective case-cohort study The aim of this study was to analyze SARS-CoV-2-induced acute liver injury (ALI), its association with death risk and prognosis after discharge. Despite of no difference on serum TBA, alkaline phosphatase and glutamyl transferase, two markers of cholestasis, were higher in critically ill patients than those of common cases. The present study aimed to analyze SARS-CoV-2-induced ALI, its association with death risk and the prognosis after discharge. The major findings of this study include: (1) ALI is more common in the critically ill COVID-19 patients; (2) Accumulating data demonstrated that SARS-CoV-2 infection caused multiple organ injuries, including myocardial dysfunction, lymphopenia and even acute renal These results provide evidence that ALI on admission is associated with the severity of COVID-19 patients.

title:
  Acute liver injury and its association with death risk of patients with COVID-19: a hospital-based prospective case-cohort study

abstract:
  Background: Coronavirus disease 2019 (COVID-19) is a newly respiratory infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) with multiple organ injuries. The aim of this study was to analyze SARS-CoV-2-induced acute liver injury (ALI), its association with death risk and prognosis after discharge. Methods: Three-hundred and fifty-five COVID-19 patients were recruited. Clinical data were collected from electronic medical records. ALI was evaluated and its prognosis was tracked. The association between ALI and death risk was analyzed. Results: Of 355 COVID-19 patients, 211 were common, 88 severe, and 51 critical ill cases, respectively. On admission, 223 (62.8%) patients were with hypoproteinemia, 151(42.5%) with cholestasis, and 101 (28.5%) with hepatocellular injury. As expected, ALI was more common in critical ill patients. By multivariate logistic regression, male, older age and lymphocyte reduction were three important independent risk factors predicting ALI among COVID-19 patients. Death risk analysis shows that fatality rate was higher among patients with hypoproteinemia than those without hypoproteinemia (RR=9.471, P<0.001). Moreover, fatality rate was higher among patients with cholestasis than those without cholestasis (RR=2.182, P<0.05). Follow-up observation found that more than one hepatic functional indexes of two-third patients remained abnormal 14 days after discharge. Conclusions: ALI at early stage elevates death risk of COVID-19 patients. SARS-CoV-2-induced ALI has not recovered completely 14 days after discharge.


id: cord-309301-ai84el0j
title: Organoid based personalized medicine: from bench to bedside
author: Li, Yaqi
date: 2020-11-02
txt: ./txt/cord-309301-ai84el0j.txt
cache: ./cache/cord-309301-ai84el0j.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13619-020-00059-z
doi: 10.1186/s13619-020-00059-z
summary:
  The mini-gut culture approach has been applied to the generation of organoids derived from the epithelial compartments of a variety of murine and human tissues of ecto-, meso-and endodermal origin, and promotes the study of stem cell biology of other tissues except for intestine. For translational research, tumorderived organoids can be used for biobanking, genetic repair and drug screening studies, both for personalized medicine (to choose the most effective treatment for a specific patient) and drug development (to test a compound library on a specific set of tumor organoids), as well as immunotherapy research similar in liver, small intestine, and colon stem cells, regardless of the large variation in cancer incidence of these organs. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell-and patient-derived tumor organoids

abstract:
  Three-dimensional cultured organoids have become a powerful in vitro research tool that preserves genetic, phenotypic and behavioral trait of in vivo organs, which can be established from both pluripotent stem cells and adult stem cells. Organoids derived from adult stem cells can be established directly from diseased epithelium and matched normal tissues, and organoids can also be genetically manipulated by CRISPR-Cas9 technology. Applications of organoids in basic research involve the modeling of human development and diseases, including genetic, infectious and malignant diseases. Importantly, accumulating evidence suggests that biobanks of patient-derived organoids for many cancers and cystic fibrosis have great value for drug development and personalized medicine. In addition, organoids hold promise for regenerative medicine. In the present review, we discuss the applications of organoids in the basic and translational research.


id: cord-313091-ksrxsdpp
title: Wild-type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry
author: Shirato, Kazuya
date: 2017-12-06
txt: ./txt/cord-313091-ksrxsdpp.txt
cache: ./cache/cord-313091-ksrxsdpp.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.virol.2017.11.012
doi: 10.1016/j.virol.2017.11.012
summary:
  Studies using the ATCC isolate suggest that HCoV-229E enters cells via the late endosome using cathepsin L to cleave S protein, although it can enter cells via the cell surface or early endosome in the presence of transmembrane protease serine 2 (TMPRSS2) or trypsin (Bertram et al., 2013; Kawase et al., 2009) . In the present study, we found that field isolates of HCoV-OC43 and HCoV-HKU1 could be isolated using HBTE-ALI cell culture, and we then used these clinical isolates to assess whether the mode of virus entry found in HCoV-229E was also in play in other HCoVs. For isolation of HCoVs, nasal swabs were collected from outpatients who showed respiratory infection as a cardinal symptom when assessed at a hospital in Tokyo, Japan. To evaluate the entry routes of clinical isolates of HCoVs, viruses were inoculated onto HBTE-ALI in the presence of EST or camostat (10 μM) and the amounts virus that entered were estimated by detecting subgenomic mRNAs using real-time RT-PCR (Fig. 2) .

abstract:
  Human coronaviruses (HCoVs) enter cells via two distinct pathways: the endosomal pathway using cathepsins to activate spike protein and the cell-surface or early endosome pathway using extracellular proteases such as transmembrane protease serine 2 (TMPRSS2). We previously reported that clinical isolates of HCoV-229E preferred cell-surface TMPRSS2 to endosomal cathepsin for cell entry, and that they acquired the ability to use cathepsin L by repeated passage in cultured cells and were then able to enter cells via the endosomal pathway. Here, we show that clinical isolates of HCoV-OC43 and -HKU1 preferred the cell-surface TMRRSS2 to endosomal cathepsins for cell entry, similar to HCoV-229E. In addition, the cell-culture-adapted HCoV-OC43 lost the ability to infect and replicate in air-liquid interface cultures of human bronchial tracheal epithelial cells. These results suggest that circulating HCoVs in the field generally use cell-surface TMPRSS2 for cell entry, not endosomal cathepsins, in human airway epithelial cells.


id: cord-317993-012hx4kc
author: Movia, Dania
date: 2020-07-24
txt: ./txt/cord-317993-012hx4kc.txt
cache: ./cache/cord-317993-012hx4kc.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/ani10081259
doi: 10.3390/ani10081259
summary:
  SIMPLE SUMMARY: This commentary focuses on the methods currently available to test the efficacy and safety of new orally inhaled drugs for the treatment of uncurable respiratory diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis or lung cancer, prior to entering human experimentation. Inhalation is the preferred administration method for treating respiratory diseases [13] , as: (i) it delivers the drug directly at the site of action, resulting in a rapid therapeutic onset with considerably lower drug doses, (ii) it is painless and minimally invasive thus improving patients'' compliance, and (iii) it avoids first-pass metabolism, providing optimal pharmacokinetic conditions for drug absorption and reducing systemic side effects [14] [15] [16] . In the context of OID preclinical testing, lung organoids can be used for modeling respiratory diseases and, therefore, as a platform for screening the efficacy of inhalation therapies [115, 116] .

title:
  Preclinical Development of Orally Inhaled Drugs (OIDs)—Are Animal Models Predictive or Shall We Move Towards In Vitro Non-Animal Models?

abstract:
  SIMPLE SUMMARY: This commentary focuses on the methods currently available to test the efficacy and safety of new orally inhaled drugs for the treatment of uncurable respiratory diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis or lung cancer, prior to entering human experimentation. The key question that the authors try to address in this manuscript is whether there is value in using and refining current animal models for this pre-clinical testing, or whether these should be relinquished in favor of new, more human-relevant non-animal methods. ABSTRACT: Respiratory diseases constitute a huge burden in our society, and the global respiratory drug market currently grows at an annual rate between 4% and 6%. Inhalation is the preferred administration method for treating respiratory diseases, as it: (i) delivers the drug directly at the site of action, resulting in a rapid onset; (ii) is painless, thus improving patients’ compliance; and (iii) avoids first-pass metabolism reducing systemic side effects. Inhalation occurs through the mouth, with the drug generally exerting its therapeutic action in the lungs. In the most recent years, orally inhaled drugs (OIDs) have found application also in the treatment of systemic diseases. OIDs development, however, currently suffers of an overall attrition rate of around 70%, meaning that seven out of 10 new drug candidates fail to reach the clinic. Our commentary focuses on the reasons behind the poor OIDs translation into clinical products for the treatment of respiratory and systemic diseases, with particular emphasis on the parameters affecting the predictive value of animal preclinical tests. We then review the current advances in overcoming the limitation of animal animal-based studies through the development and adoption of in vitro, cell-based new approach methodologies (NAMs).


id: cord-319936-5uze06rp
title: A phase 1 trial of nebulised heparin in acute lung injury
author: Dixon, Barry
date: 2008-05-06
txt: ./txt/cord-319936-5uze06rp.txt
cache: ./cache/cord-319936-5uze06rp.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/cc6894
doi: 10.1186/cc6894
summary:
  INTRODUCTION: Animal studies of acute lung injury (ALI) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation. Studies in animal models of ALI have demonstrated that nebulised heparin improved the PaO 2 /FiO 2 ratio and reduced histological ALI = acute lung injury; APTT = activated partial thromboplastin time; BAL = bronchoalveolar lavage; ELISA = enzyme-linked immunosorbent assay; PaO 2 /FiO 2 = arterial oxygen partial pressure to inspired oxygen fraction ratio; PTF = prothrombin fragments; TCT = thrombin clotting time; t-PA = tissue plasminogen activator. Analysis of variance was used to compare the effect of heparin dose on the P a O 2 /F i O 2 ratio, lung compliance, the alveolar dead space fraction, the APTT, the TCT and intrapulmonary PTF and t-PA levels. We found administration of nebulised heparin to mechanically ventilated patients with ALI was feasible, was not associated with serious adverse events, and increased APTT levels at higher doses.

abstract:
  INTRODUCTION: Animal studies of acute lung injury (ALI) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation. No human studies have been undertaken to date. We assessed the feasibility, safety and potential anticoagulant effects of administration of nebulised heparin to patients with ALI. METHODS: An open label phase 1 trial of four escalating doses of nebulised heparin was performed. A total of 16 ventilated patients with ALI were studied. The first group was administered a total of 50,000 U/day, the second group 100,000 U/day, the third group 200,000 U/day and the fourth group 400,000 U/day. Assessments of lung function included the PaO(2)/FiO(2 )ratio, lung compliance and the alveolar dead space fraction. Monitoring of anticoagulation included the activated partial thromboplastin time (APTT) and the thrombin clotting time. Bronchoalveolar lavage fluid was collected and the prothrombin fragment and tissue plasminogen activator levels were assessed. Analysis of variance was used to compare the effects of dose. RESULTS: No serious adverse events occurred for any dose. The changes over time for the PaO(2)/FiO(2 )ratio, lung compliance and the alveolar dead space fraction levels were similar for all doses. A trend to increased APTT and thrombin clotting time levels was present with higher doses (P = 0.09 and P = 0.1, respectively). For the highest dose, the APTT reached 64 seconds; following cessation of nebulised heparin, the APTT fell to 39 seconds (P = 0.06). In bronchoalveolar lavage samples a trend to reduced prothrombin fragment levels was present with higher doses (P = 0.1), while tissue plasminogen activator levels were similar for all doses. CONCLUSION: Administration of nebulised heparin to mechanically ventilated patients with ALI is feasible. Nebulised heparin was not associated with any serious adverse events, and at higher doses it increased APTT levels. Larger trials are required to further investigate the safety and efficacy of nebulised heparin. In these trials due consideration must be given to systemic anticoagulant effects. TRIAL REGISTRATION: Australian Clinical trials registry ACTRN12606000388516.


id: cord-320681-b3ui95vx
title: COVID-19: Melatonin as a potential adjuvant treatment
author: Zhang, Rui
date: 2020-06-01
txt: ./txt/cord-320681-b3ui95vx.txt
cache: ./cache/cord-320681-b3ui95vx.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32217117/
doi: 10.1016/j.lfs.2020.117583
summary:
  Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology. Herein, we review the evidence indicating that melatonin will have supportive adjuvant utility in treating COVID-19 induced pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In SARS-CoV and MERS-CoV infected animal model, marked inflammatory and immune responses may activate a "cytokine storm", and apoptosis of epithelial cells and endothelial cells; subsequently, vascular leakage, abnormal T cell and macrophages responses ensue and induce ALI/ARDS or even death [13] . The amplification of the inflammatory response would promote cellular apoptosis or We postulated that lungs infected by SARS-CoV-2, and a suppressed immune response, elevated inflammation and excessive oxidation stress proceed unabated, this results in the activation of the cytokine storm.

abstract:
  Abstract This article summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis. The recent outbreak of COVID-19 has become a pandemic with tens of thousands of infected patients. Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology. This leads to a cytokine storm and subsequent progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and often death. Melatonin, a well-known anti-inflammatory and anti-oxidative molecule, is protective against ALI/ARDS caused by viral and other pathogens. Melatonin is effective in critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, which might also be beneficial for better clinical outcomes for COVID-19 patients. Notably, melatonin has a high safety profile. There is significant data showing that melatonin limits virus-related diseases and would also likely be beneficial in COVID-19 patients. Additional experiments and clinical studies are required to confirm this speculation.


id: cord-331887-kagggou1
author: liu, Chang
date: 2020-09-09
txt: ./txt/cord-331887-kagggou1.txt
cache: ./cache/cord-331887-kagggou1.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0378874120332499
doi: 10.1016/j.jep.2020.113364
summary:
  Compared with those in ALI, the expression of CXCL2, CXCL1, CXCL6, NFKBIA, IFNG, IL6, IL17A, IL17F, IL17C, MMP9 and TNFAIP3, which are involved in the IL-17 signalling pathway, were significantly decreased in the LJF group according to the qRT-PCR analyses. CONCLUSIONS: In view of the network pharmacology and RNA-Seq results, the study identified the main active ingredient and potential targets of LJF involved in protecting against ALI, which suggests directions for further research on LJF. LJF significantly inhibited CXCL2, CXCL1, CXCL6, NFKBIA, IFNG, IL6, IL17A, 290 IL17F, IL17C, MMP9, and TNFAIP3 mRNA expression in lung tissue homogenates according to 291 RNA-Seq, which indicates that the IL-17 signalling pathway is critical for treatment of 292 LPS-induced ALI with LJF (Fig.S4) . Consistent with the RNA-Seq data, the expression of CXCL2, CXCL1, CXCL6, 295 NFKBIA, IFNG, IL6, IL17A, IL17F, IL17C, MMP9 and TNFAIP3 in lung tissue was 296 significantly decreased compared with that in the ALI and LJF groups according to the qRT-PCR 297 analyses (P<0.05) (Fig.8) .

title:
  An integrated network pharmacology and RNA-Seq approach for exploring the preventive effect of Lonicerae japonicae flos on LPS-induced acute lung injury

abstract:
  ETHNOPHARMACOLOGICAL RELEVANCE: Lonicerae japonicae flos (LJF, the dried flower bud or newly bloomed flower of Lonicera japonica Thunb.), a typical herbal medicine, targets the lung, heart and stomach meridian with the function of clearing heat and detoxication. It ameliorated inflammatory responses and protected against acute lung inflammation in animal models. Acute lung injury (ALI) is a kind of inflammatory disease in which alveolar cells are damaged. However, a network pharmacology study to thoroughly investigate the mechanisms preventing ALI has not been performed. AIM OF THE STUDY: In this study, we examined the main active ingredients in LJF and the protective effects of LJF on LPS-induced ALI in rats. MATERIALS AND METHODS: First, the main active ingredients of LJF were screened in the TCMSP database, and the ALI-associated targets were collected from the GeneCards database. Then, we used compound-target and target-pathway networks to uncover the preventive mechanisms of LJF. Furthermore, we assessed the preventive effects of LJF in an LPS-induced rat model with the RNA-Seq technique to validate the possible molecular mechanisms of the effects of LJF in the treatment of ALI. RESULTS: The network pharmacology results identified 28 main active compounds in LJF, and eight chemical components highly related to the potential targets, which were potential active compounds in LJF. In all, 94 potential targets were recognized, including IL6, TNF, PTGS2, APP, F2, and GRM5. The pathways revealed that the possible targets of LJF involved in the regulation of the IL-17 signalling pathway. Then, in vivo experiments indicated that LJF decreased the levels of proinflammatory cytokines (TNF-, IL-1, and IL-6) in serum and bronchoalveolar lavage fluid, decreased the levels of oxidative stress factors (MDA and MPO) and increased the activities of SOD and GSH-Px in lung tissue. The RNA-Seq results revealed that 7811, 775 and 3654 differentially expressed genes (DEGs) in Ctrl (control group), ALI-LJF (Lonicerae japonicae flos group) and ALI-DXSM (dexamethasone group), respectively. KEGG pathway analysis showed that the DEGs associated with immune response and inflammation signalling pathways and the IL-17 signalling pathway were significantly enriched in LJF. Compared with those in ALI, the expression of CXCL2, CXCL1, CXCL6, NFKBIA, IFNG, IL6, IL17A, IL17F, IL17C, MMP9 and TNFAIP3, which are involved in the IL-17 signalling pathway, were significantly decreased in the LJF group according to the qRT-PCR analyses. CONCLUSIONS: In view of the network pharmacology and RNA-Seq results, the study identified the main active ingredient and potential targets of LJF involved in protecting against ALI, which suggests directions for further research on LJF.


id: cord-333520-v2sb90rc
author: Gardin, Chiara
date: 2020-08-26
txt: ./txt/cord-333520-v2sb90rc.txt
cache: ./cache/cord-333520-v2sb90rc.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/jcm9092762
doi: 10.3390/jcm9092762
summary:
  Exosomes derived from mesenchymal stem cells (MSCs) are being explored for the management of a number of diseases that currently have limited or no therapeutic options, thanks to their anti-inflammatory, immunomodulatory, and pro-angiogenic properties. Next, we describe some of the most significant clinical evidence of the successful use of MSC-derived exosomes in animal models of lung and heart injuries, which might strengthen our hypothesis in terms of their utility for also treating critically ill COVID-19 patients. Recently, MSC-derived exosomes have been demonstrated to have comparable and even greater effects than cells themselves in improving inflammation and injury in a variety of pre-clinical lung disease models, including ALI/ARDS (Table 1) . From the studies discussed above, it emerged that the rationale for using MSC-derived exosomes, MVs, or EVs in ALI/ARDS is based on several processes, many of which are shared with those identified in the parent MSCs. These include immunomodulation and anti-inflammatory properties on host tissue, reduction of the permeability of alveolar epithelium and endothelium, improvement of alveolar fluid clearance, enhancement of macrophage phagocytosis, and tissue repair through direct mitochondrial transfer with host cells (Figure 2 ).

title:
  Could Mesenchymal Stem Cell-Derived Exosomes Be a Therapeutic Option for Critically Ill COVID-19 Patients?

abstract:
  Coronavirus disease 2019 (COVID-19) is a pandemic viral disease originated in Wuhan, China, in December 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The severe form of the disease is often associated with acute respiratory distress syndrome (ARDS), and most critically ill patients require mechanical ventilation and support in intensive care units. A significant portion of COVID-19 patients also develop complications of the cardiovascular system, primarily acute myocardial injury, arrhythmia, or heart failure. To date, no specific antiviral therapy is available for patients with SARS-CoV-2 infection. Exosomes derived from mesenchymal stem cells (MSCs) are being explored for the management of a number of diseases that currently have limited or no therapeutic options, thanks to their anti-inflammatory, immunomodulatory, and pro-angiogenic properties. Here, we briefly introduce the pathogenesis of SARS-CoV-2 and its implications in the heart and lungs. Next, we describe some of the most significant clinical evidence of the successful use of MSC-derived exosomes in animal models of lung and heart injuries, which might strengthen our hypothesis in terms of their utility for also treating critically ill COVID-19 patients.


id: cord-334528-xenq90xj
title: Acute lung injury and acute respiratory distress syndrome: experimental and clinical investigations
author: Chen, Hsing I
date: 2011-03-17
txt: ./txt/cord-334528-xenq90xj.txt
cache: ./cache/cord-334528-xenq90xj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/22783284/
doi: 10.3724/sp.j.1263.2011.00044
summary:
  This literature review includes a brief historical retrospective of ALI/ARDS, the neurogenic pulmonary edema due to head injury, the long-term experimental studies and clinical investigations from our laboratory, the detrimental role of NO, the risk factors, and the possible pathogenetic mechanisms as well as therapeutic regimen for ALI/ARDS. [33, 34] In addition to the aforementioned animal experimentations and clinical observations that NO production through the iNOS may be involved in the lung injury due to various causes, our research team demonstrated that endotoxemia produced in anesthetized rats by intravenous administration of lipopolysaccharide (LPS, endotoxin) provoked systemic hypotension, endothelial damage and ALI accompanied by increased plasma nitrate/nitrite and expression of iNOS mRNA, TNF α and IL-1 β . The detrimental role of inducible nitric oxide synthase in the pulmonary edema caused by hypercalcemia in conscious rats and isolated lungs

abstract:
  Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) can be associated with various disorders. Recent investigation has involved clinical studies in collaboration with clinical investigators and pathologists on the pathogenetic mechanisms of ALI or ARDS caused by various disorders. This literature review includes a brief historical retrospective of ALI/ARDS, the neurogenic pulmonary edema due to head injury, the long-term experimental studies and clinical investigations from our laboratory, the detrimental role of NO, the risk factors, and the possible pathogenetic mechanisms as well as therapeutic regimen for ALI/ARDS.


id: cord-337973-djqzgc1k
title: Long Period Modeling SARS-CoV-2 Infection of in Vitro Cultured Polarized Human Airway Epithelium
author: Hao, Siyuan
date: 2020-08-28
txt: ./txt/cord-337973-djqzgc1k.txt
cache: ./cache/cord-337973-djqzgc1k.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32869024/
doi: 10.1101/2020.08.27.271130
summary:
  title: Long Period Modeling SARS-CoV-2 Infection of in Vitro Cultured Polarized Human Airway Epithelium We also identified that SARS-CoV-2 does not infect HAE from the basolateral side, and the dominant SARS-CoV-2 permissive epithelial cells are ciliated cells and goblet cells, whereas virus replication in basal cells and club cells was not detectable. Our observation that SARS-CoV-2 was unable to infect epithelial cells from the 299 basolateral side supports that the viral entry receptor ACE2 is polarly expressed at the apical 300 side 30, 31 . We 332 determined that 1 pfu of SARS-CoV-2 in Vero-E6 cells has a particle (viral genome copy) 333 number of 820, suggesting that a load of 2.46 x 10 5 particles is required to productively infect 1 334 cm 2 of the airway epithelium, which is much higher than the small DNA virus parvovirus human 335 bocavirus 1 (HBoV1) we studied 55 .

abstract:
  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates throughout human airways. The polarized human airway epithelium (HAE) cultured at an airway-liquid interface (HAE-ALI) is an in vitro model mimicking the in vivo human mucociliary airway epithelium and supports the replication of SARS-CoV-2. However, previous studies only characterized short-period SARS-CoV-2 infection in HAE. In this study, continuously monitoring the SARS-CoV-2 infection in HAE-ALI cultures for a long period of up to 51 days revealed that SARS-CoV-2 infection was long lasting with recurrent replication peaks appearing between an interval of approximately 7-10 days, which was consistent in all the tested HAE-ALI cultures derived from 4 lung bronchi of independent donors. We also identified that SARS-CoV-2 does not infect HAE from the basolateral side, and the dominant SARS-CoV-2 permissive epithelial cells are ciliated cells and goblet cells, whereas virus replication in basal cells and club cells was not detectable. Notably, virus infection immediately damaged the HAE, which is demonstrated by dispersed Zonula occludens-1 (ZO-1) expression without clear tight junctions and partial loss of cilia. Importantly, we identified that SARS-CoV-2 productive infection of HAE requires a high viral load of 2.5 × 105 virions per cm2 of epithelium. Thus, our studies highlight the importance of a high viral load and that epithelial renewal initiates and maintains a recurrent infection of HAE with SARS-CoV-2.


id: cord-340865-sut3nf2a
title: Blockage of P2X7 attenuates acute lung injury in mice by inhibiting NLRP3 inflammasome
author: Wang, Shuang
date: 2015-04-29
txt: ./txt/cord-340865-sut3nf2a.txt
cache: ./cache/cord-340865-sut3nf2a.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S156757691500199X
doi: 10.1016/j.intimp.2015.04.035
summary:
  LPS administration increased P2X7 expression in the lung parenchyma and P2X7 −/− mice showed decreased polymorphonuclear cell infiltration, less inflammatory cytokine production and reduced collagen deposition [8] . In this study, we demonstrated that pharmacological blockade of P2X7 by using selective antagonists effectively ameliorated ALI in mice via inhibiting NLRP3 inflammasome pathway. Enhanced protein expression of P2X7, NLRP3, and ASC was observed in the lungs from LPS-induced lung injury mice compared with control mice treated by PBS (Fig. 1) . Coincident with the cell counts, the total protein level was also elevated in the LPS-induced lung injury group, which was significantly reduced by A438079 treatment (Fig. 3d) . In this study, P2X7 expression was significantly enhanced at the protein level in the lung tissues from ALI mice, paralleled with alveolar damage and inflammatory cytokine production. We found that blockage of P2X7 inhibited the activation of NLRP3 inflammasome pathway, neutrophil accumulation and production of proinflammatory cytokines, resulting in reduction of lung damage.

abstract:
  NLRP3 inflammasome is engaged in the inflammatory response during acute lung injury (ALI). Purinergic receptor P2X7 has been reported to be upstream of NLRP3 activation. However, the therapeutic implication of P2X7 in ALI remains to be explored. The present study used lipopolysaccharide (LPS)-induced mouse model to investigate the therapeutic potential of P2X7 blockage in ALI. Our results showed that P2X7/NLRP3 inflammasome pathway was significantly upregulated in the lungs of ALI mice as compared with control mice. P2X7 antagonist A438079 suppressed NLRP3/ASC/caspase 1 activation, production of IL-1β, IL-17A and IFN-γ and neutrophil infiltration but not the production of IL-10, resulting in a significant amelioration of lung injury. Moreover, blockage of P2X7 significantly inhibited NLRP3 inflammasome activation and IL-1β production in bone marrow derived macrophages. Similar results were obtained using another P2X7 inhibitor brilliant blue G (BBG) in vivo. Thus, pharmacological blockage of P2X7/NLRP3 pathway can be considered as a potential therapeutic strategy in patients with ALI.


id: cord-349201-d88g5toc
author: Yu, Feng
date: 2020-10-13
txt: ./txt/cord-349201-d88g5toc.txt
cache: ./cache/cord-349201-d88g5toc.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33049802/
doi: 10.1002/rcm.8971
summary:
  title: Exploring the biomarkers associated with different host inflammation of acute respiratory distress syndrome (ARDS) from lung metabolomics in mice RATIONALE: The aim of this study was to analyze the metabolomics of lung with different host inflammation of acute respiratory distress syndrome (ARDS) for the identification of biomarkers for predicting severity under different inflammatory conditions. RF analysis of lung-targeted metabolomics data defined a set of 15 metabolites that constitute the best predictors of differences in host inflammation status: in particular, increased 4hydroxyphenylacetic acid, 1-aminocyclopentanecarboxylic acid (ACPC), and cis-aconitic acid, Tridecane and hydroxybenzoic acid were strong predictors of the hyper-inflammatory subgroup in CLP-induced ALI ( Figure 3B ). Interestingly, RF analysis of lung-targeted metabolomics data showed that the metabolic biomarker group with 5 products was a strong predictor of the hyper-inflammatory subgroup in CLP-induced ALI ( Figure 3B ).

title:
  Exploring the biomarkers associated with different host inflammation of acute respiratory distress syndrome (ARDS) from lung metabolomics in mice

abstract:
  RATIONALE: The aim of this study was to analyze the metabolomics of lung with different host inflammation of acute respiratory distress syndrome (ARDS) for the identification of biomarkers for predicting severity under different inflammatory conditions. METHODS: Cecal ligation and puncture (CLP) and lipopolysaccharide (LPS)‐intratracheal injection induced acute lung injury (ALI). A mouse model was used to explore lung metabolomic biomarkers in ALI/ARDS. The splenectomy model was used as an auxiliary method to distinguish between hyper‐ and hypo‐inflammatory subtypes. Plasma, lung tissue and bronchoalveolar lavage fluid (BALF) samples were collected from mice after CLP/LPS. The severity of lung injury was evaluated. Expression of Tumor Necrosis Factor‐α (TNF‐α) in mice serum and lung was tested by ELISA and PCR. Polymorphonuclear cells in BALF were counted. The lung metabolites were detected by GC/MS, and the metabolic pathways predicted using the KEGG database. RESULTS: The LPS/CLP‐Splen group had more severe lung injury than the corresponding ALI group; that in the CLP‐Splen group was more serious than in the LPS‐Splen group. TNF‐α expression was significantly elevated in the serum and lung tissue after LPS or CLP, and higher in the LPS/CLP‐Splen group than in the corresponding ALI group. The level of TNF‐α in the CLP‐Splen group was elevated significantly over that in the LPS‐Splen group. Both these groups also showed significant neutrophil exudation within the lungs. During differential inflammation, more differential metabolites were detected in the lungs of the CLP‐group ALI mice than inthe LPS group. A total of 41 compounds were detected in the lungs of the CLP and CLP‐Splen groups. Contrastingly, 8 compounds were detected in the lungs of the LPS and LPS‐Splen groups. The LPS‐Splen and CLP‐Splen groups had significant neutrophil exudation in the lung. Random forest analysis of lung‐targeted metabolomics data indicated 4‐hydroxyphenylacetic acid,1‐aminocyclopentanecarboxylic acid (ACPC), cis‐aconitic acid, and hydroxybenzoic acid as strong predictors of hyper‐inflammatory subgroup in the CLP group. Furthermore, with splenectomy, 13 differential metabolic pathways between the CLP and LPS groups were revealed. CONCLUSIONS: Hyper‐inflammatory subgroups of ARDS have a greater inflammatory response and a more active lung metabolism. Combined with host inflammation background, biomarkers from metabolomics could help evaluate the response severity of ARDS.


id: cord-354829-god79qzw
author: Mao, Kaimin
date: 2020-09-23
txt: ./txt/cord-354829-god79qzw.txt
cache: ./cache/cord-354829-god79qzw.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32969837/
doi: 10.18632/aging.104042
summary:
  title: Identification of robust genetic signatures associated with lipopolysaccharide-induced acute lung injury onset and astaxanthin therapeutic effects by integrative analysis of RNA sequencing data and GEO datasets Here we performed a statistical meta-analysis of five publicly available gene expression datasets from LPS-induced ALI mouse models, conducted RNA-sequencing (RNA-seq) to screen differentially expressed genes (DEGs) in response to LPS administration and AST treatment, and integrative analysis to determine robust genetic signatures associated with LPS-induced ALI onset and AST administration. We subsequently integrated the RNA-seq and microarray meta-analysis data, and 11 core DEGs (Timp1, Ly6i, Cxcl13, Irf7, Cxcl5, Ccl7, Isg15, Saa3, Saa1, Tgtp1, and Gbp11) that were upregulated in ALI models and downregulated significantly after AST treatment were identified ( Table 2) . To further identify the robust expression signature related to LPS-induced ALI and investigate the transcriptional changes in response to the treatment of ALI by AST, we performed RNA-seq on three groups of mice and integrated the data with the results of the above mentioned meta-analysis.

title:
  Identification of robust genetic signatures associated with lipopolysaccharide-induced acute lung injury onset and astaxanthin therapeutic effects by integrative analysis of RNA sequencing data and GEO datasets

abstract:
  Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening clinical conditions predominantly arising from uncontrolled inflammatory reactions. It has been found that the administration of astaxanthin (AST) can exert protective effects against lipopolysaccharide (LPS)-induced ALI; however, the robust genetic signatures underlying LPS induction and AST treatment remain obscure. Here we performed a statistical meta-analysis of five publicly available gene expression datasets from LPS-induced ALI mouse models, conducted RNA-sequencing (RNA-seq) to screen differentially expressed genes (DEGs) in response to LPS administration and AST treatment, and integrative analysis to determine robust genetic signatures associated with LPS-induced ALI onset and AST administration. Both the meta-analyses and our experimental data identified a total of 198 DEGs in response to LPS administration, and 11 core DEGs (Timp1, Ly6i, Cxcl13, Irf7, Cxcl5, Ccl7, Isg15, Saa3, Saa1, Tgtp1, and Gbp11) were identified to be associated with AST therapeutic effects. Further, the 11 core DEGs were verified by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC), and functional enrichment analysis revealed that these genes are primarily associated with neutrophils and chemokines. Collectively, these findings unearthed the robust genetic signatures underlying LPS administration and the molecular targets of AST for ameliorating ALI/ARDS which provide directions for further research.


