key: cord-1045984-995ftf3q authors: Yamaoka-Tojo, Minako title: Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19 date: 2020-08-24 journal: Biomed J DOI: 10.1016/j.bj.2020.08.007 sha: b3e4627fd9da0f0277a342033f133c98932e5b34 doc_id: 1045984 cord_uid: 995ftf3q In atherosclerosis patients, vascular endothelial dysfunction is commonly observed alongside damage of the vascular endothelial glycocalyx, an extracellular matrix bound to and encapsulating the endothelial cells lining the blood vessel wall. Although atherosclerotic risk factors have been reported in severe patients with coronavirus disease 2019 (COVID-19), the exact mechanisms are unclear. The mortality associated with the COVID-19 outbreak is increased by comorbidities, including hypertension, diabetes, obesity, chronic obstructive pulmonary disease (COPD), and cardiovascular disease. Besides, older individuals and smokers have significantly worse outcomes. Interestingly, these comorbidities and risk factors are consistent with the pathophysiology that causes vascular endothelial glycocalyx damage. Moreover, vascular glycocalyx dysfunction causes microvascular leakage, which results in interstitial pulmonary abnormal shadows (multiple patchy shadows with a ground glass inter-pneumonic appearance). This is frequently followed by severe acute respiratory distress syndrome (ARDS), closely related to coagulo-fibrinolytic changes contributing to disseminated intravascular coagulation (DIC) and Kawasaki disease shock syndrome, as well as inducing activation of the coagulation cascade, leading to thromboembolism and multiple organ failure. Notably, SARS-CoV-2, the causative virus of COVID-19, binds to ACE2, which is abundantly present not only in human epithelia of the lung and the small intestine, but also in vascular endothelial cells and arterial smooth muscle cells. Moreover, COVID-19 can induce severe septic shock, and sepsis can easily lead to systemic degradation of the vascular endothelial glycocalyx. In the current review, we propose new concepts and therapeutic goals for COVID-19-related vascular endothelial glycocalyx damage, based on previous vascular endothelial medicine research. It has been said that scientists could win the Nobel Prize in physiology or medicine if they could invent a cure for the common cold. Since the common cold is caused by various viruses, which can easily mutate their genes, it has been extremely difficult to develop any specific medicine or vaccine for influenza infection. For this reason, following infection, individuals are advised to wait for recovery by taking coping medications for the symptoms, such as fever, cough/sputum, diarrhea, and headache, as well as getting sufficient nutrition and rest. It is known that 15% of common colds are caused by conventional human coronavirus (HCoV) infections (e.g., patients. It is known that patients with chronic obstructive pulmonary disease (COPD) are more likely to develop pneumonia as a result of COVID-19 infection. Furthermore, according to accumulating evidence, high-risk patients with critical COVID-19 are more frequently older (>65 years of age), male, obese, smokers, and have common comorbidities, such as hypertension (57%), obesity (42%), and diabetes (34%) 5 . Thus, some cardiologists speculated that a large Interestingly, these phenomena can be explained centrally with one concept: the vascular endothelial glycocalyx, an extracellular matrix bound to and encapsulating the endothelial cells lining the blood vessel wall. In the current review, previously unrevealed key components in severe 18 . In support of this, multivariable J o u r n a l P r e -p r o o f regression analysis showed increased odds of in-hospital death with old age 9 . It appears that COVID-19 is more likely to deteriorate due to an increased in comorbidities in elderly, which may lead to immune dysfunction in elderly COVID-19 patients. In other words, microvascular leakage, which acts as a window for SARS-CoV-2 organ invasion, is caused by more advanced vascular endothelial glycocalyx damage in elderly patients 19 . In addition, the vascular endothelial glycocalyx is more easily damaged in elderly people than young, and common comorbidities are known to perturbate the vascular endothelial glycocalyx 20 . The vascular endothelial glycocalyx is systemically damaged under the conditions of old age and multiple comorbidities, which may be a potent mechanism for the development of lethal complications in COVID-19 patients. (RAAS). Furthermore, ACE2 is highly expressed on failing human hearts and pericytes, which could lead to the development of microvascular 29, 30 . The vascular endothelial glycocalyx is stabilized by shear stress 31 , which is pivotal for proper nitric oxide (NO) production 32, 33 . Glycosaminoglycans are constantly degraded through enzymes, and also synthesized and extruded through vesicles of the Golgi apparatus to maintain homeostatic balance 34 . As shown in Figure 2 , homeostasis is broken down, and vascular endothelial glycocalyx shedding/degradation occurs in conditions of cellular stress, ischemia/reperfusion injury 35 65 , and heart failure 66 . In ApoE knockout mice, an inhibitor of hyaluronan synthesis, 4-metylumbelliferone (4-MU) has been shown to interfere with the protective function of the endothelial glycocalyx, thereby facilitating leukocyte adhesion, subsequent inflammation, and progression of atherosclerosis 56 . The vascular endothelial glycocalyx is crucial to endothelial function 67 , as it is involved in microvascular reactivity, and modulates the interaction between the endothelium and blood constituents 68 . In addition, the vascular endothelial glycocalyx protects endothelial cells from shear J o u r n a l P r e -p r o o f stress caused by blood flow, and serves as a vascular permeability barrier 69 . As shown in Figure permeability and contributes to interstitial edema in various organs 81, 82 . The systemic breakdown of the glycocalyx occurs dramatically in fatal disease conditions, such as severe infectious diseases, sepsis, hemorrhagic shock, burn, traumatic brain injury 83 , and traumatic endotheliopathy, a syndrome associated with high mortality 84 . severity and male hormones, or the possibility that male smokers are included to a greater extent in these studies has been investigated, although there remain no definitive conclusions. We propose that sex differences in the vascular endothelial glycocalyx could represent a crucial factor for the sex difference of COVID-19 severity and mortality. In ACS patients, it has been reported that males shed more syndecan-1 than females 65 . Circulating levels of syndecan-4 have been associated with incident myocardial infarction, and the association is stronger in women than in men 117 . These data imply either an increase in the amount of glycocalyx, a denser glycocalyx, or higher protease activity in male 1) A disintegrin and metalloprotease 17 (ADAM17) ADAM17 was initially described to specifically cleave the precursor of TNF-α (pro-TNF-α) 128 . ADAM17 activity is induced in sepsis, and leads to shedding of components of leukocytes and endothelial cell tether machinery, facilitating systemic inflammation 129 . It is already known that ADAM17 can release the ectodomains of a diverse variety of membrane-anchored cytokines, cell adhesion molecules, receptors, ligands, and enzymes. Since ADAM17 leads to shedding of membrane-bound ACE2 and release of the soluble extracellular domain of ACE2 130 , ADAM17 and other proteases to do ACE2 shedding are expected to be valid as treatments for patients with COVID-19 131 . Of relevance, ADAM17 is co-expressed with syndecan-1 and has been shown to mediate syndecan-1 shedding in lung epithelial cells, which may aggravate endothelial glycocalyx disorders 132, 133 . Thus, careful consideration should be given to an ADAM17-related therapy, which is expected to shed membrane-bound ACE2, for COVID-19 patients. Vascular endothelial glycocalyx has cardiovascular protective effects. Since it has been shown to protect against myocardial edema in a rat Numerous anti-inflammatory mediators, such as TNF-α or its receptor inhibitor (etanercept) 37 , allopurinol 38 , sphingosine-1 phosphate (S1P) 89 , and hydrocortisone, have been shown to have protective roles on the vascular endothelial glycocalyx 141 . Since these substances are expected to have anti-inflammatory and anti-oxidative effects, which impair vascular endothelial glycocalyx, they affects not only vascular endothelial cells but also vascular endothelial glycocalyx composition. 142, 143 The simplest way to achieve protection of the endothelial glycocalyx is to maintain a sufficiently high concentration of plasma proteins 20 . Indeed. the early and empiric use of fresh frozen plasma in hemodynamically unstable patients with bleeding has led to a decrease in early hemorrhagic deaths 144, 145 . Endothelial dysfunction not only leads to coagulation abnormalities, but also to inflammation and the breakdown 150 . In theory, antioxidants seem to be a therapeutic option for COVID-19; however, the results of various large-scale clinical trials to date suggest that this would be difficult to induce. The reason being that many antioxidants lose their effectiveness immediately after administration, and may affect the redox regulatory control necessary to maintain homeostasis. Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum antiviral activity in vitro, inhibits the replication of SARS-CoV-2 in vitro 151 . The previous study revealed that ivermectin is a specific inhibitor of importin α/β-mediated nuclear importable to inhibit replication of HIV and dengue virus 152 . It has already reported that ivermectin can improve the prognosis of patients with COVID-19, and ivermectin is currently considered to be one of the drugs with the highest potential. 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