key: cord-349807-ar77cnsa
authors: Rouadi, Philip W.; Idriss, Samar A.; Naclerio, Robert M.; Peden, David B.; Ansotegui, Ignacio J.; Canonica, Giorgio Walter; Gonzalez-Diaz, Sandra Nora; Rosario Filho, Nelson A.; Ivancevich, Juan Carlos; Hellings, Peter W.; Murrieta-Aguttes, Margarita; Zaitoun, Fares H.; Irani, Carla; Karam, Marilyn R.; Bousquet, Jean
title: Immunopathological features of air pollution and its impact on inflammatory airway diseases (IAD)
date: 2020-10-05
journal: World Allergy Organ J
DOI: 10.1016/j.waojou.2020.100467
sha: 
doc_id: 349807
cord_uid: ar77cnsa

Air pollution causes significant morbidity and mortality in patients with inflammatory airway diseases (IAD) such as allergic rhinitis (AR), chronic rhinosinusitis (CRS), asthma, and chronic obstructive pulmonary disease (COPD). Oxidative stress in patients with IAD can induce eosinophilic inflammation in the airways, augment atopic allergic sensitization, and increase susceptibility to infection. We reviewed emerging data depicting the involvement of oxidative stress in IAD patients. We evaluated biomarkers, outcome measures and immunopathological alterations across the airway mucosal barrier following exposure, particularly when accentuated by an infectious insult.

The presence in the air of one or more natural or anthropogenic substances at a concentration, or location, for a duration, above their natural levels with the potential to cause an adverse health effect defines air pollution. 1 Indoor air pollution refers to chemical, biological, and physical exposure of air pollutants in homes, schools, and workplaces. Similar to indoor air pollution, ambient (outdoor) air pollution can result from chemical substances or biologically derived contaminants modified by climate change or human activity such as bioaerosols and aeroallergens. Air quality guidelines endorsed by the World Health Organization (WHO) aim to provide clean air in and around the home. 2 Air pollution reduced life expectancy in 2017 by 1 year and 8 months on average worldwide. 3 WHO has linked 4.3 million deaths globally in 2012 to household cooking using coal, wood and biomass stoves. Outdoor air pollution in the same year caused an estimated 3.7 million deaths. 4 In inflammatory airway disease (IAD) patients an estimated 7-11% increased risk in asthma-related mortality was commensurate with a rise in ambient pollutant concentrations such as NO2, PM2.5, or ozone when computed few days prior to asthma death. 5 Similar but smaller increments in chronic obstructive pulmonary disease (COPD)-related mortality were attributed to pollution and ranged from 0.78% to 1.78%. 6 In the respiratory tract, air pollution can impact wellness in healthy people and patients with IAD, irrespective of their atopic status. Hence, the airway mucosal barrier may be disrupted by immunopathological mechanisms resulting from effects of pollution and IAD. The co-occurrence of IAD phenotypes (allergic rhinitis, and chronic rhinosinusitis, COPD and asthma) within an individual increases the likelihood of pollutant induced exacerbation of disease or infection.

We reviewed the following IADs in relation to air pollution. Allergic rhinitis (AR), is an IgE mediated inflammatory disease generated by a spectrum of outdoor aeroallergens like pollens or indoor aeroallergens such as dust mites, cockroaches, cat allergens, or molds. CRS represents multiple overlapping rhinosinusitis phenotypes with different endotypes. 7 Asthma is characterized by chronic atopic or non-atopic inflammation of the airway with superimposed episodes of acute exacerbations. The majority of exacerbations are triggered by respiratory viral infections, most commonly human rhinovirus. 8, 9 Other triggers include allergens and atmospheric pollutants. 10, 11 COPD, another chronic inflammatory airway disease, is characterized by airflow limitation and cough. Acute exacerbation of COPD, like in the upper airway, can be triggered by infection and inhalation of irritants. 12, 13 

Chemical pollutants are health-damaging atmospheric aerosol and non-aerosol particles originating from a variety of natural (eg, volcanic eruptions) or anthropogenic sources (eg, biomass burning, fossil fuel combustion, or traffic related particles). Primary pollutants such as particulate matter (PM) and volatile organic compounds are aerosol particles directly emitted as solid or liquid droplets in the air. In the atmosphere, natural gasto-particle conversion can culminate in secondary chemical pollutant particles like are ozone and PM. 14 

Particularte matter (PM) is a mixture of solid and liquid particles suspended in indoor and outdoor air. Their source, size, classification, and airway distribution patterns are well described. [15] [16] [17] Various human indoor activities cause resuspension and deposition of particles in indoor air, a process governed primarily by the effective size of the particle. This can range from hours for PM 10 to several months for 2-mm particulate pollutants. 18 PM 2.5 broadly represents around 50% of the total mass of PM 10 and can be inhaled more deeply into the lungs, with a portion depositing in the alveoli and entering the pulmonary and systemic circulation. 17 The submicron PM family, ultrafine particles and nanoparticles, due to their small size, have a relatively large surface area allowing a greater proportion of compounds to be displayed at the surface such as metals and organic compounds. 19, 20 They cannot be taken by macrophages and can escape phagocytosis. When retained in the lungs, the ensuing inflammation can result in asthma and lung fibrosis; 20,21 yet they can allocate to distant organs through systemic circulation resulting in different toxicological phenotypes such as diabetes and heart disease. [22] [23] [24] The adverse health effects of PM are not uniform since PM is not a single entity; rather its constituents and their proportion in ambient air can change from one geographical location to another depending on the type of emissions inherent to each area. 25 Volatile organic compounds (VOCs) and formaldehyde VOCs are primary pollutants located mainly indoors and include benzene, toluene, xylenes, terpenes, and polycyclic aromatic hydrocarbons. They produce a secondary pollutant, formaldehyde, by an indoor chemical reaction between ozone or nitrogen oxide and terpene. 26 Formaldehyde appears to be associated with a higher risk of nasopharyngeal carcinoma 27 and leukemia. 28 The primary domestic, 29-31 microbial, 32 and socio-cultural sources of VOCs 33,34 are well elaborated.

Diesel exhaust represents the most important local contributor to ambient air pollution and has been classified by WHO as carcinogenic to humans. 35 It is a complex mixture of chemicals and metals stratified into 3 fractions: a solid fraction (made of a soot of carbon core, metals, and their oxides), 36 a gaseous fraction (made of nitrogen, oxygen, and polycyclic aromatic hydrocarbons -PAHs), and a liquid fraction 37 where PAHs can adsorb into soot or water droplets. 38, 39 Ultrafine particles, nitrogen oxide, and PM (in the range of 2.5 mm) can be produced also by internal combustion of diesel engines. Metal elements include Chromium, Magnesium, Zinc, and Lead and are associated with engine emissions and abrasion of tires and brake pads. Vanadium and Nickel are tracers of long-range transport from the use of heavy fuel oil. 40 The relatively large surface area of diesel exhaust particles (DEPs) permits many of these chemicals and metals to attach to its core. Thus, most of the deleterious effects of DEPs are due to chemicals that are adsorbed onto their surface. 41 Ozone and nitrogen oxide (NOx)

To date, ozone is considered the most damaging air pollutant in terms of adverse effects on human health, vegetation, and crops. [42] [43] [44] [45] [46] [47] It produces short-and long-term effects on cardiorespiratory function. 45 Recent evidence suggests there is no threshold concentration below which there are no effects on health. Ground-level ozone is formed in the atmosphere by a complex reaction of its precursors, nitrogen oxide (NOx), carbon monoxide, and volatile organic compounds in the presence of sunlight. 48 Background ozone concentrations are strongly correlated with the increased global NOx emissions derived from human-generated fossil fuel combustion and biomass burning. 49 Tobacco smoke (TBS)

Tobaco smoke (TBS) emits a wide range of gases, aerosolized liquids, and fine particulate matter including VOC and formaldehyde, nitrogen oxide, PM2.5, and nicotine. 50,51 TBS is estimated to cause approximately 480,000 excess deaths per year, 52 and it can contribute to 30% of all cancer deaths. 53 Among other actions, TBS can induce DNA damage, 51 change in sputum (mucin) quality, and depressed antioxidant and antimicrobial activity in smokers and among COPD patients. 54, 55 Household dust Household dust represents a convenient means to sample respiratory exposure to pollutants. In one study, the respirable fraction of dust constituted less than 1% of the total weight of dust surrounding us, and on scan electron microscopy consisted of large flakes (>20 mm diameter) to which are adherent smaller particles. 56 The median aerodynamic diameter of respirable dust particles allows their deposition both in the nose and lungs. The chemical composition of these flakes suggests household dust might be an important carrier vehicle of organic pollutants into the airways in addition to its intrinsic risk of oxidative stress. 56 

Allergens can pollute indoor and outdoor air and exacerbate AR and asthma. Indoor allergenic pollutants can be derived from skin scales of pets (eg, cats, dogs), urine of rodents (eg, mice), molds, or from fecal material of arthropods such as house dust mites and cockroaches. Outdoor allergens are aeroallergens originating from grasses, trees, weeds, or molds. Outdoor pollen also modulates indoor aeroallergen concentration. The concentration of aeroallergens in the indoor environment is governed by complex bioaerosol dynamics. 57 For example, airborne cat allergen (Fel d1) is mostly associated with large particles (>9 mm), but around 1 / 4 of Fel d1 are carried on particles less than 4 micra in diameter. Thus Fel d1 can be deposited in the alveoli but most importantly suspended for several days in the air favoring distribution of the allergen in the environment. [58] [59] [60] Also, the 33 groups of mite allergens listed in the WHO nomenclature of allergens are composed of particles ranging in diameter from 10 to 40 mm. 61 Hence, they can become airborne upon disturbance and can be carried on house dust that becomes a vector for exposure. How dust mite allergen particles can induce and Volume 13, No. 10, Month 2020 trigger asthma in lower airways remains to be determined. 62 

The diversity and functioning of the normal microbiome are crucial for maintaining the health of the host. While the effects of PM on human health are well established, the impact of infectious particles on bacterial ecosystems has been overlooked.

In vitro studies suggest black carbon, a major component of PM, is strongly implicated in predisposition to respiratory infectious diseases, 25, 63 and induces structural and functional changes in the biofilms of both Streptococcus pneumonia and Staphylococcus aureus. 64 This is manifested by increase in biofilm thickness and tolerance to degradation by proteolytic enzymes, thereby promoting colonization of the respiratory tract. Similarly, evidence suggests indoor and outdoor dust modifies microbial growth, virulence, and biofilm formation of opportunistic pathogens. By exposing 3 opportunistic bacteria (Pseudomonas aeruginosa, Escherichia coli, and Enterococcus faecalis)

to progressively increasing concentrations of indoor and outdoor dust, a differential growth pattern of pathogens was noted. This was commensurate with increased biofilm formation and sensitivity to oxidative stress following hydrogen peroxide challenge. 65 Consequently, the detrimental impact of particulate pollutants on human health is not only due to direct effects on the host but also may involve the effect on bacterial behavior in the host.

Oxidative stress is a disproportionate generation of free radicals beyond the body antioxidant capacity. It translates into a non-IgE mediated Th2 airway inflammation following exposure to a pollutant. In brief, reactive oxygen species (ROS), generated naturally as by-product of cell growth and metabolism, can be produced following pollutant exposure. 66,67 ROS include oxygen radicals (eg, superoxide, hydroxyl, hydroperoxyl) and certain non-radicals (eg, H 2 O 2 , ozone, singlet oxygen) that are easily converted into radicals. 68 ROS have a pivotal role in cell signaling in the oxidation/reduction cascades following exposure and ultimately generation of anti-oxidant mechanisms thru nrf-2, activator protein 1, and nuclear factor-kappa B. [69] [70] [71] [72] Antioxidants are scavengers of ROS and can be enzymatic or non-enzymatic systems, constitutive or de novo synthesized by activated gene expression, according to ROS load. The inflammatory phase of oxidative stress involves cytokines-and chemokines-mediated activation and recruitment of inflammatory cells secondary to direct effect of pollutants on airway epithelial cells. 67 This can propagate oxidative stress further and augment the inflammatory response and tissue damage. 73 Alternatively, ROS can contribute directly to cell injury and apoptosis by disrupting cellular and nuclear membranes in the epithelial barrier wall and altering the function of cellular enzymes. 74, 75 A different mechanism by which environmental pollution can trigger disease in the nose is via a neurogenic mechanism. 76 Another component of oxidative pathway is the exposure-driven adjuvant effect on atopy where environmental pollution acts as an exacerbating factor for allergic airway disease by enhancement of allergic airway hypersensitivity in atopic individuals. The evidence emerges from experimental protocols involving inhalation of pollutants and allergen challenge which show pollutants can act synergistically to heighten the allergic response with increased expression of Th2 inflammatory biomarkers. 76, 77 This is in contrast to healthy individuals which express either Th1 or a mixed Th1/Th2 profile in controlled exposure studies. 78 Epidemiological studies suggest pollution modulates AR, [79] [80] [81] [82] [83] [84] [85] rhinosinusitis, 86 and asthma. 85, 87 Other studies suggest a positive association between exposure and prevalence of AR and asthma 83, [88] [89] [90] [91] in children and adults predominately in reports on short-term exposure 88 and residential proximity studies to sources of traffic pollution. 87, 92 However, other long-term exposure studies provided evidence to the contrary. [93] [94] [95] This could be due to differences in study design, methods of exposure assessment, and complex nature of studied pollutants. 79 InIn-vivovivo studies in both human and animal models suggest pollutant exposure induces inflammatory changes in normal, chronically diseased and allergic nasal and sinonasal tissues ( Table 1 ). The cytokine profile of affected tissues suggests activation of the oxidative inflammatory pathways. [96] [97] [98] Moreover, there is compelling evidence for involvement of oxidative stress inflammatory pathways following pollutant exposure in the pathogenesis of rhinitis, CRS, and asthma irrespective of atopic status. This stems from an abundance of literature on oxidative stress biomarkers studied under natural or experimental allergen exposure both in seasonal and perennial AR described in Table 1 . In fact, dust mite or ragweed allergic patients exposed to diesel exhaust particlesDEPs in climate chamber expressed higher nasal symptom scores following dust mite or ragweed challenge, respectively, when compared to nonexposed but allergen-challenged patients. 99, 100 Also in the lower airways, short-term natural increase in ambient air ozone was associated with deteriorating lungh function tests in atopic asthmatics despite use of proper asthma controller therapy. 101 Similarly, an ozone exposure protocol revealed atopic asthmatics expressed depressed spirometry testing results compared to healthy volunteers. 102 Along with this, climate chamber studies revealed (ozone) exposure of healthy or allergic asthmatics induces a neutrophilic 103 or a mixed neutrophilic and eosinophilic 104 inflammatory profile in the lower airways, respectively. Furthermore, gene expression profiles of sputum cells recovered from healthy volunteers and allergic asthmatic patients also confirmed significant difference in inflammatory response to ozone exposure. 105 Analysis of biomarkers activity greatly improved our understanding of cascade and signal pathways involved in atopic and non-atopic phenotypes of airway disease following exposure. Although most oxidative stress biomarkers require tissue specimen collection, some studies suggest an analysis of biomarkers can be determined non-invasively in exhaled breath condensates or blood. [106] [107] [108] [109] [110] [111] Natural allergen exposure reverses oxidative and antioxidative status compared to asymptomatic period, with a persistent oxidative state outside pollination season in allergic patients when compared to healthy controls. AR and asthma comorbidity in children does not seem to augment oxidative stress markers compared to AR alone, 111 although adult patients with seasonal AR and asthma manifest an exaggerated stress response during natural allergen exposure compared to AR alone. 106 Clinically, oxidative stress correlates with nasal symptom scores in children with perennial AR and can predict AR severity independent of total IgE. 109 Additionally, ROS status does not correlate with atopic skin sensitization in children with perennial AR. 108 Furthermore, dust mite challenge in asthmatics or sensitized mice resulted in oxidative damage to nucleic acids as well as lipids and proteins and subsequently triggered DNA repair pathways. Further blockage of DNA repair proteins resulted in increased production of DNA double-strand breaks and cell apoptotic enzymes suggesting importance of DNA repair in suppressing airway inflammation. 75 Endogenous antioxidant response in atopic respiratory diseases is complex and oxidative stress response to anti-inflammatory drugs isare poorly understood. Antioxidant enzymes mostly studied in atopic respiratory diseases include heme oxygenase 1 and 2, 112 , NADPH oxidases, 113 catalase, 98,114 superoxide dismutase, 98, 107, 114 dual oxidases 1 and 2 (in CRS patients), 96 paraoxonase, 109 and glutathione peroxidase. 98, 111 Antioxidant activity can also be measured by serum thiol-SH and total antioxidant status ( Table 1 ). In this respect, evidence suggests oxidative stress decreases antioxidant enzyme activity or total antioxidant status in atopic children 108, 109, 111 or in human in vitro controlled exposure studies, 98 whereas other studies present evidence to the contrary. For example, heme oxygenase antioxidant (iso)enzyme-1 activity was preferentially increased in a human in vitro model of perennial AR, 112 and upregulated in a human exposure model of COPD aggravated by infection; 115 ; also dual oxidase antioxidant (iso) enzymes showed preferential upregulation in different phenotypes and endotypes of CRS. 96, 97 Contrary to this, antioxidant enzymes can be downregulated in asthma and rhinitis irrespective of atopic status, 107 and in vitro animal exposure models challenged by an infectious insult. 72 Importantly, genetic polymorphism in antioxidant/ detoxifying genes like GSTM1 and GSTP1 can alter oxidative stress response in patients with COPD and those with AR following exposure. 116, 117 Exogenous (dietary) antioxidants are scavengers of oxygen free radicals and can act on different levels of defensive antioxidation pathways. 118, 119 Epidemiologic, 120 in vivo 121, 122 and in vitro 123 studies suggest a beneficial role of exogenous antioxidants in patients with IAD or in controlled exposure studies of healthy sinonasal epithelial cells. However, lack of clinical trials data clearly supporting their efficacy, in addition to their potential role in skewing Th1/Th2 balance towards a Th2-type immunity as suggested in vitro, 124 renders their indication restricted to special situations such as over exposure to environmental pollutants, among others. 125 Nacetylcysteine maintains a potent antioxidant effect in in vitro studies 98 or in ovalbuminsensitized rats by downregulating tumor necrosis factor-alpha in recruited inflammatory cells. 126 Along these lines, intranasal steroids can exhibit an exogenous antioxidant regulatory role in seasonal AR by decreasing exhaled breath condensates of leukotriene B4 and 8-Isoprostane, although no effect was seen on exhaled carbon monoxide and nitrogen oxide. 106 In another study involving children with AR and asthma, no effect of topical nasal steroid therapy was noted on measured lipid peroxidation oxidative stress biomarkers and antioxidant enzymes. 111 Data on potential antioxidant effect of inhaled steroids in adult asthmatics is scarce. Epidemiological studies suggested prior intake of oral 127 or inhaled steroids 128 in adult asthmatic patients had no effect on asthma control, as measured by clinical symptoms and FEV1 testing, with PM and ozone exposure. Other similar studies noted increased consumption of asthma controller therapy (bronchodilators, inhaled corticosteroids, or both) with PM10 129 or NO 2 exposure 130 in adults. Moreover, in children inhaled steroid therapy downregulated induced expression of heme oxygenase-1 in non-smoking patients with bronchiectasis but had no effect on exhaled carbon monoxide. 131 Furthermore, desloratadine can exert an antioxidant effect in children with perennial AR by increasing antioxidant enzyme activities (catalase and superoxide dismutase) and decreasing lipid peroxidation marker (malonaldehyde) although no effect was seen on total antioxidant status. 114 When compared to placebo, fexofenadine improved nasal symptom scores in ragweed AR patients following ragweed challenge and DEP controlled exposure. 100 The majority of controlled human exposure studies to ambient pollutants have been conducted in climate chambers on healthy individuals. [132] [133] [134] [135] For example, relative to clean air, mixtures of VOCs increased ratings of nasal irritation, odor intensity 136 and cognitive symptoms (memory loss, dizziness), and a two-fold increase in polymorphonuclear cells in nasal lavage immediately following exposure. 137 Similar studies using different pollutants showed no detectable effects on nasal symptom scores or markers of nasal inflammation. 134, 138 Additionally, healthy subjects exposed to room air, nanoparticles, or O 3 /terpene showed no significant changes in inflammatory biomarkers in blood, sputum or nasal secretions and pulmonary function tests. However, only nanoparticles exposure increased significantly high frequency variability in heart rate, thereby indicating a shift in autonomic balance to a more parasympathetic tone. 133 Low level ozone exposure in healthy subjects resulted in increased sputum production of airway inflammatory cells such as neutrophils, monocytes, and dendritic cells, and modification of cell surface phenotypes of antigen presenting cells. 139 Using a similar protocol the reported decrement in lung spirometry testing (FEV1) of healthy subjects was associated with increased neutrophilic airway inflammation following exposure; 140 the latter likely being more pronounced in healthy individuals with GSTM1 null genotype. 141 More importantly, comparing healthy controls to atopic asthmatics, exposure to high levels of ultrafine particles in a climate chamber was associated with a small but significant fall in arterial oxygen saturation, a fall in forced expired volume over 1 s (FEV1) the morning after exposure, and a transient slight decrease in low frequency (sympathetic) power during quiet rest. 142 These controversial results can be related partly to the nature and concentration of the investigated pollutant or its experimental duration of exposure keeping in mind brief exposure to a single pollutant in a climate chamber does not reflect chronic exposure to multiple pollutants in real life. Controlled exposure studies in atopic patients involving allergen challenge revealed more consistent results. For example, dust mite allergic patients reported worsening nasal symptom scores following intranasal dust mite challenge and DEP exposure commensurate with increased histamine levels in nasal washes, all suggestive of induced mast-cell degranulation. 143 Similarly, controlled exposure studies in ragweed allergic patients challenged with DEP and ragweed outside their pollen season reported higher total nasal symptoms scores 100 or increased levels of specific IgE and expression of Th2 inflammatory cytokines, when compared to ragweed challenged alone. 77 Taken together, controlled airway exposure studies to ambient pollutants in healthy individuals show small but significant negative health effects whereas exposure studies in allergic patients support the role of pollutants in increasing atopic airway hypersensitivity. Large scale translational studies are needed to correlate the bio-cellular toxic effects of pollution with epidemiological studies.

Signal and cascade pathways triggered across the airway mucosal barrier at first encounter of pollutants are complex (see Fig. 1 ). Airway mucosal cells can recognize pollutants through an epithelial toll-like receptors (TLR)-mediated mechanism either directly or indirectly by the intermediary of pattern recognition receptors (see below). More precisely, pollutants such as PM, cigarette smoke, and ozone can present themselves directly to subclasses of surface TLRs, namely TLR2 and TLR4, which can serve as ligands for these pollutants. Alternatively, pollutants can be bound to pattern recognition receptors, a collective conglomerate of receptors which encompasses TLRs and normally can recognize conserved molecular structures derived from microbial agents or released by damaged nonmicrobial cells. Once triggered, pattern recognition receptors and TLRs attract antigen presenting cells and leukocytes to the site of inflammation resulting in priming of the airway to subsequent mucosal infectious insults. 144 Afterwards, when eventuated by an infectious challenge, alveolar macrophages mount a heightened inflammatory response aimed at containing and clearing bacteria while producing minimal collateral tissue damage. 145, 146 The immunological "storm" resulting from co-exposure and infection is studied in different clinical models of respiratory cells and also in patients with IAD such as COPD ( Table 2) . Another signal pathway is mediated by submucosal innate lymphoid cells (ILCs) which can differentiate into adaptive subsets. ILC1s relates to immune reactions in CRS without nasal polyps, COPD, and some viral and bacterial infections; whereas ILC2s becomes important in regulating type 2 immunity and some helminthic and viral infections. 147, 148 Other immunologic and antimicrobial responses to pollutant exposure modulate expression of host defense peptides and antiviral mechanisms, impair mucus production crucial for capturing pollutants or weaken tight junctions essential for the epithelial airway defense barrier. 149, 150 Epidemiological studies suggest indoor and outdoor air pollution increase the risk of respiratory tract infections in both pediatric 151-154 and adult populations. 80, 151, 152, 155 For example, morbidity of the recent COVID-19 pandemic disease has been linked partly to air pollution. [156] [157] [158] [159] Also, air pollution can aggravate the severity of asthma caused by respiratory viral infections. 160 Moreover, in vitro studies suggest air pollution may suppress innate and adaptive immunity and increases susceptibility to bacterial and viral respiratory infections in both human and animal clinical models, following short-or long-term exposure (see Table 2 ). For example, in the upper airways diesel exhaust exposure increased the number of human nasal epithelial cells infected by Influenza A virus in vitro The proposed mechanism was enhancement of virus attachment and entry into respiratory cells mediated by radical oxygen species, despite increased antiviral interferon-dependent signaling and interferon-stimulated gene expression by DEP exposure. 161 Also, in vitro Rrhinovirus (RV) 16 infectivity following nitrogen oxide and ozone exposure in human respiratory epithelial cells Loss of low-level DEP-exposed MDMf along their differentiation into macrophages likely due to dysfunctional (loss of mitochondrial membrane electrical potential and lysosomal function) and phenotypic (TLRmediated reduction in CD14 and CD11 surface marker expression) structural changes in MDMf of healthy exposed individuals. This can likely contribute to inflammation in COPD by decreased MDMf proinflammatory cytokines (CXCL8) production. resulted in increased ICAM 1 receptor expression (receptor for RV16) and pro-inflammatory IL-8 cytokine production. 71 In another combined human and animal model, activated nasal airway microbial proteins at the surface mucosal liquid, which include lysozyme, human cathelicidin antimicrobial peptide, and human b defensins, were attenuated following (PM) exposure and Staphylococcus aureus infection. The ensuing impaired bacterial killing resulted from adsorption and electrostatic interactions between either pollutant or bacteria with activated microbial proteins leading to the depletion of the latter. 162 The literature on the lower airways exceeds that on the upper airways. In this respect, susceptibility to infections following exposure was examined at several stages of immunological alterations triggered in host cells.

Starting with the epithelial barrier level, an initial in vivo PM exposure of bronchial epithelial cells in mice followed by experimental infection with Pseudomonas aeruginosa resulted in decreased levels of an epithelial ciliary marker (b tubulin) and a non-ciliary epithelial (Clara cells) marker, and their gene expression/transcription regulator, all suggesting airway remodeling is a contributing factor to the impaired bacterial clearance. 163 Furthermore, an initial infection with Pseudomonas aeruginosa induced an epithelial antimicrobial peptide human beta defensin 2; but as the model was pre-exposed to PM, induction of human beta defensin 2 was suppressed and a cell senescence biomarker (SA-b-gal) was upregulated in an ROS-dependent process. 164 Also, in an in vitro human model, a PM-enhanced susceptibility to Streptococcus pneumoniae infection was heightened by increased bacterial adhesion and penetration into bronchial epithelial cells. This was mediated by a receptor for platelet-activating factor, a putative receptor for PM-stimulated pneumococcal adhesion to airway cells. 165 On a submucosal level, macrophages and monocytes play a central role in phagocytosis. The study of immunopathological alterations in phagocytosis has shown inconsistent results. For example, in an exposure (PM)-infectious animal model, impaired Streptococcus pneumoniae clearance and phagocytosis resulted from decreased macrophages internalization of bacteria, although increased binding of microbe to surface of macrophages was reported. 166 In a similar model increased susceptibility to Staphylococcus aureus infection resulted from depressed phagocytosis index and abnormal natural killer cell response. 167 Also, in another animal exposure model increased infectivity to Listeria monocytogenes resulted from decreased ROS-induced nitric oxide production by alveolar macrophages. 168 In contrast, natural (chronic) PM exposure of human bronchoalveolar lavage fluid decreased macrophage cytokine (CXCL8) release and downregulated induced phagosomal oxidative burst. Per contra, no impairment in macrophage redox potential, proteolysis or phagocytosis was observed likely due to the experimental chronicity of exposure. 169 Additionally, in an analogous model using high levels of the same pollutant (PM), the impaired antimicrobial defense resulted from defective macrophage activation of T cells by class II þ major histocompatibility complex and subsequent decrease in interferon-g production, but unaltered phagocytic activity. 170 Interestingly, no increase of neutrophils and TNF-a levels was observed in bronchoalveolar lavage following exposure and infection suggesting acute exposure to relatively high level of PM does not trigger a classic or sustained inflammatory response. 170 Besides suggesting interference with innate immunity, exposure studies suggest further alterations in adaptive immunity as evidenced by immunopathological relationships between antigen presenting cell cytokines, the corresponding sensitized T cells subsets, and recruited neutrophils (see Table 2 ). As such, a Listeria monocytogenes-mediated suppression of macrophages immune response upon low dose DEP exposure manifested as "dysfunctional" production of macrophages-derived cytokines. This was associated with downregulation of innate protective cytokines (e.g. IL-1b, tumor necrosis factor-a, IL-12, IL-2 and interferon-g), suppression of adaptive CD4 and CD8 T cell immune response, and upregulation of macrophage bactericidal anti-inflammatory cytokines (IL-10 and IL-6). 171 Other examples of altered cytokine release include the pro-inflammatory 169 Besides the role of cytokines in fine tuning extent of inflammation in these models, T cell subsets like T cytotoxic (CD8 þ ) and regulatory T cells (Treg) in addition to neutrophils have been studied. DEP exposure in rats increased susceptibility to Listeria monocytogenes infection by attenuating T cell mediated immunity, namely CD4 þ T helper lymphocytes and CD8 þ T cytotoxic cells; 168 PM exposure in neonatal mice resulted in depression of adaptive response to influenza virus A infection and by an increased expression in Treg cells and IL-10 in lung tissues. Interestingly, the induced immunosuppressive effect was reversed by Treg depletion and restored by either Treg transfer or recombinant IL-10 treatment. 172 Furthermore, airway neutrophilia, which is instrumental in bacterial clearance, has been studied in inin-vitrovitro infectious exposure model in relationship to Th1 and Th17 proinflammatory cytokine release. The concomitant increase in bronchoalveolar lavage fluid IL-17 with airway neutrophilia, and their attenuation in IL-17 "knock out" mice following exposure and infection suggested the importance of IL-17 in inducing neutrophil-mediated airway inflammation. Also, decreased induction of IL-17A-mediated airway neutrophilia following exposure and infection in IL-1R1mice compared with wild-type controls also suggests IL-1 signaling is required in IL-17Aexacerbated neutrophilia. 173 Moreover, in an in vivo exposure-infectious animal model modulated by interferon-g priming to mimic viral infection, an impaired PM-mediated bacterial phagocytosis correlated with activation of genes encoding neutrophil-recruiting chemokines and increased histopathology suggestive of severe pneumonia. 174 Still, in an animal in vivo model, exposure followed by LPS infection induced cytokine changes in the lung suggestive of a Th1/Th2 imbalance and manifested by increased expression of IL-4 among others, and a concordant decrease in IFN-g expression. 72 The infectious-exposure model is an attractive tool to explore immunopathological alterations in COPD patients or in laboratory cells exposed to secondhand smoking. In a mice model, 8 weeks secondhand smoking pre-exposure was followed by infection with non-typeable Haemophilus influenza which is a pathogen commonly implicated in acute exacerbation of COPD. The model revealed increased number of immune cell infiltrates except for macrophages, and a suppressed induction of a robust adaptive immune response manifested as decreased IFN-g. Also, a downregulated T cell adaptive response manifested by decreased bacterial clearance and diminished efficiency of specific antibody subclass switching, both mitigated by anti-viral vaccination. 175 In a similar animal model examining the immunological effect of antibiotic therapy, cigarette smoke exposure followed by Streptococcus pneumoniae infection resulted in recruitment of macrophages and monocytes in lung tissue and alveolar fluid reportedly to confine infection to the lung; also a decreased number of neutrophils but a differential increase in neutrophil-mediated antimicrobial peptide, myeloperoxidase. Antibiotic therapy had no effect on mice survival rate but reduced lung injury and induced a differential change of cytokine levels in bronchoalveolar lavage fluid most importantly downregulation of Th1 and Th17 inflammatory cytokines. 176 Human in-vitro pre-exposure and infectious models are designed to mimic acute exacerbations in stable but exposed COPD patients. DEP exposure followed by non-typeable Haemophilus influenza infection did not compromise mucosal barrier function in COPD or healthy patients. However, epithelial endoplasmic reticulum activity was markedly disrupted in COPD patients, manifested by depressed gene expression of the integrated stress response markers in an ROS-mediated process. 115 In another model, macrophages differentiating from locally recruited monocytes in lungs of COPD patients were pre-exposed to low level DEP and subsequently challenged with TLR agonists or heat killed E.coli. This resulted in structural and functional changes in innate and adaptive immune system consisting of mitochondrial and lysosomal dysfunction in macrophages, decreased expression of their surface recognition markers, loss of macrophage differentiation, and reduction in proinflammatory cytokine production (e.g.IL-8). 177 The majority of exposure-infection human and animal models have examined immunological alterations following long-term (weeks) and lowdose pre-exposure periods which best mimics real-life outdoor pollutant exposure or indoor secondhand smoking relevant to COPD. Nevertheless, other models which studied brief and short-term (hours to days) exposure periods have yielded mixed results. For example, one-week diesel exhaust pre-exposure of mice in vivo decreased Pseudomonas aeruginosa clearance from bronchial epithelial cells, whereas in the same model a six-months pre-exposure did not. 163 Also, in an in vivo model, mice were pre-exposed to PM for 1 day (short term) or 2 weeks (long term), later infection with Influenza virus A and survival rate was assessed over the ensuing 10 days following contamination. Short-term exposure improved mice survival rate and triggered a robust immune response whereas long-term exposure did not, 178 reportedly mediated by macrophage cytokine gene expression regulator Kdm6a. To model secondhand smoking exposure or for recent initiation of active smoking, mice were exposed to brief (2 h per day for 2 days) low dose of side stream cigarette smoke or to prolonged (2.5 weeks) high dose cigarette smoke, respectively, and later inoculated with Streptococcus pneumonia. Surprisingly, brief exposure did not show significant survival benefit whereas prolonged exposure in mice did, reportedly due to diminished propagation of bacteria into the systemic circulation during chronic exposure. 176 Finally, in a mice model examining only chronic secondhand smoking exposure and its impact on non-typeable Haemophilus influenza antimicrobial response, 8 weeks secondhand smoking preexposure, theoretically mimicking mainstream smoking, compromised the ability of host T cellmediated adaptive immune system to mount an effective response against non-typeable Haemophilus influenza infection. 175 Taken together, these models suggest exposure impairs innate and adaptive immunity against airway microbial infections. Limitations inherent to the design of these models compel a careful interpretation of results taking into consideration the response to infectivity of animal host cells, the duration and intensity 64, 163, 178, 179 of pollutant pre-exposure, and the nature of microbial agents used for contamination.

We reviewed evidence for the involvement of oxidative stress pathways and their nature in healthy individuals and patients with inflammatory airway diseases following exposure to a spectrum of important chemical, allergic and infectious air contaminants. When comparing exposure clinical models in patients with AR, CRS, and allergic asthma, the signal and cascade pathways can generate important oxidative and anti-oxidative markers and induce specific changes in adaptive and innate immune system. Thus, exposure can amplify the inflammatory process in patients with AR, CRS, and allergic asthma supporting evidence that, at least in atopic individuals, exposure can increase airway hypersensitivity. When accentuated by an infectious insult, pre-exposure clinical models in patients with inflammatory airway diseases show specific immunopathological alterations at mucosal and submucosal levels of the airway epithelial barrier and ultimately in the adaptive immune system. The resultant increased susceptibility to infection can be due to either increased infectivity of microbial agents or to a ROS-mediated direct effect of pollutant on host immune defense cells.

The complex nature and composition of chemical air pollutants and their aerodynamic properties is reflected in conflicting epidemiological and experimental results on exposure and its impact on health. Also, the oxidative stress-mediated immunopathological changes have highlighted important antioxidant markers, which can be therapeutically bio-engineered. Since there is no clear consensus on efficacy of natural or synthetic antioxidants, 125, 180, 181 current research should search for new therapeutic modalities and define the role of currently available ones such as antihistamines, intranasal or inhaled steroids, antibiotics and anti-viral vaccination in patients with inflammatory airway diseases challenged by exposure and at times by an infectious process. Volume 13, No. 10, Month 2020 

Atmospheric Chemistry and Physics: From Air Pollution to Climate Change

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Human and animal research Not applicable.

Not applicable.Availability of data and materials Not applicable.

We attest that all authors contributed significantly to the creation of this manuscript.-Philip Rouadi and Samar Idriss initiated the work, contributed substantially to the conception and design of the study, the acquisition, analysis, and interpretation of data. -Philip Rouadi supervised the manuscript.Ethics committee approval Not applicable.

All authors agreed to the publication of this work.

The authors have nothing to declare relative to this paper.