An update on immunologic mechanisms in the respiratory mucosa in response to air pollutants

Every day, we breathe in more than 10,000 L of air that contains a variety of air pollutants that can pose negative consequences to lung health. The respiratory mucosa formed by the airway epithelium is the first point of contact for air pollution in the lung, functioning as a mechanical and immunologic barrier. Under normal circumstances, airway epithelial cells connected by tight junctions secrete mucus, airway surface lining fluid, host defense peptides, and antioxidants and express innate immune pattern recognition receptors to respond to inhaled foreign substances and pathogens. Under conditions of air pollution exposure, the defenses of the airway epithelium are compromised by reductions in barrier function, impaired host defense to pathogens, and exaggerated inflammatory responses. Central to the mechanical and immunologic changes induced by air pollution are activation of redox-sensitive pathways and a role for antioxidants in normalizing these negative effects. Genetic variants in genes important in epithelial cell function and phenotype contribute to a diversity of responses to air pollution in the population at the individual and group levels and suggest a need for personalized approaches to attenuate the respiratory mucosal immune responses to air pollution. Every day, we breathe in more than 10,000 L of air that contains a variety of air pollutants that can pose negative consequences to lung health. The respiratory mucosa formed by the airway epithelium is the first point of contact for air pollution in the lung, functioning as a mechanical and immunologic barrier. Under normal circumstances, airway epithelial cells connected by tight junctions secrete mucus, airway surface lining fluid, host defense peptides, and antioxidants and express innate immune pattern recognition receptors to respond to inhaled foreign substances and pathogens. Under conditions of air pollution exposure, the defenses of the airway epithelium are compromised by reductions in barrier function, impaired host defense to pathogens, and exaggerated inflammatory responses. Central to the mechanical and immunologic changes induced by air pollution are activation of redox-sensitive pathways and a role for antioxidants in normalizing these negative effects. Genetic variants in genes important in epithelial cell function and phenotype contribute to a diversity of responses to air pollution in the population at the individual and group levels and suggest a need for personalized approaches to attenuate the respiratory mucosal immune responses to air pollution. GlossaryBIOMASSPlant materials (eg, coal, charcoal, tobacco, wood, and crop waste) and animal waste (dung) used as fuel. Indoor biomass burning generates PAHs and is associated with COPD development in women. Traditional biomass burned in open fires and traditional stoves are used by almost half the world's population and contribute to more than 1 million COPD-related deaths annually.COAL FLY ASHA fine-grained, powdery particulate material produced from the burning of pulverized coal in a coal-fired boiler. Fly ash is collected in a coal-fired boiler through several different means, typically before the smoke reaches the smoke stack. Approximately 70% to 75% of fly ash generated is disposed of in landfills or storage lagoons.CYTOCHROME P450A protein group comprised of 20 different families involved in xenobiotic metabolism. The enzymes encoded by 6 cytochrome P450 genes (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) are responsible for metabolism of more than 90% of all commonly used drugs.β-DEFENSINSA distinct family of antimicrobial peptides produced by epithelial cells of mucosal surfaces, as well as by neutrophils, natural killer cells, and cytotoxic T lymphocytes. Defensins have direct antimicrobial activity, as well as the ability to activate inflammatory responses.FARM DUST EXTRACTIn this particular study farm dust was collected from the stables of traditional German farms housing cows 50 km around Munich.GEOGENIC DUSTNaturally derived particles often found in rural arid and agricultural areas; examples include volcanic ash, windborne ash from wildfires, and mineral dusts.IL-6/SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT3) SIGNALINGA signaling pathway operating through Janus kinase 1 tyrosine phosphorylation. Pathway signaling results in acute-phase reactant proliferation, differentiation, and costimulation. STAT3 mutations result in hyper-IgE syndrome and deficient IL-17 production. IL-6 (important in TH17 differentiation) deficiencies result in enhanced susceptibility to infection with Candida and Listeria species.LL-37A cathelicidin released from neutrophils and epithelial cells. LL-37 is induced by vitamin D.MUCUSA mixture of proteins and liquids, but 95% of its content is water. High-molecular-weight glycoproteins called mucins form a gel with water. Mucins interact with cilia to influence mucociliary clearance. MUC5AC is the predominant secreted mucin in airway surface epithelium.THYMIC STROMAL LYMPHOPOIETIN (TSLP)A cytokine secreted by gastrointestinal, skin, and lung epithelial cells that promotes TH2 differentiation through its effect on tissue dendritic cells and innate lymphoid cells. Its name arises from its initial identification in thymic stromal cells.TIGHT JUNCTIONSSupramolecular complexes composed of transmembrane proteins (occludin, claudins, and junctional adhesion molecules) and cytoplasmic proteins. Cytoplasmic proteins facilitate cytoskeletal interactions and intercellular signaling. Transmembrane proteins regulate cell adhesion, as well as paracellular permeability and cell migration.TRANSEPITHELIAL ELECTRICAL RESISTANCE (TEER)A measure of how tightly an epithelium separates one compartment from another. TEER is dependent on how permeant tight junctions are to the ion diffusion.The Editors wish to acknowledge Daniel Searing, MD, for preparing this glossary. Plant materials (eg, coal, charcoal, tobacco, wood, and crop waste) and animal waste (dung) used as fuel. Indoor biomass burning generates PAHs and is associated with COPD development in women. Traditional biomass burned in open fires and traditional stoves are used by almost half the world's population and contribute to more than 1 million COPD-related deaths annually. A fine-grained, powdery particulate material produced from the burning of pulverized coal in a coal-fired boiler. Fly ash is collected in a coal-fired boiler through several different means, typically before the smoke reaches the smoke stack. Approximately 70% to 75% of fly ash generated is disposed of in landfills or storage lagoons. A protein group comprised of 20 different families involved in xenobiotic metabolism. The enzymes encoded by 6 cytochrome P450 genes (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) are responsible for metabolism of more than 90% of all commonly used drugs. A distinct family of antimicrobial peptides produced by epithelial cells of mucosal surfaces, as well as by neutrophils, natural killer cells, and cytotoxic T lymphocytes. Defensins have direct antimicrobial activity, as well as the ability to activate inflammatory responses. In this particular study farm dust was collected from the stables of traditional German farms housing cows 50 km around Munich. Naturally derived particles often found in rural arid and agricultural areas; examples include volcanic ash, windborne ash from wildfires, and mineral dusts. A signaling pathway operating through Janus kinase 1 tyrosine phosphorylation. Pathway signaling results in acute-phase reactant proliferation, differentiation, and costimulation. STAT3 mutations result in hyper-IgE syndrome and deficient IL-17 production. IL-6 (important in TH17 differentiation) deficiencies result in enhanced susceptibility to infection with Candida and Listeria species. A cathelicidin released from neutrophils and epithelial cells. LL-37 is induced by vitamin D. A mixture of proteins and liquids, but 95% of its content is water. High-molecular-weight glycoproteins called mucins form a gel with water. Mucins interact with cilia to influence mucociliary clearance. MUC5AC is the predominant secreted mucin in airway surface epithelium. A cytokine secreted by gastrointestinal, skin, and lung epithelial cells that promotes TH2 differentiation through its effect on tissue dendritic cells and innate lymphoid cells. Its name arises from its initial identification in thymic stromal cells. Supramolecular complexes composed of transmembrane proteins (occludin, claudins, and junctional adhesion molecules) and cytoplasmic proteins. Cytoplasmic proteins facilitate cytoskeletal interactions and intercellular signaling. Transmembrane proteins regulate cell adhesion, as well as paracellular permeability and cell migration. A measure of how tightly an epithelium separates one compartment from another. TEER is dependent on how permeant tight junctions are to the ion diffusion. The Editors wish to acknowledge Daniel Searing, MD, for preparing this glossary. Every day, we breathe in more than 10,000 L of air that contains a variety of air pollutants, including urban particulate matter, diesel exhaust particles, geogenic dusts, and biomass combustion byproducts, that can pose potential negative consequences to lung health (Fig 1). The respiratory mucosa is the first line of defense to protect our lungs and is formed from a constellation of mechanical and immunologic impedances.1Georas S.N. Rezaee F. Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation.J Allergy Clin Immunol. 2014; 134: 509-520Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 2Parker D. Prince A. Innate immunity in the respiratory epithelium.Am J Respir Cell Mol Biol. 2011; 45: 189-201Crossref PubMed Scopus (240) Google Scholar, 3Hiemstra P.S. Parallel activities and interactions between antimicrobial peptides and complement in host defense at the airway epithelial surface.Mol Immunol. 2015; 68: 28-30Crossref PubMed Scopus (7) Google Scholar The coordinated activities of the respiratory mucosa include airway surface lining fluid with host defense peptides, mucus production for entrapment of inhaled particulates, tight junctions between epithelial cells to restrict transit to deeper lung tissues, and innate immune receptors and signaling pathways that can activate and recruit immune cells (Fig 2). Despite this multipronged defense system, the respiratory mucosa can be overwhelmed by air pollution, which leads to impaired host defense, decreased barrier function, and augmented induction of inflammatory mediators. As a result, excessive respiratory mucosal immune responses to air pollution can contribute to chronic respiratory disease pathologies, including asthma and chronic obstructive pulmonary disease (COPD), and the ability to defend the lung against inhaled pathogens.Fig 2Respiratory mucosa in response to air pollution exposure. Air pollution gaseous and particle components interact with airway surface lining fluid; surfactants; host defense peptides; tight junctions; pathogen recognition receptors, including Toll-like receptors and NOD-like receptors; and redox-sensitive pathways (Fig 3) to modulate the viability and immune responses of airway epithelial cells and recruited immune cells.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The present review will provide an update of recent literature (2017-2019) in the context of seminal articles in the field with a focus on crosscutting host responses and genetic contributions to diverse air pollutant types. The literature reviewed focused on in vitro studies of human airway epithelial cells, clinical exposure models, and cohort studies. Host responses to allergen or tobacco smoke exposure are not discussed. Host responses to air pollution will highlight recent advances in the context of airway surface lining fluid, pathogen exposures, immune mediator production, oxidative stress pathways, and how genetic variants in these pathways influence individual-level responses. Observational and experimental data linking air pollution to respiratory mucosal immune responses have been supported by a vast array of different compositions, concentrations, exposure durations, and frequencies both in isolation and in combination.4Hiemstra P.S. Grootaers G. van der Does A.M. Krul C.A.M. Kooter I.M. Human lung epithelial cell cultures for analysis of inhaled toxicants: lessons learned and future directions.Toxicol In Vitro. 2018; 47: 137-146Crossref PubMed Scopus (3) Google Scholar, 5De Grove K.C. Provoost S. Brusselle G.G. Joos G.F. Maes T. Insights in particulate matter-induced allergic airway inflammation: focus on the epithelium.Clin Exp Allergy. 2018; 48: 773-786Crossref PubMed Scopus (6) Google Scholar The consistency and overlapping of the experimental findings (described below in greater detail), despite the variety of potential air pollution exposure conditions, suggest that dominant biological pathways are activated by nonspecific triggers contained within each composition. For the scope of the review, we define air pollution as a byproduct of human activities (eg, combustion and urban particulate matter) but not from natural processes (eg, viruses, bacteria, and allergens). In some cases we explore coexposure studies that have interrogated host responses to natural processes in the context of human activities. Robust experimental designs routinely report detailed characteristics of source material used in experiments, including season and geographic source where the material was collected, definition of any combustion engine characteristics (fuel source, work load, engine model, temperature, humidity, and oxygen content), particulate matter quantities (in units per cubic meter), hydrocarbon combustion byproducts (nitrogen dioxides, and sulfur dioxides), and extraction and dilution parameters, to aid in interpretation of results from diverse exposures. Additionally, routine inclusion of National Institutes for Standards and Technology (NIST) standard reference materials (SRMs) ensures reproducibility of results and provides context for unique source materials generated across the globe in research laboratories. Despite careful documentation of air pollution composition for observational and experimental studies, a real-world complexity exists that air pollution exposure is rarely experienced in isolation and likely includes concomitant exposures to geogenic dusts, allergens, bacteria, and viruses.6Carlsten C. Synergistic environmental exposures and the airways capturing complexity in humans: an underappreciated world of complex exposures.Chest. 2018; 154: 918-924Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Furthermore, components of air pollution, including polyaromatic hydrocarbons (PAHs) produced from combustion engines, can undergo photochemical reactions and agglomeration that are influenced by meteorological events that are difficult to reproduce in research environments.7Zhang Y. Wang L. Feng H. Hu G. Wang L. Liu J. et al.Effects of 1,4-naphthoquinone aged carbon black particles on the cell membrane of human bronchial epithelium.Environ Toxicol Pharmacol. 2017; 54: 21-27Crossref PubMed Scopus (4) Google Scholar Elemental composition and charge of pollution is also important to consider because various host defense cationic peptide functions can be compromised by introduction of charged components, as observed with residual coal fly ash.8Vargas Buonfiglio L.G. Mudunkotuwa I.A. Abou Alaiwa M.H. Vanegas Calderon O.G. Borcherding J.A. Gerke A.K. et al.Effects of coal fly ash particulate matter on the antimicrobial activity of airway surface liquid.Environ Health Perspect. 2017; 125: 077003Crossref PubMed Scopus (2) Google Scholar The composition of air pollution is dynamic and complex, changing from location to location9Chowdhury P.H. Okano H. Honda A. Kudou H. Kitamura G. Ito S. et al.Aqueous and organic extract of PM2.5 collected in different seasons and cities of Japan differently affect respiratory and immune systems.Environ Pollut. 2018; 235: 223-234Crossref PubMed Scopus (4) Google Scholar and season to season,10Becker S. Dailey L.A. Soukup J.M. Grambow S.C. Devlin R.B. Huang Y.C. Seasonal variations in air pollution particle-induced inflammatory mediator release and oxidative stress.Environ Health Perspect. 2005; 113: 1032-1038Crossref PubMed Scopus (0) Google Scholar, 11Chen Y. Luo X.S. Zhao Z. Chen Q. Wu D. Sun X. et al.Summer-winter differences of PM2.5 toxicity to human alveolar epithelial cells (A549) and the roles of transition metals.Ecotoxicol Environ Saf. 2018; 165: 505-509Crossref PubMed Scopus (4) Google Scholar and influenced by human activities and meteorological events.7Zhang Y. Wang L. Feng H. Hu G. Wang L. Liu J. et al.Effects of 1,4-naphthoquinone aged carbon black particles on the cell membrane of human bronchial epithelium.Environ Toxicol Pharmacol. 2017; 54: 21-27Crossref PubMed Scopus (4) Google Scholar Despite variations in compositions, common themes have emerged from air pollution exposure research, clearly defining an effect on respiratory mucosal immune responses important in lung health and disease. We define these in greater detail below and, where possible, highlight the source material. Airway surface lining fluid is composed of periciliary sol with high water content, which is capped by a mucus component that can be shuttled in a directional fashion toward the laryngopharynx by ciliated epithelial cells.1Georas S.N. Rezaee F. Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation.J Allergy Clin Immunol. 2014; 134: 509-520Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 12Widdicombe J.H. Regulation of the depth and composition of airway surface liquid.J Anat. 2002; 201: 313-318Crossref PubMed Scopus (108) Google Scholar Airway and serous epithelial cells contribute to composition of the airway surface lining fluid by regulating ion and fluid transport in addition to secreting host defense peptides, including human LL-37, lysozyme, β-defensins, lipocalins, and secretory leukocyte protease inhibitor (Fig 2).2Parker D. Prince A. Innate immunity in the respiratory epithelium.Am J Respir Cell Mol Biol. 2011; 45: 189-201Crossref PubMed Scopus (240) Google Scholar, 3Hiemstra P.S. Parallel activities and interactions between antimicrobial peptides and complement in host defense at the airway epithelial surface.Mol Immunol. 2015; 68: 28-30Crossref PubMed Scopus (7) Google Scholar, 13Kesic M.J. Meyer M. Bauer R. Jaspers I. Exposure to ozone modulates human airway protease/antiprotease balance contributing to increased influenza A infection.PLoS One. 2012; 7: e35108Crossref PubMed Scopus (0) Google Scholar The first point of contact for air pollution in the respiratory mucosa is the mucus layer of airway surface lining fluids.12Widdicombe J.H. Regulation of the depth and composition of airway surface liquid.J Anat. 2002; 201: 313-318Crossref PubMed Scopus (108) Google Scholar Secreted mucins are affected by diesel exhaust exposure, with an increase in MUC5B and MUC16 levels observed in atopic patients in bronchoalveolar lavage fluid after 2 hours of exposure to 300 μg/m3 PM2.5 from freshly generated diesel exhaust.14Mookherjee N. Piyadasa H. Ryu M.H. Rider C.F. Ezzati P. Spicer V. et al.Inhaled diesel exhaust alters the allergen-induced bronchial secretome in humans.Eur Respir J. 2018; 51Crossref PubMed Scopus (3) Google Scholar MUC5AC is also upregulated by urban particulate matter (SRM-1649B) in a mechanism linked to early growth response gene 1.15Xu F. Cao J. Luo M. Che L. Li W. Ying S. et al.Early growth response gene 1 is essential for urban particulate matter-induced inflammation and mucus hyperproduction in airway epithelium.Toxicol Lett. 2018; 294: 145-155Crossref PubMed Scopus (0) Google Scholar SRM-1649B exposure–induced activation of early growth response gene 1 leads to downstream activator protein 1 and nuclear factor κB (NF-κB) transcription factor activation, 2 pathways important in promoting proinflammatory immune responses.16Li J. Kartha S. Iasvovskaia S. Tan A. Bhat R.K. Manaligod J.M. et al.Regulation of human airway epithelial cell IL-8 expression by MAP kinases.Am J Physiol Lung Cell Mol Physiol. 2002; 283: L690-L699Crossref PubMed Google Scholar, 17Silbajoris R. Osornio-Vargas A.R. Simmons S.O. Reed W. Bromberg P.A. Dailey L.A. et al.Ambient particulate matter induces interleukin-8 expression through an alternative NF-kappaB (nuclear factor-kappa B) mechanism in human airway epithelial cells.Environ Health Perspect. 2011; 119: 1379-1383Crossref PubMed Scopus (25) Google Scholar A reductionist approach using fluoranthene, benzo(a)pyrene, and benzo(b)fluoranthene, individual PAHs contained within SRM-1649B, revealed a consistent induction of MUC5AC. The aryl hydrocarbon receptor (AhR) recognizes diverse PAHs, suggesting that MUC5AC levels might be modulated by the AhR. Beneath the airway surface lining fluid are differentiated epithelial cells of multiple types that form a tight mechanical impedance through cell-cell junctions.18Hirota J.A. Knight D.A. Human airway epithelial cell innate immunity: relevance to asthma.Curr Opin Immunol. 2013; 24: 740-746Crossref Scopus (29) Google Scholar Disruption of tight junctions formed by zonula occludens 1 and E-cadherin complexes between cells can be measured experimentally based on a reduction in transepithelial electrical resistance or an increase in diffusion of fluorescently labeled probes (eg, fluorescein isothiocyanate–dextran).4Hiemstra P.S. Grootaers G. van der Does A.M. Krul C.A.M. Kooter I.M. Human lung epithelial cell cultures for analysis of inhaled toxicants: lessons learned and future directions.Toxicol In Vitro. 2018; 47: 137-146Crossref PubMed Scopus (3) Google Scholar Air pollution exposure can decrease epithelial barrier function associated with cell death, although experimental conditions designed to reproduce the current exposure conditions from a Euro V diesel bus engine or a nonroad diesel engine operating at steady load do not reproduce these findings.19Zarcone M.C. Duistermaat E. Alblas M.J. van Schadewijk A. Ninaber D.K. Clarijs V. et al.Effect of diesel exhaust generated by a city bus engine on stress responses and innate immunity in primary bronchial epithelial cell cultures.Toxicol In Vitro. 2018; 48: 221-231Crossref PubMed Scopus (2) Google Scholar, 20Zarcone M.C. van Schadewijk A. Duistermaat E. Hiemstra P.S. Kooter I.M. Diesel exhaust alters the response of cultured primary bronchial epithelial cells from patients with chronic obstructive pulmonary disease (COPD) to non-typeable Haemophilus influenzae.Respir Res. 2017; 18: 27Crossref PubMed Scopus (10) Google Scholar Results from the same research group suggest that the effect of air pollution on epithelial barrier function is condition dependent and can only occur at high concentrations.21Zarcone M.C. Duistermaat E. van Schadewijk A. Jedynska A. Hiemstra P.S. Kooter I.M. Cellular response of mucociliary differentiated primary bronchial epithelial cells to diesel exhaust.Am J Physiol Lung Cell Mol Physiol. 2016; 311: L111-L123Crossref PubMed Scopus (13) Google Scholar Air pollution exposure has been epidemiologically linked to increased respiratory tract infections in patients of all ages and in multiple jurisdictions.22MacIntyre E.A. Gehring U. Molter A. Fuertes E. Klumper C. Kramer U. et al.Air pollution and respiratory infections during early childhood: an analysis of 10 European birth cohorts within the ESCAPE Project.Environ Health Perspect. 2014; 122: 107-113Crossref PubMed Scopus (110) Google Scholar, 23Wong C.M. Yang L. Thach T.Q. Chau P.Y. Chan K.P. Thomas G.N. et al.Modification by influenza on health effects of air pollution in Hong Kong.Environ Health Perspect. 2009; 117: 248-253Crossref PubMed Scopus (0) Google Scholar, 24Pirozzi C.S. Jones B.E. VanDerslice J.A. Zhang Y. Paine 3rd, R. Dean N.C. Short-term air pollution and incident pneumonia. A case-crossover study.Ann Am Thorac Soc. 2018; 15: 449-459Crossref PubMed Scopus (6) Google Scholar The mechanism or mechanisms responsible for these population-level observations of compromised respiratory mucosal immunity are likely multifactorial and could include changes in receptor expression for pathogens, antiviral mechanisms, or host defense peptide biology. Intercellular adhesion molecule-1 (ICAM-1) is a receptor for human rhinovirus B, which infects epithelial cells of the respiratory mucosa to induce cold symptoms, with more severe consequences for those with underlying chronic respiratory diseases.25Jartti T. Gern J.E. Role of viral infections in the development and exacerbation of asthma in children.J Allergy Clin Immunol. 2017; 140: 895-906Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar ICAM-1 is upregulated by air pollution in lung epithelial cells mediated by NF-κB transcriptional events downstream of oxidative stress–induced classical IL-6/signal transducer and activator of transcription 3 signalling.26Liu C.W. Lee T.L. Chen Y.C. Liang C.J. Wang S.H. Lue J.H. et al.PM2.5-induced oxidative stress increases intercellular adhesion molecule-1 expression in lung epithelial cells through the IL-6/AKT/STAT3/NF-kappaB-dependent pathway.Part Fibre Toxicol. 2018; 15: 4Crossref PubMed Scopus (0) Google Scholar Coexposure of airway epithelial cells to rhinovirus 1B and nitrogen dioxide (NO2) appears to induce a synergistic upregulation of ICAM-1, which could exaggerate the infectivity of epithelial cells.27Spannhake E.W. Reddy S.P. Jacoby D.B. Yu X.Y. Saatian B. Tian J. Synergism between rhinovirus infection and oxidant pollutant exposure enhances airway epithelial cell cytokine production.Environ Health Perspect. 2002; 110: 665-670Crossref PubMed Google Scholar The IL-8 cytokine response induced by rhinovirus 16 and pollution (NO2 or ozone) can be attenuated by N-acetyl-cysteine (NAC), suggesting that oxidative stress could affect ICAM-1/rhinovirus responses in epithelial cells of the respiratory mucosa. Interactions between air pollution and the low-density lipoprotein receptor, the receptor for rhinovirus-A, or cadherin-related family member 3, the receptor for rhinovirus-C, have not been examined in the context of air pollution to date. Importantly, cadherin-related family member 3 was only discovered on air-liquid interface differentiated primary human airway epithelial cells,28Bochkov Y.A. Watters K. Ashraf S. Griggs T.F. Devries M.K. Jackson D.J. et al.Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication.Proc Natl Acad Sci U S A. 2015; 112: 5485-5490Crossref PubMed Scopus (174) Google Scholar which emphasizes the value of increasing complexity in cell-culture model systems that more closely recapitulate human physiology. PAHs are a byproduct of fossil fuel combustion and biomass. PAHs can induce oxidative stress and are ligands for AhR, which subsequently mediates transcriptional responses that affect cellular detoxification and survival pathways.29Denison M.S. Nagy S.R. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals.Annu Rev Pharmacol Toxicol. 2003; 43: 309-334Crossref PubMed Scopus (1185) Google Scholar In primary human airway epithelial cells, activation of AhR by diesel exhaust particles (NIST SRM1975) is able to attenuate basal and induced levels of CXCL10, a cytokine important in coordinating antiviral responses in immune cells expressing the CXCR3 receptor.30Meldrum K. Gant T.W. Leonard M.O. Diesel exhaust particulate associated chemicals attenuate expression of CXCL10 in human primary bronchial epithelial cells.Toxicol In Vitro. 2017; 45: 409-416Crossref PubMed Scopus (4) Google Scholar Activation of AhR by organic combustion is conserved with a variety of biomass materials, including dung from diverse animals with distinct diets, all of which induce concentration-dependent increases in IL-8 and GM-CSF from primary human airway epithelial cells.31McCarthy C.E. Duffney P.F. Wyatt J.D. Thatcher T.H. Phipps R.P. Sime P.J. Comparison of in vitro toxicological effects of biomass smoke from different sources of animal dung.Toxicol In Vitro. 2017; 43: 76-86Crossref PubMed Scopus (4) Google Scholar Transcriptional activity related to antiviral responses was further interrogated by using an interferon-sensitive response element luciferase reporter cell line, demonstrating that exposure to dung smoke impaired responses to viral mimic challenge. Furthermore, CXCL10 gene and protein induction by viral mimic challenge was attenuated if prior exposure to dung smoke had occurred. Diverse compositions of the exposures used in these 2 studies converge on a likely mechanism of AhR activation/oxidative stress, attenuated interferon transcriptional activity, and reduced production of mediators of antiviral responses by human airway epithelial cells. Air pollution also affects the activity of host defense peptides, evolutionary conserved defenses that disrupt pathways important in survival of pathogenic bacteria,3Hiemstra P.S. Parallel activities and interactions between antimicrobial peptides and complement in host defense at the airway epithelial surface.Mol Immunol. 2015; 68: 28-30Crossref PubMed Scopus (7) Google Scholar in airway surface lining fluid.8Vargas Buonfiglio L.G. Mudunkotuwa I.A. Abou Alaiwa M.H. Vanegas Calderon O.G. Borcherding J.A. Gerke A.K. et al.Effects of coal fly ash particulate matter on the antimicrobial activity of airway surface liquid.