Control of local immunity by airway epithelial cells

The lung is ventilated by thousand liters of air per day. Inevitably, the respiratory system comes into contact with airborne microbial compounds, most of them harmless contaminants. Airway epithelial cells are known to have innate sensor functions, thus being able to detect microbial danger. To avoid chronic inflammation, the pulmonary system has developed specific means to control local immune responses. Even though airway epithelial cells can act as proinflammatory promoters, we propose that under homeostatic conditions airway epithelial cells are important modulators of immune responses in the lung. In this review, we discuss epithelial cell regulatory functions that control reactivity of professional immune cells within the microenvironment of the airways and how these mechanisms are altered in pulmonary diseases. Regulation by epithelial cells can be divided into two mechanisms: (1) mediators regulate epithelial cells’ innate sensitivity in cis and (2) factors are produced that limit reactivity of immune cells in trans.

[1]  D. Tsikas,et al.  Bronchial Epithelial Cell-Derived Prostaglandin E2 Dampens the Reactivity of Dendritic Cells , 2011, The Journal of Immunology.

[2]  T. Brunner,et al.  Why does the gut synthesize glucocorticoids? , 2014, Annals of medicine.

[3]  Toru Takahashi,et al.  Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-kappa B activation and TNF-alpha secretion are down-regulated by lung collectin surfactant protein A. , 2003, Journal of immunology.

[4]  R. Lauwerys,et al.  Clara cell protein in serum and bronchoalveolar lavage. , 1992, The European respiratory journal.

[5]  Florence Demenais,et al.  A large-scale, consortium-based genomewide association study of asthma. , 2010, The New England journal of medicine.

[6]  Dirk E. Smith,et al.  The nucleotide-binding domain, leucine-rich repeat protein 3 inflammasome/IL-1 receptor I axis mediates innate, but not adaptive, immune responses after exposure to particulate matter under 10 μm. , 2015, American journal of respiratory cell and molecular biology.

[7]  P. Frascarolo,et al.  Essential fatty acid deficiency in well nourished young cystic fibrosis patients , 1997, European Journal of Pediatrics.

[8]  T. Standiford,et al.  Epigenetic Regulation of Tolerance to Toll-Like Receptor Ligands in Alveolar Epithelial Cells. , 2015, American journal of respiratory cell and molecular biology.

[9]  P. O'Byrne,et al.  Effect of inhaled PGE2 on exercise-induced bronchoconstriction in asthmatic subjects. , 1994, American journal of respiratory and critical care medicine.

[10]  T. Kamei,et al.  Regulatory effect of prostaglandin E2 on fibronectin release from human alveolar macrophages. , 1990, The American review of respiratory disease.

[11]  G. Liggins,et al.  A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. , 1972, Pediatrics.

[12]  N. Misso,et al.  Prostaglandin E2 and cysteinyl leukotriene concentrations in sputum: association with asthma severity and eosinophilic inflammation , 2009, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[13]  H. Hammad,et al.  Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections , 2013, Mucosal Immunology.

[14]  K. C. Kim Role of epithelial mucins during airway infection. , 2012, Pulmonary pharmacology & therapeutics.

[15]  Charles N. Serhan,et al.  Pro-resolving lipid mediators are leads for resolution physiology , 2014, Nature.

[16]  Jilly F. Evans,et al.  Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7 , 2014, British journal of pharmacology.

[17]  M. Oumouna,et al.  Cell-contact dependent inhibition of monocytes by airway epithelial cells and reversion by infection with Respiratory Syncytial Virus. , 2015, Immunobiology.

[18]  Richard C Boucher,et al.  Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice , 2004, Nature Medicine.

[19]  A. Prince,et al.  Toll-like receptors in normal and cystic fibrosis airway epithelial cells. , 2004, American journal of respiratory cell and molecular biology.

[20]  Naftali Kaminski,et al.  TGF-β is a critical mediator of acute lung injury , 2001 .

[21]  J. Blander,et al.  Vita-PAMPs: signatures of microbial viability. , 2013, Advances in experimental medicine and biology.

[22]  S. Ju,et al.  A Major Lung CD103 (αE)-β7 Integrin-Positive Epithelial Dendritic Cell Population Expressing Langerin and Tight Junction Proteins1 , 2006, The Journal of Immunology.

[23]  T. Welte,et al.  Hypoxic epithelial necrosis triggers neutrophilic inflammation via IL-1 receptor signaling in cystic fibrosis lung disease. , 2015, American journal of respiratory and critical care medicine.

[24]  M. Hilty,et al.  Lowering the threshold of lung innate immune cell activation alters susceptibility to secondary bacterial superinfection. , 2011, The Journal of infectious diseases.

[25]  V. Urbach,et al.  The role of Lipoxin A4 in Cystic Fibrosis Lung Disease , 2013, Computational and structural biotechnology journal.

[26]  T. Brunner,et al.  Local glucocorticoid production in the mouse lung is induced by immune cell stimulation , 2012, Allergy.

[27]  J. Wakefield,et al.  Activation of the unfolded protein response by deltaF508 CFTR. , 2008, American journal of respiratory cell and molecular biology.

[28]  David J Erle,et al.  IL-13 and epidermal growth factor receptor have critical but distinct roles in epithelial cell mucin production. , 2007, American journal of respiratory cell and molecular biology.

[29]  D. Golenbock,et al.  MUC1 mucin is a negative regulator of toll-like receptor signaling. , 2008, American journal of respiratory cell and molecular biology.

[30]  B. Lambrecht,et al.  Directed antigen targeting in vivo identifies a role for CD103+ dendritic cells in both tolerogenic and immunogenic T-cell responses , 2011, Mucosal Immunology.

[31]  K. Kaestner,et al.  DNA Binding of the Glucocorticoid Receptor Is Not Essential for Survival , 1998, Cell.

[32]  A. Bourdin,et al.  Club cells, CC10 and self-control at the epithelial surface , 2014, European Respiratory Journal.

[33]  R. Crystal,et al.  Cilia dysfunction in lung disease. , 2015, Annual review of physiology.

[34]  M. Johansson,et al.  The gastrointestinal mucus system in health and disease , 2013, Nature Reviews Gastroenterology &Hepatology.

[35]  C. Serhan,et al.  Identification of a human cDNA encoding a functional high affinity lipoxin A4 receptor , 1994, The Journal of experimental medicine.

[36]  A. Nicholson,et al.  Occupational, environmental and iatrogenic lung disease , 2011, Pathology of the Lungs.

[37]  M. Idzko,et al.  Iloprost has potent anti‐inflammatory properties on human monocyte‐derived dendritic cells , 2010, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[38]  E. Cario Microbiota and innate immunity in intestinal inflammation and neoplasia , 2013, Current opinion in gastroenterology.

[39]  N. Suttorp,et al.  Moraxella catarrhalis is internalized in respiratory epithelial cells by a trigger‐like mechanism and initiates a TLR2‐ and partly NOD1‐dependent inflammatory immune response , 2007, Cellular microbiology.

[40]  S. Batra,et al.  Divergent functions of Toll-like receptors during bacterial lung infections. , 2014, American journal of respiratory and critical care medicine.

[41]  Allan R. Brasier,et al.  Retinoic Acid-Inducible Gene I Mediates Early Antiviral Response and Toll-Like Receptor 3 Expression in Respiratory Syncytial Virus-Infected Airway Epithelial Cells , 2006, Journal of Virology.

[42]  W. Altemeier,et al.  Airway epithelial regulation of pulmonary immune homeostasis and inflammation. , 2014, Clinical immunology.

[43]  P. Sly,et al.  Accelerated Antigen Sampling and Transport by Airway Mucosal Dendritic Cells following Inhalation of a Bacterial Stimulus1 , 2006, The Journal of Immunology.

[44]  B. Harvey,et al.  Lipoxin A₄-mediated KATP potassium channel activation results in cystic fibrosis airway epithelial repair. , 2013, American journal of physiology. Lung cellular and molecular physiology.

[45]  D. Rosenberg,et al.  Multifaceted roles of PGE2 in inflammation and cancer , 2012, Seminars in Immunopathology.

[46]  J. Masferrer,et al.  COX‐2 is expressed in human pulmonary, colonic, and mammary tumors , 2000, Cancer.

[47]  Richard A. Flavell,et al.  Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants , 2008, Nature.

[48]  R. Kradin,et al.  Sequestration of inhaled particulate antigens by lung phagocytes. A mechanism for the effective inhibition of pulmonary cell-mediated immunity. , 1996, The American journal of pathology.

[49]  P. Herrlich,et al.  A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP‐1. , 1994, The EMBO journal.

[50]  J. Frank,et al.  Pulmonary epithelial barrier function: some new players and mechanisms. , 2015, American journal of physiology. Lung cellular and molecular physiology.

[51]  P. Kalinski,et al.  IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. , 1997, Journal of immunology.

[52]  D. Sheppard,et al.  Role of the integrin alpha v beta 6 in cell attachment to fibronectin. Heterologous expression of intact and secreted forms of the receptor. , 1994, The Journal of biological chemistry.

[53]  S. Saglani,et al.  Epithelial cytokines and pulmonary allergic inflammation. , 2015, Current opinion in immunology.

[54]  Luis Carrasco,et al.  The Emerging Roles of Viroporins in ER Stress Response and Autophagy Induction during Virus Infection , 2015, Viruses.

[55]  S. Merali,et al.  Cigarette smoke induces an unfolded protein response in the human lung: a proteomic approach. , 2008, American journal of respiratory cell and molecular biology.

[56]  Zhijian J. Chen,et al.  Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway , 2013, Science.

[57]  Robert V Farese,et al.  Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin , 1996, The Journal of cell biology.

[58]  Adan Chari Jirmo,et al.  Pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for hereditary pulmonary alveolar proteinosis , 2014, Science Translational Medicine.

[59]  Ivana V. Yang,et al.  Muc5b is required for airway defence , 2013, Nature.

[60]  Yeon-Joo Kang,et al.  Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation. , 2007, Progress in lipid research.

[61]  H. Chien,et al.  Distribution and expression of CD200 in the rat respiratory system under normal and endotoxin‐induced pathological conditions , 2010, Journal of anatomy.

[62]  A. Nicholson,et al.  Pathology of the Lungs , 2006 .

[63]  M. H. Lee,et al.  Aspirin-Triggered Lipoxins (15-epi-LX) Are Generated by the Human Lung Adenocarcinoma Cell Line (A549)–Neutrophil Interactions and Are Potent Inhibitors of Cell Proliferation , 1996, Molecular medicine.

[64]  A. Dalpke,et al.  Regulation of local immunity by airway epithelial cells , 2007, Archivum Immunologiae et Therapiae Experimentalis.

[65]  A. Aguzzi,et al.  Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. , 1995, Genes & development.

[66]  M. A. Al-Bayati,et al.  Regional Deposition of Inhaled Monodisperse Coarse and Fine Aerosol Particles in Small Laboratory Animals , 1988 .

[67]  X. Hua,et al.  Analysis of NLRP3 in the Development of Allergic Airway Disease in Mice , 2012, The Journal of Immunology.

[68]  L. Larivière,et al.  Endotoxin-tolerant Mice Have Mutations in Toll-like Receptor 4 (Tlr4) , 1999, The Journal of experimental medicine.

[69]  E. Flaño,et al.  Toll-Like Receptor Expression and Induction of Type I and Type III Interferons in Primary Airway Epithelial Cells , 2013, Journal of Virology.

[70]  Nicola J. Rinaldi,et al.  Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammation. , 2008, American journal of respiratory and critical care medicine.

[71]  I. Ruczinski,et al.  TSLP polymorphisms are associated with asthma in a sex‐specific fashion , 2010, Allergy.

[72]  D. Voelker,et al.  Surfactant Protein A Inhibits Peptidoglycan-induced Tumor Necrosis Factor-α Secretion in U937 Cells and Alveolar Macrophages by Direct Interaction with Toll-like Receptor 2* , 2001, The Journal of Biological Chemistry.

[73]  B. Celli,et al.  Protective role for club cell secretory protein-16 (CC16) in the development of COPD , 2015, European Respiratory Journal.

[74]  J A Gustafsson,et al.  Negative cross-talk between RelA and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids. , 1995, Molecular endocrinology.

[75]  J. Cidlowski,et al.  Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. , 2005, The New England journal of medicine.

[76]  S. Randell,et al.  CD14-dependent Lipopolysaccharide-induced β-Defensin-2 Expression in Human Tracheobronchial Epithelium* , 2000, The Journal of Biological Chemistry.

[77]  K. Ariizumi,et al.  Identification and expression profiling of a human C‐type lectin, structurally homologous to mouse dectin‐2 , 2005, Experimental dermatology.

[78]  M. Hernandez,et al.  Sputum inflammatory cells from patients with allergic rhinitis and asthma have decreased inflammasome gene expression. , 2011, The Journal of allergy and clinical immunology.

[79]  A. Cross,et al.  Cutting Edge: Enhanced Pulmonary Clearance of Pseudomonas aeruginosa by Muc1 Knockout Mice1 , 2006, The Journal of Immunology.

[80]  M. Bacchetta,et al.  Prostaglandin E₂regulation of cystic fibrosis transmembrane conductance regulator activity and airway surface liquid volume requires gap junctional communication. , 2011, American journal of respiratory cell and molecular biology.

[81]  H. Hoogsteden,et al.  Altered expression of epithelial junctional proteins in atopic asthma: possible role in inflammation. , 2008, Canadian journal of physiology and pharmacology.

[82]  D. Sin,et al.  The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome is activated by urban particulate matter. , 2012, The Journal of allergy and clinical immunology.

[83]  P. White,et al.  Cloning and expression of rat cDNA encoding corticosteroid 11 beta-dehydrogenase. , 1989, The Journal of biological chemistry.

[84]  S. Steinberg,et al.  MUC1 is a novel marker for the type II pneumocyte lineage during lung carcinogenesis. , 1998, Cancer research.

[85]  R. F. Hoyt,et al.  Augmentation of functional prostaglandin E levels on the respiratory epithelial surface by aerosol administration of prostaglandin E. , 1991, The American review of respiratory disease.

[86]  B. Levy,et al.  Resolvins: natural agonists for resolution of pulmonary inflammation. , 2011, Progress in lipid research.

[87]  Bart N Lambrecht,et al.  Alveolar macrophage in the driver's seat. , 2006, Immunity.

[88]  Lena Holm,et al.  The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria , 2010, Gut microbes.

[89]  Robert Bals,et al.  Differential Recognition of TLR-Dependent Microbial Ligands in Human Bronchial Epithelial Cells1 , 2007, The Journal of Immunology.

[90]  A. Barclay,et al.  A critical function for CD200 in lung immune homeostasis and the severity of influenza infection , 2008, Nature Immunology.

[91]  J. Resau,et al.  Cyclooxygenase metabolism of endogenous arachidonic acid by cultured human tracheal epithelial cells. , 1989, The American review of respiratory disease.

[92]  P. Chanez,et al.  Supplementing defect in club cell secretory protein attenuates airway inflammation in COPD. , 2015, Chest.

[93]  P. Ricciardi-Castagnoli,et al.  Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. , 1998, Science.

[94]  B. Lambrecht,et al.  Division of labor between dendritic cell subsets of the lung , 2008, Mucosal Immunology.

[95]  I. Pavord,et al.  Effect of inhaled prostaglandin E2 on allergen-induced asthma. , 1993, The American review of respiratory disease.

[96]  C. Ziegler,et al.  Thymic stromal lymphopoietin-mediated extramedullary hematopoiesis promotes allergic inflammation. , 2013, Immunity.

[97]  G. Edelman,et al.  Multiple integrins mediate cell attachment to cytotactin/tenascin. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[98]  B. Stripp,et al.  Mucin is produced by clara cells in the proximal airways of antigen-challenged mice. , 2004, American journal of respiratory cell and molecular biology.

[99]  D. Schwartz,et al.  Detrimental role of the airway mucin Muc5ac during ventilator-induced lung injury , 2012, Mucosal Immunology.

[100]  E. Raz Organ-specific regulation of innate immunity , 2007, Nature Immunology.

[101]  V. Glumoff,et al.  Regulation of surfactant proteins by LPS and proinflammatory cytokines in fetal and newborn lung. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[102]  H. Hammad,et al.  Interleukin-1α controls allergic sensitization to inhaled house dust mite via the epithelial release of GM-CSF and IL-33 , 2012, The Journal of experimental medicine.

[103]  D. Sheppard,et al.  Restricted distribution of integrin beta 6 mRNA in primate epithelial tissues. , 1993, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[104]  J. Drazen,et al.  Human alveolar macrophages have 15-lipoxygenase and generate 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid and lipoxins. , 1993, The Journal of clinical investigation.

[105]  大屋 円 Human pulmonary surfactant protein D binds the extracellular domains of toll-like receptors 2 and 4 through the carbohydrate recognition domain by a mechanism different from its binding to phosphatidylinositol and lipopolysaccharide , 2006 .

[106]  Annette S. Kim,et al.  Viral acute lower respiratory infections impair CD8+ T cells through PD-1. , 2012, The Journal of clinical investigation.

[107]  M. Blackburn,et al.  Central role of Muc5ac expression in mucous metaplasia and its regulation by conserved 5' elements. , 2007, American journal of respiratory cell and molecular biology.

[108]  Meshell D. Johnson,et al.  Differential Response of Primary Alveolar Type I and Type II Cells to LPS Stimulation , 2013, PloS one.

[109]  Dirk E. Smith,et al.  CD34+ hemopoietic progenitor cells are potent effectors of allergic inflammation. , 2009, The Journal of allergy and clinical immunology.

[110]  R. Locksley,et al.  Spatiotemporally separated antigen uptake by alveolar dendritic cells and airway presentation to T cells in the lung , 2012, The Journal of experimental medicine.

[111]  C. Chung,et al.  PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis , 2009, Proceedings of the National Academy of Sciences.

[112]  N. Kaminski,et al.  The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. , 1999, Cell.

[113]  B. Rubin,et al.  Club cell 10-kDa protein attenuates airway mucus hypersecretion and inflammation , 2014, European Respiratory Journal.

[114]  Seung Yong Park,et al.  Endoplasmic reticulum stress influences bronchial asthma pathogenesis by modulating nuclear factor κB activation. , 2013, The Journal of allergy and clinical immunology.

[115]  Zheng Liu,et al.  Clara Cell 10-kDa Protein Gene Transfection Inhibits NF-κB Activity in Airway Epithelial Cells , 2012, PloS one.

[116]  P. O'Byrne,et al.  Protective effects of inhaled PGE2 on allergen-induced airway responses and airway inflammation. , 1999, American journal of respiratory and critical care medicine.

[117]  B. Harvey,et al.  Lipoxin A4 Stimulates Calcium-Activated Chloride Currents and Increases Airway Surface Liquid Height in Normal and Cystic Fibrosis Airway Epithelia , 2012, PloS one.

[118]  G. Zhu,et al.  PD-1 on dendritic cells impedes innate immunity against bacterial infection. , 2009, Blood.

[119]  K. Ridge,et al.  The inflammasome in lung diseases. , 2012, American journal of physiology. Lung cellular and molecular physiology.

[120]  J. Sheehan,et al.  Innate immunity and mucus structure and function. , 2008, Novartis Foundation symposium.

[121]  M. Hernandez,et al.  Atopic asthmatic patients have reduced airway inflammatory cell recruitment after inhaled endotoxin challenge compared with healthy volunteers. , 2012, The Journal of allergy and clinical immunology.

[122]  F. R. Papa,et al.  The role of endoplasmic reticulum stress in human pathology. , 2015, Annual review of pathology.

[123]  J. Tschopp,et al.  NLRP3 inflammasome is required in murine asthma in the absence of aluminum adjuvant , 2011, Allergy.

[124]  B. Moore,et al.  Prostaglandin E2 and the pathogenesis of pulmonary fibrosis. , 2011, American journal of respiratory cell and molecular biology.

[125]  R. Dahl,et al.  Mapping of TLR5 and TLR7 in central and distal human airways and identification of reduced TLR expression in severe asthma , 2014, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[126]  J. Denburg,et al.  In situ hematopoiesis: a regulator of TH2 cytokine-mediated immunity and inflammation at mucosal surfaces , 2015, Mucosal Immunology.

[127]  I. Pavord,et al.  Bronchoprotective role for endogenous prostaglandin E2 , 1995, The Lancet.

[128]  J. Celli,et al.  Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes? , 2014, Nature Reviews Microbiology.

[129]  T. Hartert,et al.  The role of prostaglandins in allergic lung inflammation and asthma , 2015, Expert review of respiratory medicine.

[130]  P. Howarth,et al.  Defective epithelial barrier function in asthma. , 2011, The Journal of allergy and clinical immunology.

[131]  F. Lasitschka,et al.  Bronchial Epithelial Cells Induce Alternatively Activated Dendritic Cells Dependent on Glucocorticoid Receptor Signaling , 2014, The Journal of Immunology.

[132]  Eric Vivier,et al.  Innate lymphoid cells — a proposal for uniform nomenclature , 2013, Nature Reviews Immunology.

[133]  Nicola J. Rinaldi,et al.  Partial Inhibition of Integrin αvβ6 Prevents Pulmonary Fibrosis without Exacerbating Inflammation , 2008 .

[134]  N. Flamand,et al.  Pulmonary CD103 expression regulates airway inflammation in asthma. , 2015, American journal of physiology. Lung cellular and molecular physiology.

[135]  W. Alkema,et al.  Prednisolone-induced differential gene expression in mouse liver carrying wild type or a dimerization-defective glucocorticoid receptor , 2010, BMC Genomics.

[136]  E. Flaño,et al.  Local Blockade of Epithelial PDL-1 in the Airways Enhances T Cell Function and Viral Clearance during Influenza Virus Infection , 2013, Journal of Virology.

[137]  Shaohua Chen,et al.  The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies , 2013, Journal of Hematology & Oncology.

[138]  S. Johnston,et al.  Expression of programmed death-1 ligand (PD-L) 1, PD-L2, B7-H3, and inducible costimulator ligand on human respiratory tract epithelial cells and regulation by respiratory syncytial virus and type 1 and 2 cytokines. , 2006, The Journal of infectious diseases.

[139]  A. Braun,et al.  Spatiotemporal and functional behavior of airway dendritic cells visualized by two-photon microscopy. , 2011, The American journal of pathology.

[140]  A. Dalpke,et al.  Airway epithelial cells modify immune responses by inducing an anti‐inflammatory microenvironment , 2008, European journal of immunology.

[141]  N. Kaminski,et al.  Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema. , 2003, Nature.

[142]  S. Maruoka,et al.  Pulmonary CD103+ dendritic cells prime Th2 responses to inhaled allergens , 2011, Mucosal Immunology.

[143]  A. Verkman,et al.  Role of airway surface liquid and submucosal glands in cystic fibrosis lung disease. , 2003, American journal of physiology. Cell physiology.

[144]  S. Ju,et al.  A major lung CD103 (alphaE)-beta7 integrin-positive epithelial dendritic cell population expressing Langerin and tight junction proteins. , 2006, Journal of immunology.

[145]  T. Wynn,et al.  Muc5ac: a critical component mediating the rejection of enteric nematodes , 2011, The Journal of experimental medicine.

[146]  J. Connett,et al.  Club cell protein 16 and disease progression in chronic obstructive pulmonary disease. , 2013, American journal of respiratory and critical care medicine.

[147]  J. Kolls Faculty Opinions recommendation of IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses. , 2010 .

[148]  G. Rosen,et al.  Uptake, release and novel species-dependent oxygenation of arachidonic acid in human and animal airway epithelial cells. , 1988, Biochimica et biophysica acta.

[149]  K. Howie,et al.  Mast Cell-Activated Bone Marrow Mesenchymal Stromal Cells Regulate Proliferation and Lineage Commitment of CD34+ Progenitor Cells , 2013, Front. Immunol..

[150]  F. Martinon,et al.  Inflammasome Components NALP 1 and 3 Show Distinct but Separate Expression Profiles in Human Tissues Suggesting a Site-specific Role in the Inflammatory Response , 2007, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[151]  I. Pavord,et al.  Induced sputum eicosanoid concentrations in asthma. , 1999, American journal of respiratory and critical care medicine.

[152]  D. Sheppard,et al.  Characterization of the integrin alpha v beta 6 as a fibronectin-binding protein. , 1992, The Journal of biological chemistry.

[153]  Toru Takahashi,et al.  Direct Binding of Toll-Like Receptor 2 to Zymosan, and Zymosan-Induced NF-κB Activation and TNF-α Secretion Are Down-Regulated by Lung Collectin Surfactant Protein A1 , 2003, The Journal of Immunology.

[154]  E. Gwyer Findlay,et al.  Macrophage-Mediated Inflammation and Disease: A Focus on the Lung , 2012, Mediators of inflammation.

[155]  N. Kaminski,et al.  TGF-beta is a critical mediator of acute lung injury. , 2001, The Journal of clinical investigation.

[156]  J. Penninger,et al.  Brief Definitive Report , 2003 .

[157]  C. Ruppert,et al.  Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. , 2008, American journal of respiratory and critical care medicine.

[158]  N. Kaminski,et al.  Loss of integrin αvβ6-mediated TGF-β activation causes Mmp12-dependent emphysema , 2003, Nature.

[159]  H. Dienemann,et al.  Dectin-1 Is Expressed in Human Lung and Mediates the Proinflammatory Immune Response to Nontypeable Haemophilus influenzae , 2014, mBio.

[160]  Bernard Malissen,et al.  Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF , 2013, The Journal of experimental medicine.

[161]  山田 ちえ子 Surfactant protein A directly interacts with TLR4 and MD-2, and regulates inflammatory cellular response : importance of supratrimeric oligomerization , 2006 .

[162]  J. Kline,et al.  Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[163]  M. Matthay,et al.  Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin. , 1991, The Journal of clinical investigation.

[164]  D. Sheppard,et al.  The αvβ6 integrin modulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells. , 2012, The Journal of clinical investigation.

[165]  Edwards,et al.  11 b-Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress , 1997 .

[166]  E. Weibel,et al.  Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia. , 2015, The American review of respiratory disease.