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Viral infections are recognized as significant triggers of exacerbations; however, less is understood about the how microbial bioproducts such as the endotoxin (lipopolysaccharide (LPS)) trigger episodes. Indeed, increased levels of LPS have been linked to asthma onset, severity and steroid resistance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>The goal of this study was to identify mechanisms underlying bacterial\u2010induced exacerbations by employing LPS as a surrogate for infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We developed a mouse model of LPS\u2010induced exacerbation on the background of pre\u2010existing type\u20102 allergic airway disease (AAD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>LPS\u2010induced exacerbation was characterized by steroid\u2010resistant airway hyperresponsiveness (AHR) and an exaggerated inflammatory response distinguished by increased numbers of infiltrating neutrophils\/macrophages and elevated production of lung inflammatory cytokines, including TNF\u03b1, IFN\u03b3, IL\u201027 and MCP\u20101. Expression of the type\u20102 associated inflammatory factors such as IL\u20105 and IL\u201013 were elevated in AAD but not altered by LPS exposure. Furthermore, AHR and airway inflammation were no longer suppressed by corticosteroid (dexamethasone) treatment after LPS exposure. Depletion of pulmonary macrophages by administration of 2\u2010chloroadenosine into the lungs suppressed AHR and reduced IL\u201013, TNF\u03b1 and IFN\u03b3 expression. Blocking IL\u201013 function, through either IL\u201013\u2010deficiency or administration of specific blocking antibodies, also suppressed AHR and airway inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions &amp; Clinical Relevance<\/jats:title><jats:p>We present evidence that IL\u201013 and innate immune pathways (in particular pulmonary macrophages) contribute to LPS\u2010induced exacerbation of pre\u2010existing AAD and provide insight into the complex molecular processes potentially underlying microbial\u2010induced exacerbations.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cea.13505","type":"journal-article","created":{"date-parts":[[2019,10,3]],"date-time":"2019-10-03T11:22:44Z","timestamp":1570101764000},"page":"82-94","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Lipopolysaccharide induces steroid\u2010resistant exacerbations in a mouse model of allergic airway disease collectively through IL\u201013 and pulmonary macrophage activation"],"prefix":"10.1111","volume":"50","author":[{"given":"Sara","family":"Hadjigol","sequence":"first","affiliation":[{"name":"Priority Research Centre for Healthy Lungs Department of Microbiology and Immunology, School of Biomedical Sciences &amp; Pharmacy Faculty of Health and Priority Research Centre for Healthy Lungs Hunter Medical Research Institute University of Newcastle Callaghan NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keilah G.","family":"Netto","sequence":"additional","affiliation":[{"name":"Priority Research Centre for Healthy Lungs Department of Microbiology and Immunology, School of Biomedical Sciences &amp; Pharmacy Faculty of Health and Priority Research Centre for Healthy Lungs Hunter Medical Research Institute University of Newcastle Callaghan NSW 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