TY - JOUR AB - © 2019 John Wiley & Sons Ltd Background: Acute exacerbations of asthma represent a major burden of disease and are often caused by respiratory infections. 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. Objective: The goal of this study was to identify mechanisms underlying bacterial-induced exacerbations by employing LPS as a surrogate for infection. Methods: We developed a mouse model of LPS-induced exacerbation on the background of pre-existing type-2 allergic airway disease (AAD). Results: LPS-induced exacerbation was characterized by steroid-resistant 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?, IFN?, IL-27 and MCP-1. Expression of the type-2 associated inflammatory factors such as IL-5 and IL-13 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-chloroadenosine into the lungs suppressed AHR and reduced IL-13, TNF? and IFN? expression. Blocking IL-13 function, through either IL-13-deficiency or administration of specific blocking antibodies, also suppressed AHR and airway inflammation. Conclusions & Clinical Relevance: We present evidence that IL-13 and innate immune pathways (in particular pulmonary macrophages) contribute to LPS-induced exacerbation of pre-existing AAD and provide insight into the complex molecular processes potentially underlying microbial-induced exacerbations. AU - Hadjigol, S AU - Netto, KG AU - Maltby, S AU - Tay, HL AU - Nguyen, TH AU - Hansbro, NG AU - Eyers, F AU - Hansbro, PM AU - Yang, M AU - Foster, PS DA - 2020/01/01 DO - 10.1111/cea.13505 EP - 94 JO - Clinical and Experimental Allergy PY - 2020/01/01 SP - 82 TI - Lipopolysaccharide induces steroid-resistant exacerbations in a mouse model of allergic airway disease collectively through IL-13 and pulmonary macrophage activation VL - 50 Y1 - 2020/01/01 Y2 - 2024/03/29 ER -