Rhinovirus infection induces secretion of endothelin-1 from airway epithelial cells in both in vitro and in vivo models

Respiratory Research

Research

Nathan W. Bartlett¹  Jason Girkin¹  Adam Collison¹  Joerg Mattes¹  James E. Gern²  Yury A. Bochkov²  Chimwemwe Mwase³  Michael J. O’Sullivan³  Thien-Khoi N. Phung³  Jin-Ah Park³  Alane Blythe C. Dy³  Antonella Marrocco³  Cynthia Koziol-White⁴ 

[1] College of Health, Medicine and Wellbeing, University of Newcastle and Hunter Medical Research Institute, New Lambton Heights, Australia;Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA;Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, SPH1-315, Boston, MA, USA;Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA;

关键词: Rhinovirus infection;    Epithelial endothelin-1;    Asthma exacerbations;    Bronchoconstriction;    Mechanical compression;   

DOI  :  10.1186/s12931-023-02510-6

 received in 2023-05-28, accepted in 2023-08-11,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundRhinovirus (RV) infection of airway epithelial cells triggers asthma exacerbations, during which airway smooth muscle (ASM) excessively contracts. Due to ASM contraction, airway epithelial cells become mechanically compressed. We previously reported that compressed human bronchial epithelial (HBE) cells are a source of endothelin-1 (ET-1) that causes ASM contraction. Here, we hypothesized that epithelial sensing of RV by TLR3 and epithelial compression induce ET-1 secretion through a TGF-β receptor (TGFβR)-dependent mechanism.MethodsTo test this, we used primary HBE cells well-differentiated in air–liquid interface culture and two mouse models (ovalbumin and house dust mite) of allergic airway disease (AAD). HBE cells were infected with RV-A16, treated with a TLR3 agonist (poly(I:C)), or exposed to compression. Thereafter, EDN1 (ET-1 protein-encoding gene) mRNA expression and secreted ET-1 protein were measured. We examined the role of TGFβR in ET-1 secretion using either a pharmacologic inhibitor of TGFβR or recombinant TGF-β1 protein. In the AAD mouse models, allergen-sensitized and allergen-challenged mice were subsequently infected with RV. We then measured ET-1 in bronchoalveolar lavage fluid (BALF) and airway hyperresponsiveness (AHR) following methacholine challenge.ResultsOur data reveal that RV infection induced EDN1 expression and ET-1 secretion in HBE cells, potentially mediated by TLR3. TGFβR activation was partially required for ET-1 secretion, which was induced by RV, poly(I:C), or compression. TGFβR activation alone was sufficient to increase ET-1 secretion. In AAD mouse models, RV induced ET-1 secretion in BALF, which positively correlated with AHR.ConclusionsOur data provide evidence that RV infection increased epithelial-cell ET-1 secretion through a TGFβR-dependent mechanism, which contributes to bronchoconstriction during RV-induced asthma exacerbations.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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