Rhinovirus‐induced basic fibroblast growth factor release mediates airway remodeling features

Chrysanthi L Skevaki,Eleni Volonaki,Irini S Spyridaki,Dimitrios Gourgiotis,Sebastian L Johnston,Stylianos Vittorakis,Dimitris Kletsas,Vassiliki Georgiou,Aurica G Telcian,Nikolaos G Papadopoulos,Harris Pratsinis,Stelios Psarras,Mina Gaga,Paraskevi Maggina

doi:10.1186/2045-7022-2-14

Abstract

BackgroundHuman rhinoviruses, major precipitants of asthma exacerbations, induce lower airway inflammation and mediate angiogenesis. The purpose of this study was to assess the possibility that rhinoviruses may also contribute to the fibrotic component of airway remodeling.MethodsLevels of basic fibroblast growth factor (bFGF) mRNA and protein were measured following rhinovirus infection of bronchial epithelial cells. The profibrotic effect of epithelial products was assessed by DNA synthesis and matrix metalloproteinase activity assays. Moreover, epithelial cells were exposed to supernatants from cultured peripheral blood mononuclear cells, obtained from healthy donors or atopic asthmatic subjects and subsequently infected by rhinovirus and bFGF release was estimated. bFGF was also measured in respiratory secretions from atopic asthmatic patients before and during rhinovirus-induced asthma exacerbations.ResultsRhinovirus epithelial infection stimulated mRNA expression and release of bFGF, the latter being positively correlated with cell death under conditions promoting rhinovirus-induced cytotoxicity. Supernatants from infected cultures induced lung fibroblast proliferation, which was inhibited by anti-bFGF antibody, and demonstrated increased matrix metalloproteinase activity. Rhinovirus-mediated bFGF release was significantly higher in an in vitro simulation of atopic asthmatic environment and, importantly, during rhinovirus-associated asthma exacerbations.ConclusionsRhinovirus infection induces bFGF release by airway epithelium, and stimulates stroma cell proliferation contributing to airway remodeling in asthma. Repeated rhinovirus infections may promote asthma persistence, particularly in the context of atopy; prevention of such infections may influence the natural history of asthma.

Highlights

Human rhinoviruses, major precipitants of asthma exacerbations, induce lower airway inflammation and mediate angiogenesis
We have recently demonstrated that RV infection may promote airway remodeling by inducing angiogenesis through vascular endothelial growth factor (VEGF) production by the bronchial epithelium [15]
Primary human bronchial epithelial (PHBE) and Normal human bronchial epithelial (NHBE) cells were grown in bronchial epithelial basal medium (BEBM), which was supplemented with growth supplements as recommended by the manufacturer, and they were used at passages 2–3

Summary

Introduction

Major precipitants of asthma exacerbations, induce lower airway inflammation and mediate angiogenesis. Chemical or mechanical insult to the epithelium may lead to proliferation of myofibroblasts and increased collagen production due to the action of growth factors including bFGF [10]. RVs infect and replicate in the lower airway epithelium [12], leading to local and systemic immune responses and production of inflammatory mediators [13], that have the potential of inducing and/or regulating airway remodeling [14]. We have recently demonstrated that RV infection may promote airway remodeling by inducing angiogenesis through vascular endothelial growth factor (VEGF) production by the bronchial epithelium [15]

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