Abstract
The TGF-β family of mediators are thought to play important roles in the regulation of inflammation and airway remodelling in asthma. All three mammalian isoforms of TGF-β, TGF-β1–3, are expressed in the airways and TGF-β1 and -β2 are increased in asthma. However, there is little information on the specific roles of individual TGF-β isoforms. In this study we assess the roles of TGF-β1 and TGF-β2 in the regulation of allergen-induced airway inflammation and remodelling associated with asthma, using a validated murine model of ovalbumin sensitization and challenge, and isoform specific TGF-β neutralising antibodies. Antibodies to both isoforms inhibited TGF-β mediated Smad signalling. Anti-TGF-β1 and anti-TGF-β2 inhibited ovalbumin-induced sub-epithelial collagen deposition but anti-TGF-β1 also specifically regulated airway and fibroblast decorin deposition by TGF-β1. Neither antibody affected the allergen-induced increase in sub-epithelial fibroblast-like cells. Anti- TGF-β1 also specifically inhibited ovalbumin-induced increases in monocyte/macrophage recruitment. Whereas, both TGF-β1 and TGF-β2 were involved in regulating allergen-induced increases in eosinophil and lymphocyte numbers. These data show that TGF-β1 and TGF-β2 exhibit a combination of specific and shared roles in the regulation of allergen-induced airway inflammation and remodelling. They also provide evidence in support of the potential for therapeutic regulation of specific subsets of cells and extracellular matrix proteins associated with inflammation and remodelling in airway diseases such as asthma and COPD, as well as other fibroproliferative diseases.
Highlights
Asthma is characterised by bronchial hyperreactivity, chronic inflammation and airway remodelling [1], with excess subepithelial deposition of extracellular matrix (ECM) molecules including collagens and proteoglycans [2,3,4,5,6], that correlates with increased fibroblast/myofibroblast number [4,7,8], airway hyperresponsiveness [9], and reduced lung function [10]
In the normal human lung, all three isoforms are expressed by and/or localised to the bronchial epithelium, TGF-b1 and TGF-b3 are expressed by macrophages, and TGF-b1 is expressed by vascular endothelial, smooth muscle and fibroblast-like cells as well as being bound to the sub-epithelial ECM [12,13,14,15,16,17,18]
Using an animal model and transforming growth factor-b (TGF-b) isoform specific neutralising antibodies, we show that TGF-b1 regulates OVA-induced increases in macrophages and sub-epithelial deposition of decorin
Summary
Asthma is characterised by bronchial hyperreactivity, chronic inflammation and airway remodelling [1], with excess subepithelial deposition of extracellular matrix (ECM) molecules including collagens and proteoglycans [2,3,4,5,6], that correlates with increased fibroblast/myofibroblast number [4,7,8], airway hyperresponsiveness [9], and reduced lung function [10]. The mechanisms responsible for the pathologic features of asthma are incompletely understood. They are generally considered to involve complex interactions between resident and infiltrating cells and the mediators they produce [11]. There are three mammalian isoforms, TGF-b1–3, which play important roles in regulating inflammation, cell growth and differentiation, including of ECM metabolism [1]. In situ hybridization and immunohistochemical studies indicate that
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