Genes and Pathways Regulating Decline in Lung Function and Airway Remodeling in Asthma

Hur, Gyu Young; Broide, David H.

TGF-β1 is a pleiotropic mediator which can affect the function of airway structural cells (including fibroblasts, smooth muscle cells and epithelium) implicated in the remodeling process of patients with asthma. TGF-β1 is expressed in asthmatic airway, promotes the differentiation of fibroblasts to myofibroblast, and may contribute to sub-epithelial fibrosis and proliferation of airway smooth muscle in asthma. 46 The importance of TGF-β1 and its signaling through the Smad-3 pathway in airway remodeling has been demonstrated in Smad-3 deficient mice. 47 Smad-3 deficient mice challenged with allergen develop significantly less peribronchial fibrosis, smooth muscle proliferation, and mucus production compared to wild-type mice. 47 Epithelial overexpression of Smad2 can also increase subepithelial collagen deposition and smooth muscle hyperplasia without an increase in airway inflammation. 48 Moreover, TGF-β1 modulates proliferation of airway smooth muscle. TGF-β1 in the asthmatic airway can be derived from multiple cellular sources including eosinophils, macrophages and epithelium. The importance of eosinophil expression of TGF-β1 is suggested in studies of asthmatics treated with anti-IL-5 to deplete eosinophils. 49 These studies demonstrated that asthmatics treated with anti-IL-5 (mepolizumab) for 3 months had significantly lower levels of BAL eosinophils as anticipated, although they had significantly lower levels of BAL TGF-β1 due to depletion by anti-IL5 of eosinophils in BAL expressing TGF-β1. This depletion of eosinophils expressing TGF-β1 by anti-IL-5 was associated with reduction in the levels of extracellular matrix proteins deposited in the airway, suggesting that anti-IL-5 by depleting eosinophils expressing TGF-β1 exerted an inhibitory effect on airway remodeling. In addition to eosinophils expressing TGF-β1, TGF-β2 is expressed mainly by eosinophils and is prominent in severe asthma.