The regulatory role of TGF-β in airway remodeling in asthma

Both structural and inflammatory cells are capable of secreting transforming growth factor (TGF)-β and expressing TGF-β receptors. TGF-β can induce multiple cellular responses including differentiation, apoptosis, survival and proliferation, and has been implicated in the development of several pathogenic conditions including cancer and asthma. Elevated levels of TGF-β have been reported in the asthmatic airway. TGF-β binds to its receptor complex and activates multiple pathways involving proteins such as Sma and Mad homologues, phosphatidylinositol-3 kinase and the mitogen-activated protein kinases, leading to the transcription of several genes. Cell type, cellular condition, and microenvironment, all play a role in determining which pathway is activated, which, in turn, is an indication of which gene is to be transcribed. TGF-β has been shown to induce apoptosis in airway epithelial cells. A possible role for TGF-β in the regulation of epithelial cell adhesion properties has also been reported. Enhancement of goblet cell proliferation by TGF-β suggests a role in mucus hyper-secretion. Elevated levels of TGF-β correlate with subepithelial fibrosis. TGF-β induces proliferation of fibroblast cells and their differentiation into myofibroblasts and extracellular matrix (ECM) protein synthesis during the development of subepithelial fibrosis. TGF-β also induces proliferation and survival of and ECM secretion in airway smooth muscle cells (ASMCs), suggesting a possible cause of increased thickness of airway tissues. TGF-β also induces the production and release of vascular endothelial cell growth factor and plasminogen activator inhibitor, contributing to the vascular remodeling in the asthmatic airway. Blocking TGF-β activity inhibits epithelial shedding, mucus hyper-secretion, angiogenesis, ASMC hypertrophy and hyperplasia in an asthmatic mouse model. Reduction of TGF-β production and control of TGF-β effects would be beneficial in the development of therapeutic intervention for airway remodeling in chronic asthma.