Safer approaches to therapeutic modulation of TGF-β signaling for respiratory disease

The transforming growth factor (TGF)-β cytokines play a central role in development and progression of chronic respiratory diseases. TGF-β overexpression in chronic inflammation, remodeling, fibrotic process and susceptibility to viral infection is established in the most prevalent chronic respiratory diseases including asthma, COPD, lung cancer and idiopathic pulmonary fibrosis. Despite the overwhelming burden of respiratory diseases in the world, new pharmacological therapies have been limited in impact. Although TGF-β inhibition as a therapeutic strategy carries great expectations, the constraints in avoiding compromising the beneficial pleiotropic effects of TGF-β, including the anti-proliferative and immune suppressive effects, have limited the development of effective pharmacological modulators. In this review, we focus on the pathways subserving deleterious and beneficial TGF-β effects to identify strategies for selective modulation of more distal signaling pathways that may result in agents with improved safety/efficacy profiles. Adverse effects of TGF-β inhibitors in respiratory clinical trials are comprehensively reviewed, including those of the marketed TGF-β modulators, pirfenidone and nintedanib. Precise modulation of TGF-β signaling may result in new safer therapies for chronic respiratory diseases.