TGF-beta signaling in COPD: deciphering genetic and cellular susceptibilities for future therapeutic regimen

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the developed world and associated with a high individual and socioeconomic burden. Despite emerging preventive efforts and ongoing clinical trials, the frequency and mortality of COPD are expected to continue to rise over the next decades. COPD is defined as an irreversible expiratory airflow limitation, which is caused by various degrees of the following two main features: First, small airway disease (SAD), which includes airway inflammation and remodelling, and second, emphysema, which is characterised by airspace enlargement. The major risk factor for COPD is cigarette smoke exposure; however, the molecular mechanisms linking smoke to different COPD features on the cellular level remain elusive. The transforming growth factor (TGF)-beta superfamily constitutes more than 40 members, which are essential during organ development, a process often recapitulated in chronic diseases. Emerging interest in the role of TGF-beta in the pathogenesis of COPD has recently evolved, particularly since genetic studies have demonstrated an association of gene polymorphisms of the TGF-beta superfamily with COPD. In addition, increased expression of TGF-beta1 in COPD lungs and primary cells, such as epithelial cells, macrophages, or fibroblasts isolated from COPD specimens, was reported, suggesting an impact of TGF-beta signalling on the development and progression of COPD. Thus, targeted interventions of TGF-beta signalling may represent a suitable therapeutic option in COPD. In this review, we will summarise the current understanding of the impact of TGF-beta in COPD pathogenesis. The review is separated into five chapters: 1) an introduction to COPD, 2) an introduction to TGF-beta signalling, 3) a summary of TGF-beta gene polymorphisms in COPD, 4) a summary of TGF-beta signalling in small airway disease, and 5) a summary of TGF-beta signalling in emphysema.