Mesenchymal cell fate and phenotypes in the pathogenesis of emphysema

Emphysema is characterized by the destruction of alveolar parenchymal tissue and the concordant loss of lung epithelial cells, endothelial cells, and interstitial mesenchymal cells. Key features in the pathobiology of emphysema include inflammation, alveolar epithelial cell injury/apoptosis, and excessive activation of extracellular matrix (ECM) proteases. Mesenchymal cells are versatile connective tissue cells that are critical effectors of wound-repair. The excessive loss of connective tissue and the destruction of alveolar septae in emphysema suggest that the mesenchymal cell reparative response to epithelial injury is impaired. Yet, the mechanisms regulating mesenchymal cell (dys)function in emphysema remain poorly understood. We propose that mesenchymal cell fate, modulated by transforming growth factor beta-1 (TGF-beta1) and the balance of ECM proteases and antiproteases, is a critical determinant of the emphysema phenotype. We examine emphysema in the context of wound-repair responses, with a focus on the regulation of mesenchymal cell fate and phenotype. We discuss the emerging evidence supporting that genetic factors, inflammation and environmental factors, including cigarette smoke itself, collectively impair mesenchymal cell survival and function, thus contributing to the pathogenesis of emphysema.