Potential Role of Endothelin-1 in Pulmonary Fibrosis From the Bench to the Clinic

Endothelin-1 (ET-1) plays a central role in lung fibrosis. It is released in the lung at low concentrations from the endothelium, epithelium, and vascular smooth muscle cells and orchestrates a variety of effects. In the context of wound healing, ET-1 acts with other profibrotic mediators to recruit fibroblasts and allow for their differentiation to contractile myofibroblasts. These specialized cells in turn lay down fibrotic tissue and contract at the site of lesions to restore tissue integrity. Apoptosis and reversion to quiescence ensues. However, in diseases of the lung such as idiopathic pulmonary fibrosis (IPF), the fibrotic response is uncontrolled. Progressive injury to lung tissue, isolated both temporally and geographically, is uncontrolled and eventually causes enough tissue damage to alter pulmonary architecture and compromise function. The initiating mechanisms are as of yet largely unknown; however, ET-1 has clearly emerged as a key mediator of this disease. Here, a comprehensive overview of the role of ET-1 in fibrosis is given. A guided perspective begins from the scope of its various molecular interactions to its many cellular processes, and finally to the implications of these functions in IPF.