The Role of Endothelin-1 in the Pathogenesis of Idiopathic Pulmonary Fibrosis

The endothelin system participates in a number of critical biologic pathways, including normal wound healing. In addition, emerging basic science, and animal and human data all suggest that endothelin-1 (EDN1, also known as ET-1) is a potentially important contributor in the pathobiology of fibrosing disorders, including those that affect the lung. For example, EDN1 drives fibroblast activation, proliferation, as well as differentiation into myofibroblasts — processes that lead to excessive collagen deposition. Patients with idiopathic pulmonary fibrosis (IPF) have increased levels of EDN1 in both their bronchoalveolar lavage fluid and lung tissue. Beyond this, rodent models suggest that endothelin receptor antagonists can limit bleomycin-induced lung fibrosis. This suggests a biologic rationale for the blockade of EDN1 to limit the evolution of lung fibrosis in humans. Initial results from a trial examining the efficacy of a dual endothelin receptor antagonist suggest that this approach may delay disease progression in a subset of patients with IPF.