Novel therapy for idiopathic pulmonary arterial hypertension: Can hepatocyte growth factor be beneficial?

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a progressive, nearly fatal condition that until recently has had very few treatment options. Median survival time for untreated IPAH was 2.8 years without effective drug intervention. IPAH is characterized by deregulated proliferation of pulmonary arterial endothelial and intimal smooth muscle cells resulting in progressive pulmonary vascular remodeling and an increase in pulmonary arterial pressure. In order to alleviate their symptoms, anticoagulants, diuretics, calcium channel blockers and inotropic agents have been used to treat patients with PAH. Moreover, specific targeted therapies using prostacyclins, endothelin-receptor antagonists and phosphodiesterase type-5 inhibitors have been developed recently. However, because of the insufficient proof of efficacy and poor tolerability of these agents, new therapeutic modalities continue to be explored. Hepatocyte growth factor (HGF), which was first purified as a mitogen for hepatocytes from the plasma of patients with fulminant hepatic failure, has mitogenic, motogenic, morphogenic, and antiapoptotic activities in various cell types. The pluripotent activities of HGF are mediated by a membrane- spanning tyrosine kinase receptor encoded by the c-Met proto-oncogene. HGF acts as a safe and effective organotrophic factor for protection from injury and ischemia of various organs. Phase-II and Phase-III clinical trials of HGF gene therapy for the treatment of peripheral arterial disease have been completed in both the USA and Japan. In the lung, biological and pulmotrophic roles for HGF have been well documented. In response to acute lung injury, HGF plays a role in lung regeneration and protection. Furthermore, research elucidating the pulmotrophic role of HGF has led to the development of therapeutic approaches for the treatment of chronic lung diseases.