Hepatocyte Growth Factor (HGF), an Endogenous Pulmotrophic Regulator, for the Rescue of Acute and Chronic Lung Diseases

There is now ample evidence that hepatocyte growth factor (HGF) is essential for organogenesis in embryo and tissue repair for adults in almost all organs. In the lung, HGF elicits mitogenic, morphogenic and anti-apoptotic effects on bronchial and alveolar epithelial cells. HGF also elicits an angiogenic response through enhancing endothelial cell proliferation. Several studies using animal models clearly demonstrated that endogenous HGF is required for bronchial formation and alveolar septation at an embryonic stage, and of interest, even during adult diseases, such as emphysema. HGF has an anti-inflammatory effect on lung macrophages during sepsis, or on infiltrated eosinophils during asthma. HGF elicits anti-fibrogenic activities toward myofibroblasts under chronic lung injury. These multiple functions are mediated through tyrosine phosphorylation of c-Met/HGF-receptor. During the acute and chronic lung diseases, HGF is highly produced by lung stromal cells (or in distant organs), but this beneficial response is transient, insufficient and often delayed. Such a loss in HGF-c-Met signals results in the accelerated progression of respiratory dysfunction. In other words, pulmonary disorders may be defined as an HGF-deficiency or HGF-insufficiency. Indeed, supplemental therapy with recombinant HGF protein (or HGF gene) leads to improvements in pulmonary emphysema, fibrosis and hypertention, or attenuation of chronic airway inflammation in rodent models. In this review, we wish to discuss a rationale for HGF supplemental therapy, with a focus on the pulmotrophic roles of endogenous HGF in cell biology, physiology and pathology during lung diseases.