Hepatocyte growth factor in lung repair and pulmonary fibrosis

Abstract

Pulmonary remodeling is characterized by the permanent and progressive loss of the normal alveolar architecture, especially the loss of alveolar epithelial and endothelial cells, persistent proliferation of activated fibroblasts, or myofibroblasts, and alteration of extracellular matrix. Hepatocyte growth factor (HGF) is a pleiotropic factor, which induces cellular motility, survival, proliferation, and morphogenesis, depending upon the cell type. In the adult, HGF has been demonstrated to play a critical role in tissue repair, including in the lung. Administration of HGF protein or ectopic expression of HGF has been demonstrated in animal models of pulmonary fibrosis to induce normal tissue repair and to prevent fibrotic remodeling. HGF-induced inhibition of fibrotic remodeling may occur via multiple direct and indirect mechanisms including the induction of cell survival and proliferation of pulmonary epithelial and endothelial cells, and the reduction of myofibroblast accumulation.

Figure 1

Schematic diagram depicting the development of lung fibrosis following irreparable damage to lung cells. A number of pro-survival factors including HGF, KGF and Cox-2 normally promote survival of epithelial and endothelial cells, fibroblasts quiescence and normal regulation of extracellular matrix (ECM) which altogether results in homeostasis in the lung. Injuries such as bleomycin, radiation, and pro-fibrotic factors may cause epithelial and endothelial apoptosis as well as fibroblast activation and myofibroblast proliferation – events observed in the development of lung fibrosis.

Figure 2

HGF/c-Met signal transduction. Two tyrosine phosphorylation sites (Y1349/Y1356) in the multi-functional docking domain interact with multiple adaptor proteins and signal transduction enzymes. STAT3 has been shown to bind directly to c-Met in some cell types, but the site has not been defined.

Figure 3

HGF actions for the inhibition of fibrotic remodeling.