Roles of hepatocyte growth factor activator (HGFA) and its inhibitor HAI-1 in the regeneration of injured gastrointestinal mucosa.

Hepatocyte growth factor (HGF)/scatter factor (SF) is thought to play an important role in the regeneration of injured gastrointestinal mucosa by promoting the proliferation and migration of epithelial cells. HGF/SF is secreted by stromal cells as an inactive precursor form, and is specifically activated by HGF activator (HGFA) to the active form. HGFA is also produced as a precursor form and activated by thrombin in injured tissues. The activity of HGFA is regulated by two recently identified Kunitz-type serine proteinase inhibitors, namely HGFA inhibitor type 1 (HAI-1) and type 2 (HAI-2). Although the activation of HGF/SF is a critical limiting step in the HGF/SF-induced signaling pathway, little is known about the regulation of HGF/SF activation in injured gastrointestinal mucosa. Immunohistochemically, all these proteins have been detected in gastrointestinal epithelial cells, and HAI-1 was upregulated in regenerative epithelium relative to normal epithelium. During the course of acetic acid-induced murine experimental colitis, HAI-1, but not HAI-2, was indeed upregulated in the recovery phase. In vitro study revealed that HAI-1 is not only an inhibitor, but also a specific cell-surface binding protein, of active HGFA, and acts as a reservoir of this enzyme on the cell surface. Active HGFA/HAI-1 complexes were quickly released from the cell surface by treatment with IL-1beta accompanying significant recovery of HGFA activity in the culture supernatant. These results suggest that HAI-1 is a cell-surface acceptor of activated HGFA in regenerative epithelial cells, and functions on the cell surface to localize the active HGFA that is going to enter the repair process. This concentrated HGFA activity would ensure the efficient pericellular activation of HGF in the injured gastrointestinal mucosa, and promote the proliferation and migration of gastrointestinal epithelial cells.