Hepatocyte growth factor; expression, concentration and biological activity in chronic leg ulcers

Background: Hepatocyte growth factor (HGF) is a multifunctional cytokine that is involved in recovery process after organ injuries. Objective: We studied HGF and the membrane bound receptor,c-met locally inpatients who suffered from chronic leg ulcers (greater than or equal to 1 year) caused by venous insufficiency. Methods: Skin biopsies from the edge of the ulcers were taken from patients (n = 13) and studied by immunohistochemical staining for detection of HGF and c-met. Skin biopsies from healthy volunteers (n = 10) were used as the control material. Ulcer secretion from chronic ulcers (n = 11) was examined for the presence of HGF by ELISA and the concentration of HGF was compared with acute ulcers in healthy controls (n = 10) and in patients operated for a non-invasive breast cancer (n = 12). Results: We observed that c-met expression in the ulcer area increased significantly in chronic ulcers compared to controls (p = 0.005). Concentration of ulcer-HGF in the patients with chronic ulcer was significantly higher than acute ulcers (p < 0.01). The biological activity of HGF in ulcer secret was assessed in-vitro in transferred, mouse skin epithelial cell monolayer. Enhanced migration and morphologic changes were seen after adding ulcer secret from acute ulcers (> 1 ng/mL) that was inhibited by anti-HGF antibodies. No biological activity was observed by adding ulcer secret from chronic ulcers irrespective HGF concentration. Conclusion: We conclude that in chronic skin ulcers decreased biological activity of endogenous HGF and overexpression of c-met is seen which might explain fibrosis and delayed recovery. Administration of exogenous active HGF might contribute to accelerated healing in these patients. (C) 2004 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.