Neutralization of Hepatocyte Growth Factor Leads to Retarded Cutaneous Wound Healing Associated with Decreased Neovascularization and Granulation Tissue Formation

Abstract

To elucidate biologic functions of hepatocyte growth factor and the c-Met receptor in cutaneous wound healing, we analyzed expression and localization of hepatocyte growth factor and c-Met receptor and used a strategy to neutralize endogenous hepatocyte growth factor in a cutaneous wound healing model in mice. Following excision of full-thickness skin on the dorsum of mice, expression of both hepatocyte growth factor and the c-Met receptor increased transiently in cutaneous tissues. Expressions of hepatocyte growth factor increased as early as 2 d postwounding and reached a peak on day 2, whereas the c-Met receptor expression reached a peak 2-4 d postwounding. Immunolocalization of the c-Met receptor indicated that c-Met receptor expression was upregulated in keratinocytes, vascular endothelial cells, and myofibroblasts in granulation tissue, hence these are potential target cells of hepatocyte growth factor. When normal rabbit IgG or neutralizing anti-hepatocyte growth factor IgG was locally and continuously delivered to subcutaneous lesions, the number of capillary vessels decreased with the neutralization of hepatocyte growth factor and there was an associated decreased expansion of granulation tissue. Likewise, retardation in re-epithelialization and the rate of wound closure occurred with neutralization of endogenous hepatocyte growth factor on days 4 and 7 postwounding. Therefore, hepatocyte growth factor is definitely involved in enhancing cutaneous wound healing processes, including re-epithelialization, neovascularization, and granulation tissue formation.

The Plasminogen Activation System Reduces Fibrosis in the Lung by a Hepatocyte Growth Factor-Dependent Mechanism

“…Previous reports using an inhibitory anti-HGF antibody have shown that HGF is essential for protection of the heart 27 and lungs 51 from reperfusion injury, maintenance of kidney function following obstructive nephropathy, 52 and wound healing in the skin. 53 In the current study, we showed that treatment of bleomycin-injured PAI-1 Ϫ/Ϫ mice with this inhibitory anti-HGF antibody worsened pulmonary fibrosis while a control antibody did not. This result suggests that in vivo neutralization of HGF lessens the protection that PAI-1 deficiency confers on bleomycin-induced pulmonary fibrosis.…”

Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice

“…Many types of cells, including platelets (3), neutrophils (4), macrophages (5), mast cells (6), fibroblasts (7) and keratinocytes (8) are also involved in steps leading to healing of the wound. In addition, cellular processes, such as angiogenesis (9), fibroplasia and granulation tissue formation (10,11), collagen deposition (12) and epithelialization (13) contribute to the repair. Although the process of wound healing has been extensively studied, unresolved issues remain, including those surrounding the interplay between environmental and genetic factors, which allow the healing process to occur normally.…”

Induction of hepatocyte growth factor production in human dermal fibroblasts and their proliferation by the extract of bitter melon pulp

“…Moreover, HGF is capable of stimulating migration and proliferation of keratinocytes and thus has been suggested to be involved in cutaneous physiology and wound healing [17,18]. HGF inducers may also be useful as therapeutic agents for these diseases.…”