Hepatocyte growth factor and macrophage-stimulating protein are upregulated during excisional wound repair in rats

Abstract

Hepatocyte growth factor (HGF) and macrophage-stimulating protein (MSP) are structurally related molecules that stimulate epithelial cell proliferation and migration. MSP also acts directly as a chemoattractant for resident macrophages. These activities are integral to the wound repair processes of inflammation, epithelialization and tissue remodelling. To begin to examine the involvement of HGF and MSP in healing of cutaneous wounds we have mapped the temporal expression of these two molecules and their receptors, MET and RON respectively, in adult rat excisional wounds. Four 2x2-cm full-thickness excisional wounds were created on the dorsum of 18 rats, and biopsies were taken through the wounds at 3, 5, 7, 14, 21, and 28 days postwounding. These biopsies were analyzed using immunofluorescent staining and in situ hybridization (ISH). The number of cells staining positively for HGF and MET significantly increased in response to wounding. HGF staining and mRNA peaked at 7 days postwounding whereas MET was upregulated earlier, peaking after 3 days. Both HGF and MET protein were observed in fibroblasts of the dermis and in the newly forming granulation tissue. ISH studies also revealed that fibroblasts at the wound edges and within the newly forming granulation tissue also expressed HGF and c-met mRNA. Immunofluorescent staining revealed both MSP and RON within the wound, with maximum staining occurring between 7 and 21 days for both the ligand and receptor. In addition, MSP co-localized with a small subset of ED1-positive cells (monocytes). In contrast, ED2-positive cells (macrophages) did not co-localize with MSP. Thus, increased expression of HGF, MSP and their receptors MET and RON respectively was observed in response to wounding. Furthermore, MSP co-localization with a subset of monocytes may confirm a role for MSP in the activation of mature macrophages, which may be important in tissue remodelling.

Nonsteroidal Anti-Inflammatory Drug Reduces Neutrophil and Macrophage Accumulation but Does Not Improve Tendon Regeneration

“…For example, the administration of a nonspecific inhibitor of COX activity increases ligament strength by 42% at 14 days postsurgical transection, whereas a specific COX-2 inhibitor decreases ligament strength as compared with a placebo (Dahners et al, 1988;Elder et al, 2001). Although the conclusions of these studies are weakened by the fact that no specific inflammatory cell markers were employed to verify the efficacy of the NSAIDs, the observations are consistent with the current view that inflammatory cells participate in both the degenerating and regenerating processes at sites of injury (Cowin et al, 2001;Lapointe et al, 2002b;Li et al, 2001).…”

Acceleration of wound healing by combined gene transfer of hepatocyte growth factor and prostacyclin synthase with Shima Jet

“…Increased expression of HGF and its receptor, c-met, was observed in response to wounding. 15 Hepatocyte growth factor has a significant effect on vascularization and granulation tissue formation during wound healing in vivo. 31 Moreover, HGF stimulates wound healing, with less susceptibility to cutaneous scarring.…”

“…The healing processes are regulated by a number of growth factors such as basic fibroblast growth factor, transforming growth factor-b, epidermal growth factor, keratinocyte growth factor, platelet-derived growth factor, vascular endothelial growth factor and hepatocyte growth factor (HGF). [13][14][15] Interestingly, several growth factors that accelerate wound healing have been identified. 12 Hepatocyte growth factor was first found to be a potent mitogen for mature hepatocytes after purification and cloning.…”

HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro

“…Its expression is dramatically increased in response to injury and is specifically implicated in the repair and regeneration of epithelium in the kidney, 24 skin, 25 small intestine, 26 and lung. 27 c-met also contributes to the activated phenotype of some mesenchymal cell types, such as fibroblasts 25 and muscle satellite cells. 28 In activated monocytes, c-met is a factor defining invasiveness.…”