Endostatin Inhibits Hypertrophic Scarring In A Rabbit Ear Model

OBJECTIVE:The present study was designed to use an in vivo rabbit ear scar model to investigate the efficacy of systemic administration of endostatin in inhibiting scar formation.METHODS:A total of eight male New Zealand white rabbits were enrolled. They were randomly assigned into two groups. The scar model was made by making six full skin defect wounds on each ear. For the intervention group, intraperitoneal injection of endostatin was performed each day after the wound had healed (about15th day postwounding). For the control group, an equal volume of normal saline was injected simultaneously. Thickness of scars in each group was measured by a sliding caliper and the scar microcirculatory perfusion was assessed by laser Doppler flowmetry at postwounding day15, day21, day28, and day35. Rabbits were euthanatized and their scars were harvested for histological and proteomics analysis at postwounding day35. RESULTS:Macroscopically, scars of the control group were thicker than those of the intervention group. Significant differences between two groups were observed in day21and day35(P<0.05). The scar microcirculation perfusion of the intervention group decreased after injection of endostatin; however, it dramatically increased in the control group before postwounding day21(when the difference between two groups became statistically significant), then slowly decreased in the following time points. Microscopically, scar thickness, measured by SEI (Scar elevation index) in day35post wounding was significantly reduced in the intervention group (1.09±0.19) when compared with controls (1.36±0.28). MVD (micro vessel density) observed in the intervention group (1.73±0.94) in day35was significantly lower than that of the control group (5.63±1.78). Distribution of collagen fibers in scars treated with endostatin was relatively regular, while collagen fibers distributed in untreated controls were thicker and showed disordered alignment. Western Blot Analysis shows that the expression of type I collagen and Bcl-2were both depressed by injection of endostatin.CONCLUSIONS:Our results from the rabbit ear hypertrophic scar model indicate that systemic application of endostatin could inhibit local hypertrophic scar formation, possibly through reducing scar vascularization and angiogenesis. The hypothesis is that endostatin may promote the apoptosis of endothelial cell and block its’ release of PDGF and FGF so that fibroblasts produce less collagen. Blood vessel targeted treatment may be a promising strategy for scar therapy.