PDGF AND TGF-ALPHA ACT SYNERGISTICALLY TO IMPROVE WOUND-HEALING IN THE GENETICALLY DIABETIC MOUSE

Impaired wound healing results in significant morbidity for the surgic al patient. The genetically diabetic (C57BL/KsJ-db/db) mouse is obese, hyperglycemic, insulin-resistant, and exhibits markedly impaired woun d healing. Previous studies have demonstrated that the fibroblast mito gens, BB homodimer of platelet-derived growth factor (PDGF-BB) or basi c fibroblast growth factor, plus insulin-like growth factor, act syner gistically to enhance wound closure in the genetically diabetic mouse. The purpose of this study was to determine whether the keratinocyte m itogens, epidermal growth factor (EGF) or transforming growth factor-a lpha (TGF-alpha), in combination with the fibroblast mitogen, PDGF-BB, would produce a similar synergistic enhancement in tissue repair. Ful l-thickness skin wounds created on the backs of diabetic mice received topical applications of vehicle (5% polyethylene glycol), PDGF-BB (10 mu g), EGF (1 mu g), TGF-alpha (1 mu g), or the combination of PDGF ( 10 mu g) and EGF (1 mu g) or TGF-cr (1 mu g) for 5 consecutive days st arting at wounding. Application of PDGF-BB or TGF-alpha alone to wound s in diabetic animals improved wound closure when compared to vehicle treatment. EGF did not affect healing and did not have any additive ef fects when combined with PDGF-BB. Significant improvements in wound cl osure were observed with the combination of PDGF-BB and TGF-alpha when compared to treatment with the individual growth factors. The PDGF-BB /TGF-alpha combination accelerated healing in the diabetic animals to a rate that was closer to that seen in nondiabetic mice. By histologic analysis at Day 15, all criteria for healing were more advanced in th e PDGF-BB/TGF-alpha combination wounds when compared to the other trea tment groups. As all wounds approached complete healing by Day 21, the se differences were lost. In summary, PDGF-BB and TGF-alpha acted syne rgistically in genetically diabetic mice to promote early wound healin g beyond that of the individual growth factors. Similar synergy was no t observed with the combination of PDGF-BB and EGF. (C) 1994 Academic Press, Inc.