003 α1-Antichymotrypsin – A Human Serpin with the Potential to Heal Diabetic Ulcers

α1-Antichymotrypsin (α1-ACT) is a secreted serine proteinase inhibitor of the serpin family. It is strongly upregulated during the inflammatory phase of wound repair to control the undesirable destructive side effects of cathepsin G which is released from infiltrating neutrophils. We have shown that α1-ACT and its mouse homologue spi2 exhibit a classic acute phase response after cutaneous injury in murine and human skin. The induction of spi2 gene expression following wounding is significantly less pronounced in diabetic mice. Transient overexpression of spi2 or α1-ACT significantly increased wound tensile strength in two independent diabetic models: in genetically diabetic mice, gene gun mediated delivery of spi2 or α1-ACT cDNA increased the average wound strength by 42%(P = 0.001) and 21%(P = 0.013) at d5 post-wounding respectively. In a STZ induced diabetic rat model the breaking strength of adenovirally spi2- or α1-ACT-infected wounds increased by 20%(P = 0.049) and 23%(P = 0.004) at d7 after injection respectively. Moreover, the topical application of human α1-ACT protein to wounds of diabetic mice had a significant and dose dependent effect on tensile strength at d5 post-wounding (21% increase, P = 0.003). Histological analyses of these wounds indicated less infiltration of neutrophils in the treated wounds. α1-ACT appears to be a key mediator between proteolysis and cytokine agonism and antagonism. Our data indicate that this balance is disturbed in diabetic wounds and that α1-ACT might act as a switch to initiate wound healing in diabetic ulcers.