The objective of this project is to analyze the cellular and biochemical mechanism(s) responsible for the contrasting events of adult [scar] a fetal[scarless] tissue repair following injury. Studies outlined will test the hypotheses that 1) the lack of acute inflammation in the fetus plays a critical regulatory role in scarless healing, 2) the fetal extracellular matrix consisting of hyaluronic acid has a fundamental regulatory role in the wound microenvironment, and 3) the peptide growth factors PDGF and TGF-beta differ in their expression and regulation of fetal tissue repair as compared to that in the adult. In order to elucidate mechanisms of fetal tissue repair it is our overall experimental strategy to manipulate fetal wounds to become adult-like and adult wounds to become fetal-like. The immunohistochemical microanalysis of the wound environment (cellular elements, extracellular matrix composition, peptide growth factor activity) should allow us to move from baseline descriptive studies to understanding mechanisms responsible for optimal scarless would repair. In vivo fetal rabbit wounds will be manipulated with TGF-beta, PDGF and hyaluronic acid degradation products (HADP), all of which are known to regulate and promote an adult-like repair process. In vivo adult wounds will be manipulated to regulate and promote an adult-like repair process. In vivo adult wounds will be manipulated to elevate hyaluronic acid levels or neutralize TGF-beta and PDGF in order to create a more fetal- like scarless repair. With in vitro experiments, we will utilize an isolated limb culture model, which mimics the events of fetal and adult wound healing in a serum-free chemically defined medium. The role of the inflammatory cytokines IL-1, TNF, and IFN-gamma, the growth factors TGF- veta and PDGF in controlling fetal wound responses, as well as the role of hyaluronic acid and hyaluronic acid degradation produces will be examined. Using an immunohistochemical survey, key changes observed following manipulation of adult or fetal wounds will be used to selectively study gene expression by mRNA analysis. Thus, mechanisms of scarless fetal repair can be determined. Development of this basic information regarding the cellular and biochemical components and control mechanisms in fetal wound healing may help to develop rational strategies for the treatment of the problems of wound healing excess (keloids, adhesions, strictures, visceral fibrosis).
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