Poor wound healing in compromised post surgical or chronic wound patients, represents a major national health problem. Most patients' wound healing problems result from wound tissue hypoxia. The long term objective of this proposal is to develop further understanding through animal models and in vitro studies, of how growth factors initiate and sustain the events of successful healing, particularly in the setting of ischemic tissue hypoxia. This knowledge would be used to develop effective treatment of patients with poor wound healing. The ischemic dermal ulcer model which demonstrates impaired healing, will be quantifiably evaluated for wound healing rate and quality. The role of growth factor treatment in the setting of impaired healing due to ischemia will be studied. The processes of epithelialization, granulation tissue formation, and angiogenesis will be quantified using histologic analysis, immunohistochemistry, and vascular perfusion studies. Changes in gene expression will be studied by quantitative polymerase chain reaction analysis, focusing on the FGF and TGF-B families and their receptors. Hyperbaric oxygen therapy will be studied as an adjuvant treatment in the management of impaired healing, and as a possible regulator of growth factor mediated gene expression. The effects of HBO on GM-CSF and M-CSF treatment of ischemic wounds will be examined to see if the synergistic effects of growth factors and HBO are a general phenomena. In vitro studies of the cellular response to hypoxia will allow examination of the individual component cells involved in wound healing, including fibroblasts, endothelial cells and macrophages. The role of growth factor function in the setting of variable oxygen levels will be studied. A mechanistic basis for the synergy between growth factor and intermittent hyperoxia will be pursued. Cell proliferation and gene expression as analyzed by PCR in human and rabbit cells will be measured in response to key growth factors and hypoxia.
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