A STUDY OF WOUND HEALING, INFLAMMATION AND INFECTION

University Of California San Francisco, San Francisco CA

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Abstract

The Metabolic Basis of Wound Healing: Our aim is to determine the mechanisms by which the phenotypes and functions of wound cells are determined by the extreme local environment which results from injury. The strategy is aimed at the metabolic features of wounds that elicit growth factors, stress proteins, and regulate angiogenesis and collagen synthesis. There are 5 sections; a Core and 4 projects which are as follows: Part I: Hypothesis: the hypoxic, heavily lactated, highly oxidative conditions in wounds lead to a reduction in the NAD+ pool and a subsequent loss of ADPRibosylations that mediate collagen and VEGF gene expression, protein production, and post translational modification. The effects of IGF-1 and some other growth factors are also mediated through this mechanism. Part 2: Hypothesis: oxidants produced largely by leukocytes play an essential role in wound healing by stimulating VEGF production and collagen gene expression via redox signaling. Part 3: Hypothesis: (a) "Stress proteins" represent a spectrum of phenotypic changes that are important to healing; (b) enhancement of collagen and VEGF gene expressions are only a small portion of the reparative phenotype and that oxidants and hypoxia will instigate hox genes in the course of instigating healing. In part 4, we proceed from our find that hypoxia is inimicable to angiogenesis, collagen processing, and immunity. We now hypothesize that a) the prognosis for healing in both acute and chronic and chronic wounds can be calculated from oxygen measurements, b) that cycled iatrogenic enhancement of tissue P02 stimulates angiogenesis, and c) that antibiotic resistant organisms are susceptible to oxidative leukocytic killing. Lastly, we propose to refine our knowledge of control of oxygen transport to wounds on complex flap model. Significance: Clinical advantages have accrued through our past mechanistic research. We expect to gain insights into treatment of both chronic and acute wounds.