Sepsis, traumatic injury, injury complicated by infection, and major surgery all initiate systemic responses that follow release of complex and varied combinations of cytokines, stress hormones, and bacterial lipopolysaccharide following infection by gram-negative bacteria. It has been recognized increasingly over the past decade or so that dramatic changes in arginine metabolism, particularly in NO production following expression of inducible nitric oxide synthase (iNOS), are major hallmarks of these pathophysiologic states. More recently, however, we and others have demonstrated that inflammation and trauma also can result in dramatic changes in expression of the two arginase isoforms (types I and II). It is particularly important to note that responses of the arginases and iNOS to pro- and anti-inflammatory stimuli are not identical, even within the same cell, indicating that changes in arginase expression can have a profound impact not only on NO synthesis but also on synthesis of polyamines and proline, which are involved in cell proliferation and wound healing. The overall goal of this project is to elucidate the metabolic roles of the arginases during responses to inflammatory stimuli and in conditions such as wound healing.
Specific aims of this proposal are:
AIM I. To elucidate roles of arginases I and II in synthesis of NO, proline and polyamines.
AIM II. To elucidate the functional roles of arginases I and II in vivo.
AIM III. To determine whether expression of the arginases is coordinated with expression of other arginine metabolic enzymes in inflammation and wound healing. These studies should result in an improved understanding of the complex changes in arginine metabolism during inflammation and trauma, thus providing opportunities for therapeutic interventions to alter subsets of these responses that could be used to prevent multiple organ failure or to enhance recovery from trauma.
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