Role of Arginase in Inflammation and Trauma

精氨酸酶在炎症和创伤中的作用

• 批准号: 6479361
• 负责人: SIDNEY MACHEN MORRIS
• 金额: $ 39.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479361
• 关键词: aminoacid biosynthesis; aminoacid metabolism; antiinflammatory agents; arginase; arginine; chemical synthesis; enzyme activity; gene expression; gene targeting; genetically modified animals; inflammation; isozymes; laboratory mouse; macrophage; nitric oxide; nitric oxide synthase; polyamines; proline; trauma; wound healing

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.

脓毒症、创伤性损伤、感染并发损伤和大手术都会引发革兰氏阴性菌感染后细胞因子、应激激素和细菌脂多糖复杂且多样的组合释放后的全身反应。在过去十年左右的时间里，人们越来越认识到精氨酸代谢的巨大变化，特别是诱导型一氧化氮合酶 (iNOS) 表达后 NO 产生的巨大变化，是这些病理生理状态的主要标志。然而，最近，我们和其他人已经证明，炎症和创伤也会导致两种精氨酸酶亚型（I 型和 II 型）表达的巨大变化。特别重要的是要注意，即使在同一细胞内，精氨酸酶和 iNOS 对促炎和抗炎刺激的反应也不相同，这表明精氨酸酶表达的变化不仅对 NO 合成产生深远影响，而且对 NO 合成也产生深远影响。多胺和脯氨酸的合成，参与细胞增殖和伤口愈合。该项目的总体目标是阐明精氨酸酶在炎症刺激反应和伤口愈合等情况下的代谢作用。该提案的具体目标是： 目的 I. 阐明精氨酸酶 I 和 II 在合成 NO、脯氨酸和多胺中的作用。目标二。阐明精氨酸酶 I 和 II 在体内的功能作用。目标三。确定精氨酸酶的表达是否与炎症和伤口愈合中其他精氨酸代谢酶的表达相协调。这些研究应该有助于更好地理解炎症和创伤期间精氨酸代谢的复杂变化，从而为治疗干预提供机会，以改变这些反应的子集，从而可用于预防多器官衰竭或促进创伤恢复。