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.

败血症，创伤性损伤，因感染而复杂的损伤以及大手术均启动全身反应，这些反应随后通过革兰氏阴性细菌感染后的细胞因子，应激激素和细菌脂多糖的复杂和多样化组合。在过去的十年左右的时间里，人们越来越多地认识到精氨酸代谢的急剧变化，尤其是在表达诱导型一氧化氮合酶（INOS）之后无生产中，是这些病理生理状态的主要标志。然而，最近，我们和其他人证明，炎症和创伤也可能导致两种精氨酸酶同工型的表达变化（I型和II型）。特别重要的是要注意，精氨酸酶和iNOS对促和抗炎刺激的反应即使在同一细胞内也不相同，这表明精氨酸酶表达的变化不仅会对无合成，而且对多胺和脯氨酸的合成，这与多胺和脯氨酸的合成相同，这些胺和脯氨酸涉及细胞的刺激和伤口愈合。该项目的总体目标是阐明精氨酸酶在对炎症刺激的反应过程中以及在伤口愈合等条件下的代谢作用。该提案的具体目的是：目标I。阐明精氨酸酶I和II在NO，脯氨酸和多胺的合成中的作用。目标II。阐明体内精氨酸酶I和II的功能作用。目标三。确定精氨酸酶的表达是否与其他精氨酸代谢酶在炎症和伤口愈合中的表达相协调。这些研究应提高人们对炎症和创伤过程中精氨酸代谢的复杂变化的了解，从而为治疗干预措施提供了改变这些反应的子集的机会，这些反应可用于防止多器官失败或增强创伤中的恢复。