Reactive Oxygen Species in the Resolution of Inflammation

描述（由申请人提供）：心血管疾病，如心肌梗死和中风，是一个主要的公共卫生负担，是多年动脉斑块发展的结果。大量证据表明，吞噬细胞介导的炎症在动脉粥样硬化的发病机制中起着重要作用。动脉壁和吞噬细胞产生的活性氧（ROS）被认为是诱导和维持这种炎症状态的重要因素，因此ROS的消耗已成为治疗目标。然而，现有的抗氧化清除疗法在预防心血管疾病方面尚未显示出临床疗效。这一意想不到的结果表明缺乏对ROS在炎症过程调节中的作用的理解。拟议研究的总体目标是更好地了解ROS在中性粒细胞介导的炎症调节中的作用。慢性肉芽肿病（CGD）患者患有免疫缺陷和持续性无菌炎症，提示ROS在解决吞噬细胞介导的炎症中的重要性。CGD通常是由吞噬细胞中产生ros的NADPH氧化酶复合物的催化亚基Nox2突变引起的。虽然Nox2缺乏的炎症并发症已经明确，但Nox2和ROS产生抗炎作用的机制仍未解决。这项研究的假设是由吞噬细胞NADPH氧化酶产生的ROS对于炎症的适当解决是必要的。在斑马鱼和小鼠中直接观察到中性粒细胞从炎症部位返回血管系统的反向迁移，这被认为是局部解决的重要因素

DESCRIPTION (provided by applicant): Cardiovascular diseases, such as myocardial infarction and stroke, are a major public health burden and result from years of arterial plaque development. Overwhelming evidence points to a role for phagocyte-mediated inflammation in the pathogenesis of atherosclerosis. Reactive oxygen species (ROS) produced by both the arterial wall and phagocytes are considered important for the induction and maintenance of this inflammatory state, and the depletion of ROS has consequently become a therapeutic target. However, existing antioxidant scavenging therapeutics have not demonstrated clinical efficacy in the prevention of cardiovascular disease. This unexpected result demonstrates the lack of understanding of the role that ROS play in the regulation of inflammatory processes. The overarching goal of the proposed research is to better understand the role of ROS in the regulation of neutrophil-mediated inflammation. The importance of ROS in the resolution of phagocyte-mediated inflammation is suggested by patients with chronic granulomatous disease (CGD), who suffer from immunodeficiency and persistent, sterile inflammation. CGD usually results from mutations in Nox2, the catalytic subunit of the ROS-producing NADPH oxidase complex in phagocytes. While the inflammatory complications of Nox2 deficiency have been well defined, the mechanisms through which Nox2 and ROS may produce anti-inflammatory effects remain unresolved. This research is driven by the hypothesis that ROS produced by the phagocyte NADPH oxidase are necessary for the proper resolution of inflammation. Reverse migration, the return of neutrophils from sites of inflammation to the vasculature, has been directly observed in zebrafish and mice, and it is thought to be important for the local resolution of inflammation. ROS were suggested to be important for this process, and we will use the zebrafish model to elucidate the role of ROS in reverse migration and determine the mechanism of action. Increased understanding of the roles that ROS produced by various tissues play in the inflammatory response will improve our ability to target those involved in maintaining persistent inflammatory states, such as atherosclerosis. PUBLIC HEALTH RELEVANCE: Dysregulated inflammation is an important component in the development of many diseases including atherosclerosis, cancer, and diabetes. Factors that induce inflammation are often well understood, but the mechanisms underlying the resolution of inflammation remain to be elucidated. This proposed research will contribute to human health by increasing knowledge of the resolution of inflammation, which should inform the rational design of therapeutics to modulate this process in disease states.