Reactive Oxygen Species in the Resolution of Inflammation

描述(申请人提供)：心血管疾病，如心肌梗塞和中风，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的耗竭已成为治疗的靶点。然而，现有的抗氧化剂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，人们对ROS在调节炎症过程中所起的作用缺乏了解。这项拟议研究的首要目标是更好地了解ROS在中性粒细胞介导的炎症调节中的作用。ROS在解决吞噬细胞介导的炎症中的重要性是由患有免疫缺陷和持续性无菌炎症的慢性肉芽肿病患者提出的。CGD通常由NOX2突变引起，NOX2是吞噬细胞中产生ROS的NADPH氧化酶复合体的催化亚单位。虽然NOX2缺乏引起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。这项研究是由一种假设驱动的，即吞噬细胞NADPH氧化酶产生的ROS是适当消解炎症所必需的。反向迁移，即中性粒细胞从炎症部位返回血管系统，已经在斑马鱼和小鼠身上直接观察到，这被认为是局部消退的重要因素。 发炎的症状。ROS被认为在这一过程中是重要的，我们将使用斑马鱼模型来阐明ROS在反向迁移中的作用并确定其作用机制。增加对各种组织产生的ROS在炎症反应中所起作用的了解，将提高我们针对那些参与维持持续炎症状态的人的能力，例如动脉粥样硬化。

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.