Reactive Oxygen Species in the Resolution of Inflammation

描述（由申请人提供）：心肌梗死和中风等心血管疾病是一个主要的公共卫生负担，是多年动脉斑块形成的结果。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作用。由动脉壁和吞噬细胞产生的活性氧（ROS）被认为对于这种炎症状态的诱导和维持是重要的，并且ROS的消耗因此已成为治疗靶点。然而，现有的抗氧化剂清除疗法尚未证明在预防心血管疾病中的临床功效。这个意想不到的结果表明，缺乏了解的作用，活性氧在炎症过程的调节。这项研究的总体目标是更好地了解ROS在嗜中性粒细胞介导的炎症调节中的作用。ROS在吞噬细胞介导的炎症消退中的重要性由患有免疫缺陷和持续性无菌炎症的慢性肉芽肿病（CGD）的患者提出。CGD通常由Nox2突变引起，Nox2是吞噬细胞中产生ROS的NADPH氧化酶复合物的催化亚基。虽然Nox 2缺乏的炎症并发症已经得到很好的定义，但Nox 2和ROS可能产生抗炎作用的机制仍然没有得到解决。这项研究是由吞噬细胞NADPH氧化酶产生的ROS对于炎症的适当解决是必要的假设驱动的。反向迁移，即中性粒细胞从炎症部位返回血管系统，已在斑马鱼和小鼠中直接观察到，并且被认为对局部消退很重要 炎症。ROS被认为是重要的，这一过程中，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理解，将提高我们靶向那些参与维持持续炎症状态（如动脉粥样硬化）的细胞的能力。

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.