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.
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.
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