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A novel anti-inflammatory role for the neutrophil NADPH oxidase

中性粒细胞 NADPH 氧化酶的新型抗炎作用

基本信息

批准号：
8619465
负责人：
JESSICA G MORELAND
金额：
$ 23.85万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8619465
关键词：
Allergic Reaction Anti-Inflammatory Agents Anti-inflammatory Antioxidants Catalytic Domain Cells Cellular biology Clinical Complex Confocal Microscopy Data Disease Down-Regulation Elements Endosomes Endotoxins Enzymes Equilibrium Event Failure Family Generations Goals Homeostasis Host Defense Human Immune Immune response Immune system In Vitro Infection Inflammation Inflammatory Inflammatory Response Intensive Care Intensive Care Units Interphase Cell Investigation Knowledge Laboratories Lead Leukocytes Life Mediating Medicine Minor Mitogen-Activated Protein Kinases Modeling Molecular Target Mus NADPH Oxidase Outcome Oxidants Oxidases Oxygen Pathogenesis Pathway interactions Patients Phase Phenotype Process Protein phosphatase Publishing Reactive Oxygen Species Regulation Research Resolution Rest Risk Role Sepsis Sepsis Syndrome Shock Signal Pathway Signal Transduction Sterility Stimulus Superoxides Syndrome Testing Tissues Trauma Vesicle base cell type cellular targeting clinical practice human MAPK14 protein immune activation improved killings member microbial monocyte mortality neutrophil novel novel therapeutics public health relevance response segregation upstream kinase

项目摘要

Project Summary Local and systemic inflammatory events elicit immune activation in the host to provide the necessary pro- inflammatory response based on the danger sensed, followed by active resolution and return to baseline. One common clinical example of this process is the Systemic Inflammatory Response Syndrome (SIRS), which can be activated following a range of insults that may include infection, shock, allergic reaction, or trauma. This pro- inflammatory phase of the immune response is overlapped by a compensatory anti-inflammatory response that restores immune homeostasis. Circulating neutrophils (PMN) are critically involved in mediating the consequences of systemic inflammation, in part by the generation of reactive oxygen species (ROS). PMN produce ROS via activation of the NADPH oxidase (Nox), with Nox2 (gp91phox) being the catalytic subunit in this cell type. Despite the unequivocal requirement for neutrophil-derived ROS in microbial defense, it is clearly recognized that PMN activation can lead to host tissue damage. This well-studied proinflammatory activation of PMN is counterbalanced against recent evidence supporting an anti-inflammatory role for Nox2. The current proposal focuses on defining cellular effects and molecular targets of ROS signaling in resting PMNs, and investigation of an anti-inflammatory role of Nox2 in termination of inflammation. These goals are predicated on two subsets of strong preliminary data: 1) demonstration of specific pro-inflammatory phenotypic alterations in resting PMNs in the absence of NADPH oxidase function, and 2) enhanced and persistent inflammation and increased mortality in Nox2-deficient mice using a murine model of sterile generalized inflammation. The overall hypothesis of this proposal is that Nox2 in PMN has an essential anti-inflammatory role in the regulation of the host inflammatory state. Furthermore, we hypothesize that Nox2-derived ROS are required both to maintain resting cellular quiescence and to return to homeostasis following an inflammatory insult. These hypotheses will be tested with the following aims: 1) Nox2 is active in unstimulated PMN and necessary to maintain the resting cell phenotype. 2) Nox2 has anti-inflammatory effects in PMN mediated via the p38 mitogen-activated protein kinase (MAPK) pathway. The approach to these aims will include sophisticated analysis of subcellular vesicles/endosomes of unstimulated human PMN for evidence of assembly and activation of Nox2. In addition, focused exploration of cellular targets of anti-inflammatory ROS signaling, and downstream consequences of this signaling will be undertaken. Primary human PMNs will be used for in vitro analyses of signaling pathways and confocal microscopy will be employed to localize ROS signals. A better understanding of the cell biology of host inflammation will be relevant to numerous disease processes.

项目总结