Redox Regulation of Gingival Inflammation

项目摘要摘要 派：巴格特卡 牙周病是一种高度常见的传染病。牙周炎的慢性炎症导致 逐渐破坏硬组织和软组织，增加对其他系统性疾病的易感性。东道主 调节口腔炎症反应的大小、性质和持久性的因素有 不完全理解。我们之前已经证明，由 白细胞NADPH氧化酶复合体的激活在抑制高炎性反应中起关键作用 回应。小鼠缺乏氧化酶导致严重的炎症，其特征是调节失调 中性粒细胞和巨噬细胞的反应和分解延迟。这些数据支持了一种有点违反直觉的观点 ROS在限制宿主炎症中的作用。氧化剂是否调节口腔内的炎症途径 目前还不清楚。我们的中心假设是NADPH氧化酶衍生-ROS，独立于它们的抗菌剂 功能，在体外和体内中性粒细胞和巨噬细胞效应功能的氧化还原调节中起关键作用。 此外，我们假设虽然过量的ROS与糖尿病的病理生理学有关 牙周病，低水平，局部的ROS反应是免疫调节的。这些假设将是 在两个特定的目标上进行了测试。1)确定NADPH氧化酶在PMN效应功能调节中的作用 在牙龈的急性反应中。2)确定NADPH氧化酶在巨噬细胞调节中的作用 牙周炎的功能和消退。缺乏NADPH氧化酶的条件性基因敲除小鼠的应用 中性粒细胞或巨噬细胞中选择性的活性将使我们能够专门确定氧化剂在 体内的一种细胞固有方式。这些研究产生的数据将在我们的 了解与牙周炎相关的免疫途径以及氧化剂对其的调节。此外， 我们的研究也与了解慢性肉芽肿性疾病的免疫病理学高度相关。 由NADPH氧化酶亚单位基因的遗传突变引起的危及生命的免疫缺陷。

Project Summary Abstract PI: Bagaitkar Periodontal diseases are highly common infectious diseases. Chronic inflammation in periodontitis results in the progressive destruction of hard and soft tissues and enhances susceptibility to other systemic disease. The host factors that regulate the magnitude, nature and persistence of inflammatory responses in the oral are incompletely understood. We have previously shown that reactive oxygen species (ROS) generated by the activation of leukocyte NADPH oxidase enzyme complex plays a critical role in dampening hyperinflammatory responses. Oxidase deficiency in mice resulted in profound inflammation characterized by dysregulated neutrophil and macrophages responses and resolution delays. These data support a somewhat counterintuitive role for ROS in limiting host inflammation. Whether oxidants modulate inflammatory pathways in the oral cavity is unclear. Our central hypothesis is that the NADPH oxidase derived-ROS, independent of their antimicrobial functions, play key roles in redox modulation of neutrophil and macrophage effector functions in vitro and in vivo. Further, we hypothesize that while excessive amounts of ROS are associated with the pathophysiology of periodontal diseases, low-level, localized ROS responses are immuno-regulatory. These hypotheses will be tested in two specific aims. 1) Determine the role of NADPH oxidase in the regulation of PMN effector functions in acute responses in the gingiva. 2) Determine the role of NADPH oxidase in the modulation of macrophage function and resolution of gingival inflammation. The use of conditional knockout mice that lack NADPH oxidase activity selectively in neutrophils or macrophages will enable us to specifically determine the role of oxidants in a cell intrinsic manner in vivo. The data generated by these studies will shed key mechanistic insights in our understanding of immune pathways relevant in gingival inflammation and their regulation by oxidants. Further, our studies are also highly relevant in understanding the immunopathology of chronic granulomatous disease, a life-threatening immunodeficiency caused by inherited mutations in NADPH oxidase subunit genes.