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C5A/IL 8 AND ADULT PERIODONTAL DISEASE

C5A/IL 8 和成人牙周病

基本信息

批准号：
2749338
负责人：
TONY E HUGLI
金额：
$ 22.42万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-30 至 2000-07-31
项目状态：
已结题

项目摘要

The role of complement in periodontal disease can be either protective or pathologic depending on the stage of the disease and the pathogens involved. Our hypothesis is that the humoral inflammatory factor C5a, the chemotatic cytokine IL-8 and/or formulated bacterial peptides (f-MLF) play a significant role in promoting gingival tissue injury resulting from bacterial infection. This process may be set in motion either by the anaerobic gram-negative bacteria or the proteases they elaborate. Although complement activation can be initiated directly by contact between plasma and bacterial particles, we propose that bacterial proteases are primarily responsible for prolonged generation of C5a in periodontal disease. The potent chemotactic factors C5a/f-MLF recruit neutrophils and macrophages which in turn release protases, IL-8 and other cellular cytokines that accelerate tissue degradation and promotes edema. Persistent edema due to leakage of plasma fluid from the microvasculature of the periodontium is a usual feature of periodontal diseases. Plasma protein filtrate contains C5 which may be degraded by bacterial proteases, with resultant release of the chemotaxin C5A. Prolongation of localized inflammatory cell sequestration is consistent with the hypothesis of ongoing C5a generation, which may contribute to the chronic inflammatory response that is the hallmark of periodontitis. The early events in periodontitis are likely driven by bacterial (i.e. formulated peptides) and/or humoral (i.e. C5a) chemotactic factors which initiate the cascade of cellular infiltration. The initial cellular influx may be amplified later in the process by cell-derived chemotactic factors such as PAF, IL-8 and LTB4. This proposal is designed to first demonstrate evidence for C5a/IL-8 at the injury site, examine effects of the bacterial products (i.e proteases) on the various activation factors and their receptors, and then test the hypothesis that C5a/IL-8 involvement actually occurs and contributes significantly in promoting the disease. Secondly, I propose to specifically evaluate processes such as "priming" of the neutrophils/macrophages by bacterial endotoxin, which enhances responsiveness of the cells to chemotactic factors. C5a and IL-8 receptors were recently demonstrated on cultured epithelial cells (HEp-2 and KB) and on epithelial cells in human gingival tissue (see preliminary results section). Both anti-C5a/IL-8 and anti-C5a/IL-8 receptor antibodies, capable of neutralizing binding and in vivo cellular migration, have been developed. These reagents will be used to explore the actions of the proteases from P.gingivalis on the chemotaxins and their receptors. We have shown that both Arg- and Lys-gingipain degrade C3 and C5 and generate bioactive C5a (see preliminary results section). In addition, we observed that oxygen radical treatment of C5 significantly enhanced C5a generation by the gingipains (manuscript in preparation). We propose to explore possible C5a/IL-8 induced epithelial cell functions including the release of acute phase proteins and cytokines. It is proposed that early events in the inflammatory response of periodontal disease are mediated by the chemotaxins and that understanding these events may lead to therapeutically useful modes of intervention.

补体在牙周病中的作用可以是保护性的或病理性取决于疾病的阶段和病原体牵涉其中。我们的假设是体液炎症因子C5a，即趋化细胞因子IL-8和/或配方细菌肽(f-MLF) 对牙周组织损伤有显著促进作用不受细菌感染。这一进程可以通过以下方式启动厌氧革兰氏阴性细菌或他们所阐述的蛋白酶。虽然补体激活可以通过接触直接启动在血浆和细菌颗粒之间，我们认为细菌蛋白水解酶是延长体内C5a生成的主要原因。牙周病。强大的趋化因子C5a/f-MLF新兵中性粒细胞和巨噬细胞继而释放蛋白水解酶、IL-8和其他加速组织降解并促进浮肿。持续的浮肿是由于血浆液体从牙周组织的微血管形成是牙周的常见特征。疾病。血浆蛋白滤液中含有C5，可被细菌蛋白酶，其结果是释放趋化素C5a。局部炎性细胞隔离的延长是一致的 C5a正在生成的假说，这可能有助于慢性炎症反应是牙周炎的标志。牙周炎的早期事件可能是由细菌(即配方多肽)和/或体液(即C5a)趋化因子启动细胞渗入的级联反应。最初的细胞内流可能在随后的过程中通过细胞衍生的趋化作用被放大 PAF、IL-8、LTB4等因素。这项提议旨在首先在损伤部位展示C5a/IL-8的证据，检查各种激活因子上的细菌产物(即蛋白酶) 及其受体，然后检验C5a/IL-8的假设参与实际上发生了，并对促进这种疾病。其次，我建议具体评估这样的过程作为细菌内毒素对中性粒细胞/巨噬细胞的“启动”，增强细胞对趋化因子的反应能力。补体C5a和IL-8 最近在培养的上皮细胞(Hep-2)上发现了受体和Kb)和人牙龈组织上皮细胞(见初步报告结果部分)。抗C5a/IL-8和抗C5a/IL-8受体抗体，能够中和结合和体内细胞移民，已经发展起来了。这些试剂将用于探索牙龈假单胞菌蛋白水解酶对趋化因子和趋化因子的作用它们的受体。我们已经证明精氨酸和赖氨酸都能降解牙周疼痛。 C3和C5，并产生生物活性C5a(见初步结果部分)。此外，我们观察到氧自由基对C5的治疗作用显著增强牙周疼痛的C5a生成(手稿在准备)。我们建议探索C5a/IL-8诱导上皮细胞的可能性细胞功能包括急性时相蛋白的释放和细胞因子。据认为，炎症反应中的早期事件牙周病是由趋化因子介导的，而且了解这些事件可能会导致治疗上有用的模式干预。