ACTIVATION OF MACROPHAGES IN PERIODONTAL DISEASE

牙周疾病中巨噬细胞的激活

• 批准号: 3219451
• 负责人: MICHAEL J PABST
• 金额: $ 9.68万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3219451
• 关键词: Actinomyces; cyclic nucleoside monophosphate; human tissue; hydrolysis; inflammation; laboratory mouse; lipopolysaccharides; macrophage activating factor; methylation; neutrophil; oral bacteria; osteoclasts; oxidoreductase; peptidases; periodontium disorder; phagocytosis; phosphorylation; physiologic bone resorption; preventive dentistry; prostaglandins; protein glutamine gamma glutamyltransferase; proteolysis

The long-term goal is to develop drugs that correct deficiencies in the regulation of oxygen radical production by phagocytes. Oxygen radicals are essential for efficient killing of pathogens, but inappropriate release of oxygen radicals can result in tissue damage. The pathogenicity of some microbes is due, in part, to their ability to interfere with the phagocytes' production of oxygen radicals. Regulation of oxygen radical production is a two-stage process, involving "activation" and "triggering." The first specific aim is to examine the biochemical mechanisms responsible for the activation of macrophages. Based on preliminary experiments, the following hypothesis will be tested: The enzyme that produces oxygen radicals, NADPH oxidase, has a component, cytochrome b, which moves from a storage location in granules to its site of action in the plasma membrane. The extent of this movement determines the potential activity of NADPH oxidase and therefore the state of activation of the macrophage. There is a regulatory protein in the macrophage plasma membrane that keeps the macrophage in a non-activated or "resident" state, by blocking the incorporation of cytochrome b into the plasma membrane. Cleavage of this protein by external protease results in activation. The second specific aim is to examine whether macrophage activation can cure experimental infections in mice. Drugs that cause macrophage activation, including recombinant gamma interferon and interleukin 2, muramyl dipeptide and indomethacin, will be given to mice infected with the chromic intracellular pathogen, Mycobacterium intracellulare. The reduction in the numbers of infection micro-organisms and the effect of the drugs on the microbicidal activity of the macrophages will be studied. The third specific aim is to examine the effectiveness of macrophage activating agents on the microbicidal activity of cultured human monocytes. Monocytes taken from patients with chronic mycobacterial infection will be treated with the drugs to determine whether the function of these monocytes can be improved. The effectiveness of muramyl dipeptide and gamma interferon in treating monocytes from patients who have mycobacterial infections as a result of AIDS will be tested. These macrophage activators should be able to bypass the defective T-lymphocyte function in AIDS patients. Ultimately, the knowledge and the drugs developed here might aid human patients to resist periodontal disease and other chronic diseases resulting from infection or from deficiencies in the immune system.

长期目标是开发可纠正缺陷的药物 调节吞噬细胞的氧自由基生产。 氧自由基是 有效杀死病原体至关重要，但不适当的释放 氧自由基会导致组织损伤。 一些人的致病性 微生物部分是由于它们干扰的能力 吞噬细胞的产生氧自由基。 氧自由基生产的调节是两个阶段的过程，涉及 “激活”和“触发”。 第一个具体目的是检查 导致巨噬细胞激活的生化机制。 根据初步实验，将检验以下假设： 产生氧自由基的酶，NADPH氧化酶的成分， 细胞色素B，从颗粒的存储位置移动到其站点 质膜的作用。 这一运动的程度决定了 NADPH氧化酶的潜在活性，因此 巨噬细胞的激活。 在 巨噬细胞质膜将巨噬细胞保持在未激活或 “居民”状态，通过阻止将细胞色素B掺入 质膜。 外部蛋白酶对这种蛋白质的切割导致 激活。 第二个特定目的是检查巨噬细胞是否是否 激活可以治愈小鼠的实验感染。 引起的药物 巨噬细胞激活，包括重组伽马干扰素和 白介素2，穆拉米尔二肽和吲哚美辛将被给予小鼠 感染细胞内病原体，分枝杆菌 胞内。 感染微生物的数量减少 以及药物对巨噬细胞杀生活性的影响 将被研究。 第三个具体目的是检查 巨噬细胞激活剂对培养的人的杀生活性 单核细胞。 从慢性分枝杆菌患者中获得的单核细胞 感染将用药物治疗，以确定功能是否 这些单核细胞可以改善。 穆拉米尔二肽的有效性 和伽马干扰素治疗患者的单核细胞 艾滋病导致的分枝杆菌感染将被测试。 这些 巨噬细胞激活剂应能够绕过缺陷的T淋巴细胞 艾滋病患者的功能。 最终，这里开发的知识和药物可能有助于人类 患者抵抗牙周疾病和其他慢性疾病，导致 来自感染或免疫系统中的缺陷。