KALLIKREIN KININ SYSTEM IN INFLAMMATORY BOWEL DISEASE

激肽释放酶激肽系统在炎症性肠病中的作用

• 批准号: 2518303
• 负责人: Robert W Colman
• 金额: $ 24.98万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2518303
• 关键词: antiinflammatory agents; antithrombins; aprotinin; bacterial polysaccharides; bradykinin; disease /disorder model; elastase inhibitor; genetic strain; histopathology; human genetic material tag; inflammatory bowel diseases; interleukin 1; kallikreins; kininogens; kinins; laboratory rat; molecular cloning; polymerase chain reaction; protease inhibitor; proteoglycan; receptor binding

The mechanisms underlying the pathological changes in inflammatory bowel disease are not well understood. We have found that bacterial products found in the lower bowel have the ability to produce the chronic granulomatous inflammation similar to Crohn's disease (regional ileitis) in genetically susceptible hosts. Moreover, systemic absorption of these products could explain the associated finding of arthritis and anemia. We have demonstrated that bacterial products known to activate the kallikrein-kinin system in shock associated with severe infection may initiate the local changes important in experimental intestinal inflammation. The kallikrein-kinin system is a series of enzymatic factions which release bradykinin, a peptide which induces pain, swelling, diarrhea, and-muscle contraction, all of which are characteristic symptoms of Crohn's disease. We have first documented the occurrence of activation of this system in a rat model of arthritis induced by a bacterial product, peptidoglycan-polysaccharide (PG-APS). Further, we have recently demonstrated that a specific kallikrein inhibitor can not only block contact activation in a rat model of arthritis, but also ameliorates the arthritis, anemia and acute phase reaction. Further, we have shown that the contact activation only occurs in the Lewis rat but not in the Buffalo rat, which falls to respond to PG-APS. We also have preliminary data that a specific kallikrein inhibitor blocks the contact, activation, gut inflammation and neutrophil infiltration in rats given intramural injection of PG-APS into the caecum. To delineate the mechanisms by which the contact system relates to the inflammatory changes, we propose to study 1) an additional specific kallikrein inhibitor, a novel recombinant mutant Kunitz-type protease inhibitor, 2) aprotonin, which inhibits both kallikrein and plasmin, 3) a bradykinin receptor antagonist, and 4) a recombinant elastase inhibitor. These agents will be tested for their ability to inhibit the acute and chronic phases of inflammation. In addition, we will investigate the mechanism of the differential activation of the contact system in genetically susceptible and resistant rats, including in vitro and in vivo activation of the contact system by PG-PS, endotoxin, IL-1 and lL-6. We will study the molecular genetic basis of the defect in kininogen cleavage in resistant rats. These studies should demonstrate important mechanisms in the pathogenesis of inflammatory bowel disease. Assays of the contact system could distinguish active from inactive disease, or serve as an index for therapy. In addition, the inhibitors used alone or in combination could serve in the future as potential therapeutic agents of human inflammatory bowel disease.

炎症性肠病的病理变化机制 人们对疾病的认识还不够深入。我们发现细菌产品 在较低的肠道中发现有能力产生慢性 类似克罗恩病的肉芽肿性炎症(区域性回肠炎) 在遗传易感的宿主中。此外，这些物质的系统性吸收 产品可以解释关节炎和贫血的相关发现。我们 已经证明了已知的细菌产品可以激活 激肽释放酶-激动素系统在严重感染相关休克中可能 在实验性肠道中启动重要的局部改变 发炎。激肽释放酶-激肽系统是一系列的酶。 释放缓激肽的派系，缓激肽是一种能引起疼痛、肿胀的多肽， 腹泻和肌肉收缩，所有这些都是典型的症状 克隆氏病的症状。我们首先记录了激活的发生 在细菌制品诱导的关节炎大鼠模型中， 肽多糖(PG-APS)。此外，我们最近已经 证明了一种特定的激肽释放酶抑制剂不仅可以阻断 在关节炎大鼠模型中的接触激活，但也改善了 关节炎、贫血和急性时相反应。此外，我们已经表明， 接触激活只发生在Lewis大鼠身上，而不发生在水牛身上 对PG-APS有反应。我们还有初步数据显示 一种特定的激肽释放酶抑制剂阻止接触，激活，肠道 大鼠壁内注射后炎症反应和中性粒细胞的浸润 盲肠内注射PG-APS。为了描述通过什么机制 接触系统与炎性改变有关，我们建议 研究1)另一种特殊的激肽释放酶抑制剂，一种新的重组 突变的kunitz型蛋白水解酶抑制剂，2)非质蛋白，它抑制这两种 激肽释放酶和纤溶酶，3)缓激肽受体拮抗剂，以及4)a 重组弹性蛋白酶抑制剂。这些代理将接受测试，以确定它们的 抑制急性和慢性炎症的能力。在……里面 此外，我们还将研究差异激活的机制 遗传易感和耐药大鼠的接触系统， 包括PG-PS在体外和体内对接触系统的激活， 内毒素、IL-1和IL-6。我们将研究其分子遗传学基础。 耐药大鼠激肽原裂解缺陷。这些研究应该 阐明炎症性肠病发病的重要机制 疾病。对接触系统的分析可以区分活跃的和 非活动性疾病，或作为治疗的指标。此外， 单独使用或联合使用的抑制剂在未来可能用作 人类炎症性肠病的潜在治疗药物。