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: 2143227
• 负责人: Robert W Colman
• 金额: $ 20.46万
• 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 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2143227
• 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.

炎症性肠病病理改变的机制 疾病还不太清楚。 我们发现细菌产物 发现在较低的肠道有能力产生慢性 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，全身吸收这些 产品可以解释关节炎和贫血的相关发现。我们 已经证明，已知的细菌产物可以激活 与严重感染相关的休克中的激肽释放酶-激肽系统可能 引发实验性肠道重要的局部变化 炎症激肽释放酶-激肽系统是一系列酶促反应 释放缓激肽，一种引起疼痛，肿胀， 腹泻，肌肉收缩，这些都是典型的症状 克罗恩病的症状 我们首先记录了激活的发生， 在由细菌产物诱导的关节炎大鼠模型中， 肽聚糖多糖（PG-APS）。此外，我们最近 证明了特异性激肽释放酶抑制剂不仅可以阻断 在大鼠关节炎模型中的接触激活，而且还改善了 关节炎、贫血和急性期反应。此外，我们还表明， 接触激活仅发生在刘易斯大鼠中，而不发生在布法罗大鼠中 福尔斯对PG-APS有反应。 我们也有初步的数据， 一种特异性的激肽释放酶抑制剂阻断了接触、激活、肠道 炎症和中性粒细胞浸润 将PG-APS注射到盲肠中。 来描述 接触系统与炎症变化有关，我们建议 研究1）一种额外的特异性激肽释放酶抑制剂，一种新的重组 突变的Kunitz型蛋白酶抑制剂，2）抑肽酶，其抑制 激肽释放酶和纤溶酶，3）缓激肽受体拮抗剂，和4） 重组弹性蛋白酶抑制剂。这些代理商将被测试其 抑制急性和慢性炎症的能力。在 此外，我们还将探讨差异激活的机制 在遗传易感和抗性大鼠中的接触系统， 包括PG-PS对接触系统的体外和体内活化， 内毒素、IL-1和IL-6。 我们将研究 抗性大鼠中激肽原裂解的缺陷。 这些研究应 证明了炎症性肠病发病机制的重要性 疾病接触系统的分析可以区分活性和 非活动性疾病，或作为治疗指标。此外该 单独或联合使用的抑制剂在未来可能会作为 人炎症性肠病的潜在治疗剂。