The Role Of Nitric Oxide Synthase 1 (nos1) In Sepsis

一氧化氮合酶 1 (nos1) 在脓毒症中的作用

• 批准号: 6683877
• 负责人: Zenaide Quezado
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6683877
• 关键词: bacteria infection mechanism; bacterial disease; disease /disorder model; enzyme activity; enzyme inhibitors; gene targeting; genetically modified animals; inflammation; isozymes; laboratory mouse; neutrophil; nitric oxide; nitric oxide synthase; peritonitis

Several studies have now shown that nitric oxide (NO), a free radical gas produced endogenously, has profound effects on the function of leukocytes and in the overall host immune response to infection, sepsis and septic shock. In cells, NO is synthesized by three different isoforms of an enzyme named NO synthase (NOS). Two of these isoforms, NOS1 and NOS3 are constitutively expressed, while the third, NOS2, is an inducible (by toxins and cytokines) form of the enzyme. Differing lines of evidence suggest that NOS1 may have a very important role in the pathophysiology of sepsis. The enzyme is constitutively expressed not only in neuronal cells in the brain and spinal cord, but also in the microvasculature and epithelium of the gastrointestinal tract and kidney, bronchial epithelium, myocytes of skeletal muscle, mast cells in skin, and neutrophils. Researchers have shown that, under baseline conditions and during sterile peritonitis, mice congenitally lacking NOS1 (NOS1 knock out, NOS1-KO) have increased leukocyte rolling and adhesion to the endothelium of postcapillary venules and increased leukocyte migration into the peritoneal cavity. The purpose of this study is to investigate the effects of NOS1 on extravascular neutrophil recruitment, bacterial clearance, and inflammatory tissue injury during polymicrobial peritonitis, sepsis, and septic shock. We hypothesize that absence of NOS1, either in genetically engineered mice that congenitally lack the NOS1 gene or in wild type mice (phenotype considered normal) treated with a pharmacologic inhibitor of NOS1, will increase extravascular neutrophil recruitment and improve bacterial clearance and outcome during polymicrobial peritonitis and sepsis. Following cecal ligation and puncture in wild type or NOS1-KO mice randomized to receive a NOS1 inhibitor or placebo, survival, extravascular neutrophil recruitment, microbial clearance, and inflammatory tissue injury will be measured

现在的几项研究表明，一氧化氮（NO）是一种内源产生的自由基气体，对白细胞的功能以及对感染，败血症和败血性休克的总体免疫反应具有深远的影响。在细胞中，NO由称为NO合酶（NOS）的三种不同的同工型合成。这些同工型中的两个，NOS1和NOS3是组成型表达的，而第三个NOS2是酶的诱导型（通过毒素和细胞因子）形式。不同的证据表明，NOS1在败血症的病理生理学中可能具有非常重要的作用。该酶不仅在大脑和脊髓的神经元细胞中表达，而且在胃肠道和肾脏的微举行和上皮，支气管上皮，骨骼肌心肌，骨骼肌的心肌，皮肤和中性粒细胞中。研究人员表明，在基线条件下和无菌腹膜炎期间，先天缺乏NOS1（NOS1敲出来，NOS1-KO）的小鼠增加了白细胞滚动和对毛细管后静脉内皮的粘附，并增加了白细胞迁移到周围的白细胞迁移。这项研究的目的是研究NOS1对多因素性腹膜炎，败血症和败血性休克期间NOS1对血管外性粒细胞募集，细菌清除率和炎性组织损伤的影响。我们假设缺乏NOS1，即在基因工程的小鼠中缺乏NOS1基因或在用NOS1的药理抑制剂治疗的野生型小鼠（表型正常）中，将会增加血管外性粒细胞粒细胞招募，并改善细菌清除率，并改善多成肌二颗粒质质质质质质和Sepsississisisisisisisisisisisisissisisisissisisissisis。在野生型或NOS1-KO小鼠中结扎和穿刺之后