Neuronal nitric oxide synthase: model peritonitis/sepsis

神经元一氧化氮合酶：腹膜炎/败血症模型

• 批准号: 7003945
• 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/7003945
• 关键词: antibacterial agents; bacterial disease; cell adhesion; cell migration; disease /disorder model; drug screening /evaluation; enzyme activity; enzyme inhibitors; enzyme therapy; genetically modified animals; inflammation; laboratory mouse; neurons; neutrophil; nitric oxide synthase; nonhuman therapy evaluation; peritonitis; septic shock; septicemia

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. 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. Several 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. 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. We are investigating the effects of NOS1 on extravascular neutrophil recruitment, bacterial clearance, and inflammatory tissue injury during polymicrobial peritonitis, sepsis, and septic shock. We have shown that although NOS1-KO animals have reported increased migration of neutrophils in the setting of chemical peritonitis, in the setting of live bacterial peritonitis, genetic deficiency of NOS1 is detrimental and increases mortality. In addition, we found that 7-nitroindazole, a specific inhibitor of NOS1, had opposite effects in wild type animals compared to NOS1-KO. We are studying the mechanism whereby NOS1 impacts on survival, leukocyte trafficking, and bacterial clearance during sepsis and septic shock

一氧化氮（NO）是一种内源性产生的自由基气体，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。 NO由称为NO合酶（NOS）的酶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。几条证据表明，NOS1在败血症的病理生理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。在基线条件和无菌腹膜炎期间，先天缺乏NOS1（NOS1敲出，NOS1-KO）的小鼠增加了白细胞滚动和对毛细血管后静脉内皮的粘附，并增加白细胞迁移到腹膜腔中。我们正在研究NOS1对多重性腹膜炎，败血症和败血性休克期间NOS1对血管外嗜中性粒细胞募集，细菌清除和炎症组织损伤的影响。我们已经表明，尽管NOS1-KO动物在化学腹膜炎中报告了中性粒细胞的迁移增加，但在活细菌性腹膜炎的情况下，NOS1的遗传缺乏是有害的，并增加了死亡率。此外，我们发现，与NOS1-KO相比，NOS1的特定抑制剂7-硝化剂在野生型动物中具有相反的作用。我们正在研究NOS1在败血症和化粪池休克期间对生存，白细胞运输和细菌清除的影响的机制