The role of neuronal nitric oxide synthase in a model of peritonitis and sepsis

神经元一氧化氮合酶在腹膜炎和脓毒症模型中的作用

• 批准号: 7593060
• 负责人: Zenaide Quezado
• 金额: $ 12.82万
• 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/7593060
• 关键词: Adhesions; Animals; Bacteria; Bacterial Counts; Blood; Brain; Cells; Condition; Endothelium; Endotoxins; Enzymes; Epithelium; Gastrointestinal tract structure; Genetic; Goals; Greater sac of peritoneum; Immune response; Infection; Inflammatory; Inflammatory Response; Injury; Kidney; Learning; Leukocyte Rolling; Leukocytes; Life; Lipopolysaccharides; Modeling; Molecular Profiling; Mus; Muscle Fibers; NOS1 gene; NOS1 protein, human; NOS2A gene; NOS3 gene; Neurons; Neutrophil Infiltration; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Peritoneum; Peritonitis; Platelet Count measurement; Protein Isoforms; Reporting; Role; Sepsis; Septic Shock; Skeletal Muscle; Skin; Spinal Cord; Sterility; Stimulus; Tissues; bronchial epithelium; chemokine; cytokine; human NOS2A protein; human NOS3 protein; mast cell; migration; mortality; neutrophil; postcapillary venule; tool

Nitric oxide (NO), has been shown to have 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 NO synthase (NOS), two are constitutively expressed (NOS1 and NOS3) and another (NOS2) is inducible with specific stimulus. While both NOS2 and NOS3 have been shown to have a role in sepsis and septic shock, less is known about the role of NOS1 in the host response to sepsis. There is some evidence to suggest that NOS1 might have a very important role in the host response to infection. 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-deficient) 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. At baseline, NOS1-deficient animals have higher neutrophil and lower platelet counts compared with wild type animals. We found that, although NOS1-deficient animals have reported increased migration of neutrophils into the peritoneum, in the setting of live bacterial peritonitis and sepsis, genetic deficiency of NOS1 is detrimental and increased mortality. Such detrimental effect in survival was also seen in a model of lipopolysaccharide (LPS) challenge. The mechanisms of this increased mortality in NOS1-deficient animals are yet unknown but it appears that NOS1-deficient have higher systemic bacterial counts in blood compared to wild type animals suggesting that animals deficient in NOS1 may have decreased bacterial clearance. We are now studying the mechanism whereby NOS1 impacts on survival and bacterial clearance during sepsis and septic shock. We have learned that NOS1 may alter cytokine and chemokine expression profiles during polymicrobial infections which might in turn alter the hosts ability to clear bacteria during infection.

一氧化氮（NO）已被证明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NO合酶（NOS）的三种不同的同工型合成，两种是组成型表达（NOS1和NOS3），而另一个（NOS2）则可以诱导特定的刺激。虽然NOS2和NOS3均已证明在败血症和败血性休克中起作用，但对NOS1在宿主对败血症的反应中的作用却少了。有证据表明，NOS1在宿主对感染的反应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。在基线条件下和无菌腹膜炎期间，先天缺乏NOS1（NOS1缺陷型）的小鼠对毛细血管后静脉的内皮的白细胞滚动和粘附增加，并增加了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。在基线时，与野生型动物相比，缺乏NOS1的动物具有较高的中性粒细胞，血小板计数较低。我们发现，尽管缺乏NOS1的动物报告了中性粒细胞向腹膜的迁移增加，但在活细菌性腹膜炎和败血症的情况下，NOS1的遗传缺乏是有害的，死亡率增加。在脂多糖（LPS）挑战模型中也观察到了生存中的这种有害作用。与野生型动物相比，NOS1缺陷型血液中这种死亡率增加的机制尚不清楚，但血液中的全身细菌计数较高，这表明NOS1缺乏的动物可能会降低细菌清除率。现在，我们正在研究NOS1在败血症和败血性休克期间对生存和细菌清除率影响的机制。 我们了解到，NOS1可能会在多因素感染过程中改变细胞因子和趋化因子的表达谱，这反过来又可能会改变宿主在感染过程中清除细菌的能力。