Role of S-nitrosohemoglobin in Sepsis

描述（由申请人提供）：脓毒性休克是导致 住院患者的死亡率，并定义为全身炎症 对感染的反应。这种疾病的特点是低血压， 包括肺在内的器官的炎症损伤，并最终导致 多器官衰竭和死亡。一氧化氮（NO）在其中起着关键作用。 由iNOS产生的NO引起的疾病受到广泛关注。然而，作用 一氧化氮在脓毒症中的有害和有益作用尚不清楚 报道血管系统中NO功能的重要调节剂是 血红蛋白（Hb）。最近的见解之间的反应NO和血红蛋白 显示，除了与血红素反应，NO也与 形成S-亚硝基血红蛋白（SNOHb）的关键半胱氨酸残基。SNOHb可以引起 无依赖性效应，主要在以下背景下进行研究： 血液流动的生理调节。SNOHb的潜在作用 然而，没有考虑病理学。最近的研究表明，SNOHb是 内毒素血症期间升高，在这项建议中，新的概念，SNOHb 介导内毒素诱导的肿胀和炎症反应， 提出了调节NO的不同氧化还原同系物的产生。的 NO的氧化还原衍生物，包括硝酰基阴离子（N 0-）在 疾病仍然在很大程度上未被探索，虽然功能，促进 已经提出了血管舒张和炎症反应的刺激。 本文提供的初步数据表明，SNOHb依赖性血管舒张 通过红细胞的NO形成和血管舒张作用发生 从内毒素处理的大鼠中纯化的。这些观测 这导致了一种假设，即观察到的全身性低血压和炎症， 脓毒症由SNOHb介导。这一假设将通过追求 以下具体目标：1）确定SNOHb形成的机制， 内毒素休克; 2）确定SNOHb的血管舒张机制;和3） 研究SNOHb作为肺部炎症损伤介质的作用。 这些目标的实现将产生新的见解，既分子 NO影响败血症发病机制和 可能的治疗策略来治疗这种炎症性疾病。

DESCRIPTION (provided by applicant): Septic shock is a leading cause of mortality in hospitalized patients and is defined as the systemic inflammatory response to infection. This disease is characterized by hypotension and inflammatory damage to organs including the lung and which ultimately leads to multiple organ failure and death. Nitric oxide (NO) has a critical role in this disease with NO produced from iNOS receiving much attention. However, the role of NO in sepsis remains unclear with both detrimental and beneficial roles reported. An important regulator of NO function in the vasculature is Hemoglobin (Hb). Recent insights into the reactions between NO and Hb have shown that in addition to reactions with the heme, NO also interacts with a critical cysteine residue forming S-nitrosohemoglobin (SNOHb). SNOHb can elicit NO dependent effects and has been investigated principally in the context of physiological regulation of blood flow. The potential role of SNOHb in pathology has not been considered however. Recent studies show that SNOHb is elevated during endotoxemia and in this proposal, the novel concept that SNOHb mediates endotoxin induced hypotensive and inflammatory responses, by modulating production of different redox congeners of NO is put forward. The biological role of redox derivatives of NO, including nitroxyl anion (N0-) in disease remains largely unexplored although functions in promoting vasodilatation and stimulation of inflammatory responses have been suggested. Preliminary data presented herein suggest that SNOHb dependent vasorelaxation occurs via formation of N0- and vasorelaxing effects of red blood cells purified from endotoxin treated rats are demonstrated. These observations have led to the hypothesis that systemic hypotension and inflammation observed in sepsis are mediated by SNOHb. This hypothesis will be tested by pursuit of the following specific aims: 1) Determine the mechanism of SNOHb formation in endotoxic shock; 2) Determine the vasodilatory mechanisms of SNOHb; and 3) Investigate the role of SNOHb as a mediator of inflammatory damage in the lung. Accomplishment of these aims will yield novel insights into both the molecular mechanisms by which NO impacts upon the pathogenesis of septicemia and on possible therapeutic strategies to treat this inflammatory disease.