Role of S-nitrosohemoglobin in Sepsis

描述(由申请人提供)：感染性休克是导致 住院患者的死亡率，定义为全身性炎症 对感染的反应。这种疾病的特点是低血压和 对包括肺在内的器官的炎性损害，最终导致 多器官衰竭和死亡。一氧化氮(No)在这一过程中起着关键作用。 诱导型一氧化氮合酶(INOS)产生的NO引起的疾病备受关注。然而，这个角色 脓毒症中NO的作用仍不清楚，既有有害的，也有有益的 据报道。血管系统中一氧化氮功能的一个重要调节因素是 血红蛋白(Hb)。最近对NO和Hb之间反应的洞察有 表明，除了与血红素的反应外，NO还与 形成S亚硝基血红蛋白的关键半胱氨酸残基。SNOHb可以引发 没有依赖效应，主要是在以下背景下进行的研究 血液流动的生理调节。SNOHb在人类免疫缺陷中的潜在作用 然而，病理学还没有被考虑。最近的研究表明，SNOHb是 在内毒素血症期间升高，在这项提议中，SNOHb的新概念 介导内毒素引起的降压和炎症反应，通过 提出了NO不同氧化还原同系物的调制生产方法。这个 NO的氧化还原衍生物，包括硝基阴离子(N0-)在体内的生物学作用 疾病在很大程度上仍未被探索，尽管它在促进 已经提出了扩张血管和刺激炎症反应的建议。 初步数据提示，SNOHb依赖血管松弛 通过形成N0-和红细胞的血管松弛作用而发生 从内毒素处理的大鼠中提纯。这些观察结果已经 导致假设全身性低血压和炎症在 败血症是由SNOHb介导的。这一假设将通过追求 具体目标如下：1)确定SNOHb的形成机制 内毒素休克；2)确定SNOHb的血管扩张机制；3) 探讨SNOHb在肺炎性损伤中的作用。 这些目标的实现将产生对这两个分子 一氧化氮在败血症发病机制中的作用及其机制 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.