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Nitric oxide in health and disease: Physiology, pathophysiology, and clinical measurement

机译：一氧化氮在健康和疾病中的作用：生理学，病理生理学和临床测量

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摘要

Red blood cell-dependent hypoxic vasodilation is largely mediated via the delivery of NO through S-nitrosohemoglobin (Hb-SNO). Hb-SNO is regulated through allosteric and redox mechanisms that are not well understood. Part One of this dissertation explores the biochemical features of Hb micropopulations suggested to be involved in Hb-SNO synthesis. An NO-liganded mixed valency micropopulation was synthesized in vitro and identified spectroscopically as a ferric nitrosyl species (Fe(III)NO). Remarkably, this species was found to undergo a reaction that couples heme reduction and S-nitrosylation of ss93C. The biochemical properties of this species were found to resemble those of Hb valency hybrids (VHy's) identified by others in previous work. The similarities between the two species are discussed, and a model for Hb-SNO formation, including the putative identification of the intermediates involved, is proposed. Part Two explores the insights provided by this chemistry as it is relevant to human pathophysiology in the context of Hb-SNO depletion of RBCs in stored blood. Hb-SNO and membrane S-nitrosothiols were found to be depleted after only two days of storage. The vasoactive function of stored RBCs has been shown in previous work to be impaired relative to controls. These findings, in conjunction with the this study, could implicate NO dysregulation as a primary component in the etiology of hypoxic diseases and the negative sequelae associated with blood transfusions. The results from Part Two suggest that NO blood gas measurements could serve an important role in improving clinical outcome of patients with hypoxic diseases. The goal of the work presented in Part Three is to begin to address this emerging need by developing an economical and pragmatic sensor platform for routine clinical use in both an outpatient and inpatient setting.
机译：依赖红细胞的低氧血管舒张主要通过S-亚硝基血红蛋白（Hb-SNO）的NO传递介导。 Hb-SNO通过尚未充分了解的变构和氧化还原机制进行调节。本论文的第一部分探讨了建议参与Hb-SNO合成的Hb微种群的生化特征。在体外合成了NO配位的混合价微种群，并在光谱上鉴定为亚硝酸铁基物种（Fe（III）NO）。显着地，发现该物种经历了使ss93C的血红素还原和S-亚硝基化偶合的反应。发现该物种的生化特性与先前工作中其他人鉴定的Hb价杂种（VHy's）相似。讨论了两个物种之间的相似性，并提出了Hb-SNO形成的模型，包括有关中间体的假定鉴定。第二部分探讨了这种化学方法提供的见解，因为它在血液中Hb-SNO耗尽红细胞的过程中与人类病理生理学有关。发现仅储存两天后Hb-SNO和膜S-亚硝基硫醇就被消耗掉。先前的研究表明，相对于对照而言，所储存的RBC的血管活性功能受到损害。这些发现与本研究相结合，可能暗示NO失调是缺氧性疾病和与输血相关的负面后遗症病因的主要组成部分。第二部分的结果表明，无血气测量可以在改善缺氧性疾病患者的临床结局中发挥重要作用。第三部分提出的工作目标是，通过开发一种经济实用的传感器平台来满足门诊和住院患者的常规临床使用，从而满足这一新兴需求。

著录项

  • 作者

    Angelo, Michael.;

  • 作者单位

    Duke University.;

  • 授予单位 Duke University.;
  • 学科 Biochemistry.;Electrical engineering.;Physical chemistry.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 110 p.
  • 总页数 110
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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