Mechanistic basis of lung dysfunction after RBC transfusion

描述（由申请人提供）： 红细胞输注后肺功能不全的机制在患有危重病或急性冠状动脉综合征的贫血患者中，红细胞输注与死亡率和肺部发病率增加有关，但其潜在机制尚不清楚。输血后肺部血液氧合受损相对频繁。但是对于红细胞的“储存性病变”如何导致肺部和其他不良后果知之甚少。最近发现红细胞在调节肺和外周血流量（其自身功能的主要决定因素，O2输送）中的积极作用，促使重新审视红细胞输注的风险-效益平衡。RBC在生理暴露于缺氧时释放血管扩张剂S-亚硝基硫醇（SNO），有助于O2依赖性血流调节。其结果是外周缺氧性血管舒张，以及肺缺氧性血管收缩的调节。然而，红细胞SNO似乎优化O2摄取在肺中，而不是compromisingit. Preliminary研究在存储的人红细胞显示缺乏SNO，并在红细胞依赖调节适应性血管反应在肺在体外和体内。与此同时，存在储存诱导的RBC变形能力的进行性损害，这也可能由SNO（损失）控制。该项目的中心假设是，储存诱导的RBC SNO消耗导致肺中血液流动失调，影响O2摄取。为了检验这一新的假设，我们将完成这些特定的目的：1）确定（S）NO损失在肺中储存的RBC的异常流动中的作用。2)确定RBC储存后补充SNO或预防SNO丢失是否改善了RBC的肺流量和输血后的O2摄取。将测试以下策略：a）通过修改当前血库操作来防止SNO耗尽; B）在离体或体内储存的RBC中充满SNO。使用生物化学、遗传学和药理学方法在人和小鼠RBC、分离的灌注小鼠肺和完整小鼠中实现这些目标。这些研究的结果有望为合理设计治疗方案提供信息，以改善贫血重症患者红细胞输注的疗效和结局。对退伍军人医疗保健的潜在影响贫血与退伍军人发病率和死亡率增加密切相关。红细胞输血治疗贫血是最常给予住院退伍军人的治疗方法之一。但令人惊讶的是，在一些患者群体中，RBC输注与死亡和不良肺部结局的风险增加有关。这些研究的结果应该导致红细胞处理，储存和输血的改进方法，为老年人和医学上更复杂的患者提供特别的好处，如急性病退伍军人。 公共卫生相关性： 红细胞输注后肺功能障碍的机制基础红细胞输注治疗贫血未能使许多重症患者受益，实际上可能会增加一些患者的死亡和肺部问题的风险。该项目研究输血后出现的肺部问题的分子基础，重点是红细胞中帮助其正常流过肺部以充分吸收氧气的因子的损失。我们还研究了这些问题是否可以在储存的人红细胞中预防或纠正，以及在输注人红细胞的小鼠肺中预防或纠正。

DESCRIPTION (provided by applicant): ABSTRACT Mechanistic basis of lung dysfunction after RBC transfusion Transfusion of red blood cells (RBCs) is associated with excess mortality and pulmonary morbidity in anemic patients with critical illness or acute coronary syndromes, but the underlying mechanisms are poorly understood. Impaired oxygenation of blood by the lung is relatively frequent after transfusion. But little is known of how "storage lesions" of the RBC may contribute to adverse pulmonary and other outcomes. The recent discovery of an active role of the RBC in regulating blood flow -- a major determinant of its own function, O2 delivery -- in the lung and periphery, prompts a reexamination of the risk-benefit balance in RBC transfusion. RBCs release vasodilator S-nitrosothiols (SNOs) upon physiological exposure to hypoxia, contributing to O2-dependent blood flow regulation. The result is hypoxic vasodilation peripherally, and modulation of hypoxic vasoconstriction in the lung. Yet RBC SNO appears to optimize O2 uptake in the lung rather than compromising it. Preliminary Studies in stored human RBCs show deficiency in SNOs, and in RBC-dependent regulation of adaptive vascular responses in the lung in vitro and in vivo. In parallel there is storage-induced, progressive impairment in RBC deformability, which may also be governed by (loss of) SNOs. The project's central hypothesis is that storage-induced depletion of RBC SNOs leads to dysregulation of the flow of blood in the lung, compromising O2 uptake. To test this novel hypothesis, we will accomplish these Specific Aims: 1) Determine the role of (S)NO loss in the abnormal flow of stored RBCs in the lung. 2) Determine whether pulmonary flow of RBCs and O2 uptake after transfusion are improved by SNO repletion after storage of RBCs, or prevention of the loss of SNOs. Strategies will be tested that a) prevent depletion of SNOs by modifying current blood-banking practices; b) replete SNOs in stored RBCs ex vivo or in vivo. Biochemical, genetic and pharmacological approaches are used to achieve these Aims in human and mouse RBCs, isolated perfused mouse lungs, and intact mice. The results of these studies are expected to inform the rational design of therapies to improve the efficacy and outcomes of RBC transfusion in critically ill patients with anemia. Potential Impact on Veterans' Health Care Anemia is strongly linked to increased morbidity and mortality in Veterans. RBC transfusion for anemia is among the therapies most frequently administered to hospitalized Veterans. But surprisingly, RBC transfusion is associated in some patient groups with an increased risk of death and adverse pulmonary outcomes. The results of these studies should lead to improved methods for RBC processing, storage, and transfusion, providing particular benefits for older and more medically complex patients, such as acutely ill Veterans. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Mechanistic basis of lung dysfunction after RBC transfusion Red blood cell (RBC) transfusion for anemia fails to benefit many critically ill patients, and can actually raise the risk of death and lung problems in some. This project examines the molecular basis of lung problems arising after transfusion, focusing on the loss of factors in the RBC that help it flow normally through the lungs in order to take up oxygen well. We also investigate whether these problems can be prevented or corrected in stored human RBCs, and in the lungs of mice transfused with human RBCs.