Mechanistic basis of lung dysfunction after RBC transfusion

描述(由申请人提供)： 摘要输注红细胞(RBC)后肺功能障碍的机制与危重或急性冠脉综合征贫血患者的高死亡率和肺部并发症有关，但其潜在机制尚不清楚。输血后，肺对血液的氧合功能受损的情况比较常见。但人们对红细胞的“储存性损伤”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的血液流动方面发挥着积极的作用，而血液流动是红细胞自身功能的一个主要决定因素，氧气的输送促使人们重新审视红细胞输注中的风险与收益平衡。红细胞在生理性低氧条件下释放血管扩张剂S-亚硝硫醇(SNO)，参与氧依赖的血流调节。其结果是外周缺氧性血管扩张，以及肺内缺氧性血管收缩的调节。然而，RBC SNO似乎优化了肺部的氧气摄取，而不是损害了它。在储存的人红细胞中的初步研究表明，在体外和体内，SNO和RBC对肺内适应性血管反应的依赖调节是不足的。与之平行的是，储存引起的红细胞变形性进行性损害，也可能与SNO的(丢失)有关。该项目的中心假设是，储存诱导的RBC SNO的耗尽会导致肺内血液流动的失调，从而影响氧气的摄取。为了验证这一新假说，我们将实现以下具体目标：1)确定(S)NO在储存的红细胞在肺内异常流动中的作用。2)确定红细胞保存后补充SNO或防止SNO丢失是否能改善红细胞的肺流量和输血后吸氧量。将测试以下策略：a)通过修改当前的血库做法来防止SNO的耗尽；b)在体外或体内将SNO充分储存在储存的红细胞中。生化、遗传学和药理学方法被用来在人和鼠的红细胞、分离的灌流小鼠肺和完整的小鼠身上实现这些目的。这些研究的结果有望为合理设计治疗方案提供参考，以提高危重贫血患者输注红细胞的疗效和结果。对退伍军人保健的潜在影响贫血与退伍军人发病率和死亡率的增加密切相关。红细胞输注治疗贫血是住院退伍军人最常接受的治疗方法之一。但令人惊讶的是，在一些患者组中，输注红细胞与死亡风险和不良肺部后果有关。这些研究的结果将导致改进红细胞处理、储存和输血的方法，为老年和医学上更复杂的患者提供特别的好处，如急性疾病的退伍军人。 公共卫生相关性： RBC输注后肺功能障碍的机制基础输注RBC治疗贫血不能使许多危重患者受益，实际上可能会增加一些人死亡和肺部问题的风险。这个项目研究了输血后出现的肺部问题的分子基础，重点是RBC中帮助其正常通过肺部以很好地吸收氧气的因子的损失。我们还调查了在储存的人红细胞和输注人红细胞的小鼠的肺中，这些问题是否可以预防或纠正。

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.