Free Hemoglobin Potentiates Pulmonary Vascular Dysfunction in Acute Lung Injury

描述(申请人提供)：本R21申请是对NHLBI RFA-HL-12-004《最大化NHLBI生物标本库的科学价值：科学机遇(R21)》的响应。急性肺损伤和急性呼吸窘迫综合征(ALI/ARDS)仍然是重症监护病房发病率和死亡率的常见原因。需要新的预防和治疗方法。肺血管功能障碍导致的肺动脉高压可能是ALI/ARDS预后的重要因素。然而，ALI/ARDS肺血管功能障碍的病理生理学机制尚不清楚。一个潜在的致病因素是循环中的无细胞血红蛋白，一种有效的血管收缩物质。循环中游离血红蛋白水平的升高被发现是镰状细胞性贫血患者肺动脉高压的主要原因，并与其他患者的不良临床结果有关，包括我们自己对败血症、创伤和ALI/ARDS患者的初步研究。血红蛋白诱导的ALI/ARDS肺血管损伤和肺动脉高压可能与血红蛋白的促氧化作用有关。拟议的研究将检验这样的假设：急性肺损伤患者循环中的高水平游离血红蛋白会导致肺血管功能障碍、非肺器官衰竭和不良的临床结果。我们旨在通过在一项大型临床试验中测试血浆游离血红蛋白水平与ALI/ARDS患者的肺血管功能障碍(通过肺动脉压、肺血管阻力、跨肺阻力来衡量)、心功能障碍(以心输出量和混合静脉血氧饱和度来衡量)、非肺器官功能障碍以及内皮损伤和死亡率的生物标志物之间的关系，来确定游离血红蛋白水平是否是临床ALI/ARDS患者肺血管功能障碍的重要决定因素。我们将通过检测两种主要的血红蛋白结合蛋白(血凝素和结合珠蛋白)的循环水平来确定ALI/ARDS患者游离血红蛋白水平升高的原因，以确定这些蛋白的低水平是否是导致ALI/ARDS患者循环游离血红蛋白水平升高的主要机制。最后，将通过测量脂质过氧化标记物(异前列腺素和异呋喃)来确定氧化应激是否是游离血红蛋白破坏性影响的基础，从而确定升高的游离血红蛋白如何导致该患者群体的不良结局(目标3)。总之，这项创新性的研究将确定ALI/ARDS中肺血管功能障碍的新机制，将确定一些患者游离血红蛋白水平升高的原因，以及游离血红蛋白是否会导致脂质过氧化。这项研究将由一名经验丰富的调查员进行，并拥有一支强大的支持团队和国际公认的顾问。使用合理的实验和统计方法，以及具有良好特征的患者队列，拟议的研究可能会产生重要的发现，这将促进我们对ALI/ARDS的理解。

DESCRIPTION (provided by applicant): This R21 application is in response to NHLBI RFA-HL-12-004 "Maximizing the Scientific Value of the NHLBI Biologic Specimen Repository: Scientific Opportunities (R21)". Acute Lung Injury and the Acute Respiratory Distress Syndrome (ALI/ARDS) remain common causes of morbidity and mortality in the intensive care unit. Novel therapies for prevention and treatment are needed. Pulmonary vascular dysfunction leading to pulmonary arterial hypertension may be an important contributing factor to outcomes from ALI/ARDS. However, the pathophysiology of pulmonary vascular dysfunction in ALI/ARDS is poorly understood. One potential etiologic factor is circulating cell-free hemoglobin, a potent vasoconstrictor. Elevated levels of circulating free hemoglobin have been found to be the primary cause of pulmonary arterial hypertension in sickle cell anemia and have been linked to poor clinical outcomes in other patient populations including our own preliminary studies of patients with sepsis, trauma and ALI/ARDS. Hemoglobin-induced pulmonary vascular injury and pulmonary hypertension in ALI/ARDS may be driven by the potent pro-oxidant effects of hemoglobin. The proposed studies will test the hypothesis that: High circulating levels of free hemoglobin in patients with acute lung injury contribute to pulmonary vascular dysfunction, non-pulmonary organ failure and poor clinical outcomes. We aim to determine whether free hemoglobin is an important determinant of pulmonary vascular dysfunction in clinical ALI/ARDS (Aim 1) by testing the association between plasma free hemoglobin levels and pulmonary vascular dysfunction (as measured by pulmonary artery pressure, pulmonary vascular resistance, transpulmonary resistance), cardiac dysfunction (as measured by cardiac output and mixed venous oxygen saturation), non-pulmonary organ dysfunction, and biomarkers of endothelial injury and mortality in patients with ALI/ARDS enrolled in a large clinical trial. We wll determine why patients with ALI/ARDS have elevated levels of free hemoglobin (Aim 2) by measuring circulating levels of the two major hemoglobin binding proteins (hemopexin, haptoglobin) to determine if low levels of these proteins are the primary mechanism leading to elevated levels of circulating free hemoglobin in patients with ALI/ARDS. Finally will determine how elevated free hemoglobin contributes to poor outcomes in this patient population (Aim 3) by measuring markers of lipid peroxidation (isoprostanes and isofurans) to determine if oxidant stress underlies the damaging effects of free hemoglobin. In summary, this innovative study will identify a novel mechanism of pulmonary vascular dysfunction in ALI/ARDS, will determine why some patients have elevated levels of free hemoglobin and whether free hemoglobin causes lipid peroxidation. This study will be conducted by an experienced investigator with a strong support team and internationally recognized consultants. Using sound experimental and statistical methods and a well characterized patient cohort, the proposed studies are likely to generate significant findings that will advance our understanding of ALI/ARDS.