RAS dysregulation during HDIL2: a clinical model of sepsis-induced lung injury

描述(申请人提供)：严重脓毒症是对感染的反应，包括全身性炎症反应综合征(SIRS)，最终导致急性器官衰竭，是住院患者的主要死亡原因。临床上严重的脓毒症很少被认识到，因此在广泛的器官损伤之前也很少被研究。临床前模型可能不能完全代表人类脓毒症。大剂量重组白介素2(HDIL2)是治疗晚期癌症的重要手段。高密度脂蛋白2可引起全身炎症反应综合征，并可预见地导致与脓毒症几乎无法区分的急性器官衰竭。肺水肿、休克和肾功能衰竭很常见。因此，在临床全身炎症反应综合征的发展过程中，HDIL2为研究器官衰竭的机制提供了一个独特的机会。先前的工作表明肾素-血管紧张素系统(RAS)激活与急性肺损伤的发病机制有关。我们的团队有初步数据证实RAS激活对应于HDIL2期间的器官衰竭。这些数据迫使我们假设，在临床SIRS期间，RAS失调导致肺损伤和器官衰竭。我们将在HDIL2治疗期间通过系统研究以下目标来验证这一假设。1)确定RAS失调是否与HDIL2期间的内皮屏障功能障碍有关。我们将利用创新技术从接受HDIL2的受试者身上收集内皮细胞。在此过程中，我们将测量RAS蛋白的表达，并将其与肺损伤的临床和生化证据联系起来。我们将通过在抑制ACE和增加ACE2产物的同时孵育内皮细胞来测试RAS的作用。2)确定精氨酸加压素输注是否改变了HDIL2期间RAS激活和肺损伤的进程。AVP在SIRS期间升高血压，减少儿茶酚胺的使用，从而可能降低SIRS早期RAS的激活。受试者将在HDIL2期间随机接受AVP或安慰剂治疗，并评估AVP对早期肺损伤的影响。我们将从受试者身上分离内皮细胞，并确定AVP是否改变RAS的激活。3)确定RAS抑制是否改变肺损伤和SIRS的临床进展。受试者将在HDIL2期间随机接受依那普利拉或安慰剂治疗。对肺损伤的生化和临床证据的演变进行系统的评估将确定在临床SIRS期间RAS是否对器官损伤起作用。因此，这些项目将对临床全身炎症反应综合征和脓毒症期间肺损伤和其他器官衰竭的机制提供新的见解，从而产生广泛的影响。

DESCRIPTION (provided by applicant): Severe sepsis is a response to infection that includes a systemic inflammatory response syndrome (SIRS) culminating in acute organ failure, and is a leading cause of death in hospitalized patients. Clinical severe sepsis is rarely recognized and thusly rarely studied prior to extensive organ injury. Preclinical models may not fully represent human sepsis. High dose recombinant interleukin-2 (HDIL2) is an important treatment for advanced cancers. HDIL2 causes SIRS and predictably leads to acute organ failure that is virtually indistinguishable from that seen in sepsis. Pulmonary edema, shock, and renal failure are common. HDIL2 thus offers a unique opportunity to investigate mechanisms of organ failure as it develops during clinical SIRS. Prior work implicates renin-angiotensin system (RAS) activation in the pathogenesis of acute lung injury. Our team has preliminary data that confirms RAS activation corresponds to organ failure during HDIL2. These data compel us to hypothesize that RAS dysregulation contributes to lung injury and organ failure during clinical SIRS. We will test this hypothesis during HDIL2 therapy by systematically investigating the following aims. 1) Determine if RAS dysregulation relates to endothelial barrier dysfunction during HDIL2. We will utilize innovative techniques to collect endothelial cells from human subjects receiving HDIL2. In so doing we will measure the expression of RAS proteins and relate them to clinical and biochemical evidence of lung injury. We will test the role of RAS by incubating endothelial cells while inhibiting ACE and increasing ACE2 products. 2) Determine if arginine vasopressin infusions alter the progression of RAS activation and lung injury during HDIL2. AVP increases blood pressure and decreases catecholamine use during SIRS, and thus may decrease RAS activation during early SIRS. Subjects will be randomized to receive AVP or placebo during HDIL2, and evaluate the effects of AVP upon early lung injury. We will isolate endothelial cells from subjects and determine if AVP alters RAS activation. 3) Determine if RAS inhibition alters the clinical progression of lung injury and during SIRS. Subjects will be randomized to receive enalaprilat or placebo during HDIL2. A systematic evaluation of the evolution of biochemical and clinical evidence of lung injury will determine if RAS contributes to organ injury during clinical SIRS. Accordingly, these projects will have broad impact by providing novel insight into the mechanisms of lung injury and other organ failures during clinical SIRS and sepsis.