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

描述（由申请方提供）：严重脓毒症是对感染的反应，包括最终导致急性器官衰竭的全身炎症反应综合征（SIRS），是住院患者死亡的主要原因。临床严重脓毒症很少被认识，因此很少在广泛器官损伤之前进行研究。临床前模型可能不能完全代表人类败血症。大剂量重组白细胞介素-2（HDIL-2）是治疗晚期癌症的重要手段。HDIL 2引起SIRS，并可预测地导致急性器官衰竭，这与脓毒症中所见几乎无法区分。常见肺水肿、休克和肾衰竭。因此，HDIL 2提供了一个独特的机会，以研究器官衰竭的机制，因为它在临床SIRS期间的发展。先前的工作涉及急性肺损伤的发病机制中的肾素-血管紧张素系统（RAS）激活。我们的团队有初步数据证实RAS激活对应于HDIL 2期间的器官衰竭。这些数据迫使我们假设RAS失调有助于临床SIRS期间的肺损伤和器官衰竭。我们将在HDIL 2治疗过程中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HDIL 2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HDIL 2的人类受试者中收集内皮细胞。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。我们将通过孵育内皮细胞同时抑制ACE和增加ACE2产物来测试RAS的作用。2)确定精氨酸加压素输注是否改变HDIL 2期间RAS激活和肺损伤的进展。AVP在SIRS期间增加血压并减少儿茶酚胺的使用，因此可能在早期SIRS期间减少RAS激活。受试者将在HDIL 2期间随机接受AVP或安慰剂，并评估AVP对早期肺损伤的影响。我们将从受试者中分离内皮细胞，并确定AVP是否改变RAS激活。3)确定RAS抑制是否改变肺损伤和SIRS期间的临床进展。受试者将在HDIL 2期间随机接受依那普利拉或安慰剂。对肺损伤的生化和临床证据的演变进行系统评价将确定RAS是否有助于临床SIRS期间的器官损伤。因此，这些项目将通过提供对临床SIRS和脓毒症期间肺损伤和其他器官衰竭机制的新见解而产生广泛影响。

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.