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

点击翻译按钮获取中文摘要

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.