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

HDIL2 期间 RAS 失调：脓毒症引起的肺损伤的临床模型

• 批准号: 9130382
• 负责人: KEVIN C DOERSCHUG
• 金额: $ 39.61万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130382
• 关键词: Acute; Acute Lung Injury; Advanced Malignant Neoplasm; American; Angiopoietin-2; Angiotensin II; Argipressin; Biochemical; Blood Pressure; Cancer Patient; Caring; Catecholamines; Cause of Death; Cessation of life; Clinical; Data; Development; Dose; Employee Strikes; Enalaprilat; Endothelial Cells; Evaluation; Functional disorder; Goals; Health; Homologous Gene; Human; Hypotension; Incubated; Infection; Inflammatory; Infusion procedures; Injury; Interleukin-2; Intervention; Kidney Failure; Lead; Malignant Neoplasms; Measures; Mediator of activation protein; Melanoma Cell; Modeling; Organ; Organ failure; Outcome; Pathogenesis; Patients; Peptidyl-Dipeptidase A; Permeability; Placebos; Plasma; Population Heterogeneity; Pre-Clinical Model; Proteins; Pulmonary Edema; Randomized; Recombinant Interleukin-2; Regulation; Renal Cell Carcinoma; Renin-Angiotensin System; Reporting; Research; Role; Sepsis; Sepsis Syndrome; Shock; Stimulus; Study Subject; System; T-Lymphocyte; Techniques; Testing; Time; Transcend; Ultrasonography; Work; biochemical evolution; cancer therapy; clinical investigation; cytokine; expectation; human subject; improved; innovation; insight; killings; lung injury; novel; novel therapeutic intervention; organ growth; receptor; response

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.

描述（由申请人提供）：严重败血症是对感染的反应，包括最终导致急性器官衰竭的全身炎症反应综合征（SIRS），并且是住院患者死亡的主要原因。临床严重败血症很少被识别，因此在广泛的器官损伤之前很少进行研究。临床前模型可能无法完全代表人类脓毒症。高剂量重组白细胞介素-2 (HDIL2) 是晚期癌症的重要治疗方法。 HDIL2 会引起 SIRS，并可预见地导致急性器官衰竭，这与脓毒症中所见的情况几乎没有区别。肺水肿、休克和肾衰竭很常见。因此，HDIL2 提供了一个独特的机会来研究临床 SIRS 期间发生的器官衰竭机制。先前的研究表明肾素-血管紧张素系统（RAS）激活与急性肺损伤的发病机制有关。我们的团队拥有初步数据，证实 RAS 激活与 HDIL2 期间的器官衰竭相对应。这些数据迫使我们推测 RAS 失调会导致临床 SIRS 期间的肺损伤和器官衰竭。我们将在 HDIL2 治疗期间通过系统研究以下目标来检验这一假设。 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 并增加 ACE2 产物来测试 RAS 的作用。 2) 确定精氨酸加压素输注是否会改变 HDIL2 期间 RAS 激活和肺损伤的进展。 AVP 在 SIRS 期间会增加血压并减少儿茶酚胺的使用，因此可能会减少早期 SIRS 期间的 RAS 激活。受试者将在 HDIL2 期间随机接受 AVP 或安慰剂，并评估 AVP 对早期肺损伤的影响。我们将从受试者体内分离出内皮细胞，并确定 AVP 是否会改变 RAS 激活。 3) 确定 RAS 抑制是否会改变肺损伤和 SIRS 期间的临床进展。在 HDIL2 期间，受试者将被随机分配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估将确定 RAS 是否会导致临床 SIRS 期间的器官损伤。因此，这些项目将为临床 SIRS 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。