Heme Oxygenase-1 in Lung Ischemia-Reperfusion Injury

血红素加氧酶 1 在肺缺血再灌注损伤中的作用

• 批准号: 7194243
• 负责人: PATTY J LEE
• 金额: $ 32.78万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7194243
• 关键词: Acute Lung Injury; Address; Anoxia; Apoptosis; Biliverdine; Binding; Carbon Monoxide; Cell Survival; Cells; Cytoprotection; Data; Disease; Distal; Elements; Endothelial Cells; Enhancers; Event; Generations; Genetic Transcription; Heme; In Vitro; Injury; Iron; Ischemia; Knockout Mice; Knowledge; Laboratories; Lung; Lung Transplantation; MAPK14 gene; MAPK8 gene; Mediating; Mitogen-Activated Protein Kinases; Modeling; Mus; Numbers; Organ Transplantation; Oxidants; Oxygenases; Pathogenesis; Pathway interactions; Physiological reperfusion; Principal Investigator; Process; Production; Protein Isoforms; Protein Overexpression; Pulmonary Edema; Pulmonary Embolism; Rate; Regulator Genes; Regulatory Pathway; Reperfusion Injury; Reperfusion Therapy; Response Elements; Role; STAT protein; STAT1 gene; Signal Pathway; Testing; Therapeutic; Transcription Factor AP-1; Transcriptional Activation; activating transcription factor; activator 1 protein; biological adaptation to stress; cell type; cis acting element; heme oxygenase-1; human MAPK14 protein; in vivo; insight; lung injury; lung ischemia; mitogen-activated protein kinase p38; mortality; novel; nuclear factor-erythroid 2; programs; promoter; protein protein interaction; response; response to injury; stress-activated protein kinase 1; stressor; transcription factor

DESCRIPTION (provided by applicant): Oxidant injury is a major contributor to the pathogenesis of many disease processes including acute lung injury. Anoxia-reoxygenation (A-R) In cells and ilschemia-reperfusion (I-R) in lungs are common models of oxidant injury. Lung I-R is likely the inciting injury during lung transplantation/surgery, thromboembolectomy, pulmonary embolism, and re-expansion pulmonary edema. These disorders have high mortalities with limited therapeutic options. This is largely due to our limited knowledge of underlying pathogenesis. We also lack appreciation of the degree to which regulatory events in vitro (A-R) are predictive of the events in vivo (I-R). Heme oxygenase (HO) catalyzes the initial and rate-limiting step in the oxidative degradation of heme to biliverdin with generation of carbon monoxide (CO) and iron. A variety of oxidant stressors strongly induce expression of HO-1, an inducible isoform of HO. Studies from our laboratory and others have demonstrated that HO-1 can protect against oxidant-induced lung injury. However, the ability of HO-1 to confer protection and the processes regulating its production in this setting has not been adequately addressed. In addition, the pivotal cell-type responsible for HO-1-mediated protection against oxidant lung injury is unknown. To begin to understand the processes that regulate A-R/I-R we examined the effects of HO-1 in these injury models. We have demonstrated that HO-1 is markedly induced in endothelial cells and mouse lung after A-R/I-R. In addition, the mitogen-activated protein kinases (MAPKs) are responsible for A-R-induced HO-1 expression. We now show that HO-1 overexpression significantly diminishes A-R/I-R-induced apoptosis in cultured lung endothelial cells and in mouse lung. Our data has led us to propose the following hypotheses: 1) in A-R, HO-1 is induced via novel activation pathways that involve MAPKs and cooperative transcription factor interactions; 2) in I-R, similar pathways are activated and are cytoprotective; and 3) in I-R, p38 MAPK activation of endothelial cell HO-1 is a critical event in cytoprotection. To test these hypotheses we will: 1) characterize the cis- and trans-acting elements that mediate HO-1 induction and define the consequences in vitro; 2) determine whether A-R regulates the relevant transcription factors via p38 or JNK MAPKs and define the consequences in vitro; 3) determine whether the processes identified in Aims I and 2 are important in vivo; and 4) define the role of endothelial cell p38 MAPK and HO-1 in HO-1-mediated cytoprotection in vivo.

描述（由申请人提供）：氧化损伤是许多疾病过程（包括急性肺损伤）发病机制的主要原因。 细胞缺氧再氧合 (A-R) 和肺部缺血再灌注 (I-R) 是氧化损伤的常见模型。 肺 I-R 可能是肺移植/​​手术、血栓栓塞切除术、肺栓塞和再扩张性肺水肿期间的诱发损伤。 这些疾病死亡率高，治疗选择有限。这主要是由于我们对潜在发病机制的了解有限。 我们还缺乏对体外调控事件（A-R）对体内事件（I-R）的预测程度的认识。 血红素加氧酶 (HO) 催化血红素氧化降解为胆绿素的初始限速步骤，并产生一氧化碳 (CO) 和铁。 多种氧化应激源强烈诱导 HO-1（一种 HO 的诱导亚型）的表达。 我们实验室和其他实验室的研究表明，HO-1 可以预防氧化剂引起的肺损伤。 然而，HO-1 在这种情况下提供保护的能力以及调节其产生的过程尚未得到充分解决。此外，负责 HO-1 介导的针对氧化性肺损伤的保护的关键细胞类型尚不清楚。 为了开始了解调节 A-R/I-R 的过程，我们检查了 HO-1 在这些损伤模型中的作用。 我们已经证明，A-R/I-R 后，HO-1 在内皮细胞和小鼠肺中被显着诱导。 此外，丝裂原激活蛋白激酶 (MAPK) 负责 A-R 诱导的 HO-1 表达。 我们现在表明，HO-1 过表达可显着减少培养的肺内皮细胞和小鼠肺中 A-R/I-R 诱导的细胞凋亡。我们的数据使我们提出以下假设：1）在A-R中，HO-1是通过涉及MAPK和协同转录因子相互作用的新型激活途径诱导的； 2) 在 I-R 中，相似的途径被激活并具有细胞保护作用； 3) 在 I-R 中，内皮细胞 HO-1 的 p38 MAPK 激活是细胞保护的关键事件。 为了检验这些假设，我们将：1）表征介导 HO-1 诱导的顺式和反式作用元件并定义体外后果； 2) 确定A-R是否通过p38或JNK MAPKs调节相关转录因子，并确定体外结果； 3) 确定目标 I 和 2 中确定的过程在体内是否重要； 4) 定义内皮细胞 p38 MAPK 和 HO-1 在 HO-1 介导的体内细胞保护中的作用。