The Role of Cyclooxygenase 2 in Mechanical Stress-Induced Lung Injury

环氧合酶 2 在机械应激性肺损伤中的作用

• 批准号: 8099495
• 负责人: Stephanie A Nonas
• 金额: $ 13.31万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099495
• 关键词: Acute; Acute Lung Injury; Acute respiratory failure; Affect; Animal Experimentation; Arachidonic Acids; Attenuated; Biochemical; Blood Vessels; Blood capillaries; Candidate Disease Gene; Capillary Permeability; Cell Culture System; Clinical; Cytoskeletal Modeling; DNA Sequence Rearrangement; Data; Edema; Endothelial Cells; Environmental air flow; Enzymes; Epithelial Cells; Extravasation; Functional disorder; Gene Silencing; Genetic; Goals; Histologic; Human; Hypoxia; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Institution; Instruction; Lead; Lung; Lung Compliance; Lung Inflammation; MAP Kinase Gene; MAPK14 gene; Measures; Mechanical Stress; Mechanical ventilation; Mechanics; Mediating; Modeling; Mus; NF-kappa B; Oleic Acids; Pancreatitis; Pathway interactions; Patients; Permeability; Physicians; Play; Pneumonia; Principal Investigator; Production; Prostaglandins; Protein Biochemistry; Proteins; Regulation; Research; Research Personnel; Resistance; Rodent Model; Role; Scientist; Stimulus; Stress; Stretching; Syndrome; Techniques; Therapeutic; Tidal Volume; Time; Tissues; Vascular Permeabilities; Ventilator; Ventilator-induced lung injury; Western Blotting; Work; abstracting; capillary; consomic; cyclooxygenase 2; cytokine; experience; in vitro Model; in vivo; in vivo Model; indexing; inhibitor/antagonist; killings; lung injury; lung volume; macrophage; mitogen-activated protein kinase p38; monocyte; mortality; prevent; programs; protective effect; research study; response; skills; vascular inflammation

DESCRIPTION (provided by applicant): The goal of this KOS application is provide the essential skills and experience that will allow the Principal Investigator to become a successful, independent physician-scientist. This proposal seeks to define a role for cyclooxygenase 2 (C0X2) in the pathophysiology and treatment of acute lung injury (ALI). ALI is a devastating clinical syndrome that affects more than 200,000 patients per year, with a mortality of 30-50%. Although a mainstay of therapy for ALI, mechanical ventilation, especially with high tidal volumes, can worsen existing injury or even cause de novo lung injury, a phenomenon referred to as ventilator induced lung inury (VILI). C0X2 is an inducible enzyme known to be involved in acute inflammation and increased vascular permeability. However, little is known about the expression of C0X2 in response to mechanical stress and its involvement in mechanical stress-induced lung injury. Preliminary data generated by the Principal Investigator have identified C0X2 as a candidate gene in VILI, demonstrating increased expression of C0X2 associated with increased lung inflammation and vascular barrier disruption in response to high tidal volume mechanical ventilation. Additionally, pharmacologic inhibition of C0X2 is protective, decreasing acute inflammation and enhanced permeability. We hypothesize that C0X2 expression is induced in response to high tidal volume mechanical ventilation and plays an important role in the acute inflammation and endothelial barrier disruption that accompanies VILI. We additionally hypothesize that the administration of selective C0X2 inhibitors may attenuate or prevent VILI. The Principal Investigator proposes to explore the precise mechanisms of action of C0X2 in mechanical stress-induced lung injury, using both in vivo and in vitro models. In SA #1, we will characterize the role of C0X2 in a well established, murine model of VILI correlating C0X2 expression and prostanoid production with biochemical and histologic indices of injury and exploring the regulation of 00X2 in response to mechanical stress. SA #2 will focus on cyclic stretch, a unique in vitro model of mechanical stress-induced lung injury. Using measures of endothelial resistance, immunohistochemistry, protein biochemistry, sIRNA, real time/RT-POR, and Western blotting, we will define the role of 00X2 in cyclic stress-induced cytoskeletal reorganization. In SA #3, define the efficacy of local and systemic 00X2 inhibition in VILI, using pharmacologic inhibition and gene silencing techniques. RELEVANCE (See instructions); Acute lung injury (ALI) is a devastating syndrome that kills more than 74,000 patients each year in the US and has very few therapeutic options. Mechanical ventilation is required for patients with ALI, however can itself cause or worsen lung injury. Research into the effect of mechanical stress on lung from ventilation are necessary to better understand this syndrome and to develop new treatments. (End of Abstract)

描述（由申请人提供）：本科斯应用程序的目标是提供必要的技能和经验，使主要研究者成为一个成功的，独立的医生，科学家。该提案旨在确定环氧合酶2（C 0X 2）在急性肺损伤（ALI）的病理生理学和治疗中的作用。ALI是一种毁灭性的临床综合征，每年影响超过20万患者，死亡率为30- 50%。尽管机械通气是治疗ALI的主要手段，但机械通气，尤其是具有高潮气量的机械通气，可使现有损伤恶化，甚至引起新生肺损伤，这种现象被称为呼吸机诱导的肺损伤（VILI）。C 0X 2是已知参与急性炎症和增加的血管通透性的诱导酶。然而，很少有人知道C 0X 2的表达在响应机械应力和其参与机械应力诱导的肺损伤。主要研究者生成的初步数据已将C 0X 2确定为VILI中的候选基因，表明C 0X 2表达增加与响应于大潮气量机械通气的肺部炎症增加和血管屏障破坏相关。此外，C 0X 2的药理学抑制是保护性的，减少急性炎症和增强渗透性。我们推测，COX 2的表达是诱导高潮气量机械通气，并在急性炎症和内皮屏障破坏，伴随VILI的重要作用。我们另外假设，施用选择性C 0X 2抑制剂可以减弱或预防VILI。主要研究者建议使用体内和体外模型探索C 0X 2在机械应力诱导的肺损伤中的确切作用机制。在SA #1中，我们将表征C 0X 2在建立良好的VILI小鼠模型中的作用，将C 0X 2表达和前列腺素类产生与损伤的生化和组织学指标相关联，并探索C 0X 2响应于机械应力的调节。SA #2将重点关注循环拉伸，这是机械应力诱导肺损伤的独特体外模型。通过内皮抵抗力、免疫组织化学、蛋白生化、sIRNA、真实的时间/RT-POR和Western印迹的测量，我们将确定00 X2在周期性应激诱导的细胞骨架重组中的作用。在SA #3中，使用药理学抑制和基因沉默技术，定义VILI中局部和全身00 X2抑制的疗效。相关性（参见说明）;急性肺损伤（ALI）是一种毁灭性的综合征，每年在美国造成超过74，000名患者死亡，并且治疗选择很少。ALI患者需要机械通气，但机械通气本身可导致或加重肺损伤。研究机械应力对肺通气的影响是必要的，以更好地了解这种综合征，并开发新的治疗方法。 (End摘要）