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: 8494069
• 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/8494069
• 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; 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

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.

此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。这项建议旨在 确定环氧合酶2（C 0X 2）在急性肺损伤的病理生理学和治疗中的作用 （ALI）。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，尤其是高通气患者， 潮气量，可能会恶化现有的损伤，甚至导致新生肺损伤，这种现象被称为 呼吸机相关性肺损伤（VILI）。C 0X 2是已知参与急性炎症的诱导酶。 炎症和血管通透性增加。然而，关于C 0X 2在细胞中的表达知之甚少。 对机械应力的反应及其参与机械应力诱导的肺损伤。初步数据 由主要研究者产生的结果已经将C 0X 2鉴定为VILI中的候选基因， C 0X 2表达增加与肺部炎症增加和血管屏障破坏相关 对高潮气量机械通气的反应。此外，C 0X 2的药理学抑制是 保护，减少急性炎症和增强渗透性。我们假设C 0X 2 表达是响应于高潮气量机械通气而诱导的，并且在以下方面起重要作用： VILI伴随的急性炎症和内皮屏障破坏。我们还假设 施用选择性C 0X 2抑制剂可以减轻或预防VILI。主要研究者 提出探索C 0X 2在机械应力诱导的肺损伤中的确切作用机制， 使用体内和体外模型。在SA #1中，我们将描述C 0X 2在一个公认的， VILI小鼠模型将C 0X 2表达和前列腺素类产生与生物化学和组织学 损伤指标，探讨00 X2在机械应力反应中的调节作用。#20102;重点关注 循环拉伸，一种独特的机械应力诱导的肺损伤体外模型。使用的措施 内皮抵抗、免疫组织化学、蛋白生化、sIRNA、真实的时间/RT-POR和Western 通过印迹，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，定义 使用药理学抑制和基因沉默在VILI中局部和全身00 X2抑制的功效 技术. 相关性（参见说明）; 急性肺损伤（ALI）是一种毁灭性的综合征，在美国每年有超过74，000名患者死亡 而且治疗选择很少ALI患者需要机械通气，但 其本身导致或加重肺损伤。机械应力对肺功能影响的研究 为了更好地了解这种综合征并开发新的治疗方法，