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: 8291278
• 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/8291278
• 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KOS应用程序的目标是提供基本技能和经验，使 首席研究员成为一名成功的、独立的内科科学家。这项建议旨在 环氧合酶2(C0X2)在急性肺损伤病理生理和治疗中的作用 (阿里)。ALI是一种毁灭性的临床综合征，每年影响20多万患者， 死亡率为30-50%。虽然是治疗ALI的中流砥柱，但机械通气，尤其是高位 潮气量，会加重现有的损伤，甚至引起新的肺损伤，这种现象被称为 呼吸机所致肺损伤(VILI)。C0X2是一种诱导性酶，已知参与了急性 炎症和血管通透性增加。然而，人们对C0X2在 机械应激反应及其在机械应激性肺损伤中的作用。初步数据 由首席调查员产生的已确定C0X2为VILI的候选基因，证明 C0X2表达增加与肺部炎症和血管屏障破坏相关 以应对大潮气量的机械通风。此外，C0X2的药物抑制作用是 具有保护作用，减少急性炎症，增强通透性。我们假设C0X2 大潮气量机械通气诱导表达，并在 VILI伴随的急性炎症和内皮屏障破坏。我们还假设 给予选择性C0X2抑制剂可以减弱或预防VILI。首席调查员 建议探索C0X2在机械应激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C0X2在已建立的 VILI小鼠模型中C0X2的表达和前列腺素的产生与生化和组织学的关系 损伤指标，探讨00X2对机械应力的反应规律。SA#2将重点放在 周期性拉伸，一种独特的体外机械性应激肺损伤模型。使用以下措施 内皮抵抗、免疫组织化学、蛋白质生物化学、siRNA、实时/RT-POR和Western Blotting，我们将确定00X2在循环应激诱导的细胞骨架重组中的作用。在SA#3中，定义 药物抑制和基因沉默对VILI局部和全身00X2抑制的疗效 技巧。 相关性(见说明)； 急性肺损伤(ALI)是一种毁灭性的综合征，每年在美国导致超过7.4万名患者死亡 而且几乎没有什么治疗选择。ALI患者需要机械通气，但可以 其本身会引起或加重肺损伤。机械应激对呼吸机所致肺损伤的研究 有必要更好地了解这种综合征并开发新的治疗方法。