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: 7739130
• 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/7739130
• 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 KOS 申请的目标是提供必要的技能和经验，使首席研究员成为一名成功的独立医生科学家。该提案旨在明确环氧合酶 2 (C0X2) 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 200,000 名患者，死亡率为 30-50%。尽管机械通气是 ALI 的主要治疗方法，但机械通气（尤其是高潮气量）可能会加重现有损伤，甚至导致新发肺损伤，这种现象称为呼吸机诱发性肺损伤 (VILI)。 C0X2 是一种诱导酶，已知与急性炎症和血管通透性增加有关。然而，人们对 C0X2 在机械应激反应中的表达及其在机械应激引起的肺损伤中的参与知之甚少。首席研究员生成的初步数据已将 C0X2 确定为 VILI 的候选基因，证明 C0X2 表达增加与高潮气量机械通气引起的肺部炎症增加和血管屏障破坏相关。此外，C0X2 的药理抑制具有保护作用，可减少急性炎症并增强通透性。我们假设 C0X2 表达是响应高潮气量机械通气而诱导的，并且在伴随 VILI 的急性炎症和内皮屏障破坏中发挥重要作用。我们还假设选择性 COX2 抑制剂的给药可能会减轻或预防 VILI。首席研究员建议利用体内和体外模型探索 C0X2 在机械应力引起的肺损伤中的精确作用机制。在 SA #1 中，我们将描述 C0X2 在完善的 VILI 小鼠模型中的作用，将 C0X2 表达和前列腺素生成与损伤的生化和组织学指标相关联，并探索 00X2 对机械应力的调节。 SA #2 将重点关注循环拉伸，这是机械应力引起的肺损伤的独特体外模型。使用内皮抵抗、免疫组织化学、蛋白质生物化学、sIRNA、实时/RT-POR 和蛋白质印迹的测量，我们将定义 00X2 在循环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 00X2 抑制的功效。相关性（参见说明）；急性肺损伤 (ALI) 是一种毁灭性的综合征，在美国每年导致超过 74,000 名患者死亡，而且治疗选择很少。 ALI 患者需要机械通气，但机械通气本身会导致或加重肺损伤。为了更好地了解这种综合征并开发新的治疗方法，有必要研究通气机械应力对肺部的影响。 （摘要完）