CARDIOPULMONARY SURGERY RESEARCH

心肺外科研究

• 批准号: 7489741
• 负责人: Philip J Kadowitz
• 金额: $ 6.11万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-20 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7489741
• 关键词: Angiotensin II; Antibiotic A23187; Arachidonic Acids; Biological Assay; Blood Vessels; Blood flow; Cardiac Catheterization Procedures; Cardiopulmonary; Cell membrane; Chest; Coxibs; Cyclooxygenase Inhibitors; Development; Disease; Enzyme Immunoassay; Enzymes; Epoprostenol; Essential Fatty Acids; Generations; Genetic; Goals; Hypoxia; Inflammatory; Injury; Ionophores; Knockout Mice; Laboratories; Lead; Literature; Lung; Measures; Mediating; Mediation; Mus; Normal tissue morphology; Operative Surgical Procedures; Pathway interactions; Peripheral Resistance; Phospholipids; Physiological; Platelet aggregation; Procedures; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Pulmonary Circulation; Pulmonary Hypertension; Pulmonary Vascular Resistance; Regulation; Reporting; Research; Respiratory physiology; Rodent; Role; Site; Stimulus; Structure of parenchyma of lung; Techniques; Testing; Thinking; Thromboxane A2; Thromboxanes; Tissues; Vasoconstrictor Agents; cyclooxygenase 1; cyclooxygenase 2; cytokine; improved; inhibitor/antagonist; pressure; programs; receptor; research study; response; vascular bed

The broad long-term objectives of the proposed research are to improve our current understanding of the regulation of the pulmonary vascular bed by humoral factors, including vasoactive products in the cyclooxygenase pathway. Cyclooxygenase (COX) is the initial step in the formation of prostaglandins (PGs) and thromboxane A2 (prostanoids). The prostanoids have marked effects on the pulmonary vascular bed, and PGI2 is used in the treatment of pulmonary hypertension. It is known that there are two COX isoforms in the lung. COX-1 is believed to be a constitutive enzyme involved in physiologic regulation, whereas COX-2 is an inducible isoform upregulated by inflammatory cytokines. Although it is believed that COX-2 Is not present or expressed in low levels in normal tissue, recent studies in the literature and in our laboratory show that COX-1 and COX-2 are abundantly expressed in the normal healthy rodent lung and have the capacity to generate vasoactive prostanoids from the precursor, arachidonic acid. It is our hypothesis that vasoactive prostanoids that increase pulmonary vascular resistance and decrease systemic vascular resistance are generated by COX-1 and COX-2. The first specific aim is to determine the role of COX-1 and COX-2 in the generation of vasoactive prostanoids in the intact-chest mouse using a recently developed right-heart catheterization procedure to measure pulmonary vascular pressures and blood flow. These studies will involve the use of selective COX-1 and COX-2 inhibitors, a platelet aggregation assay to determine COX-1 selectivity, and enzyme immunoassay to measure prostanoid levels in lung tissue. The second specific aim is to determine the role of COX-1 and COX-2 in the generation of vasoactive prostanoids when arachidonic acid is releasedfrom endogenous pools by agents or stimuli reported to release prostaglandins from the lung. In these experiments, the effects of the COX-1 and COX-2 inhibitors on responses to ventilatory hypoxia, angiotensin II, and ionophore A23187 will be investigated in the intact-chest mouse. These experiments will test the hypothesis that responses to ionophore A23187 are mediated by the formation of prostanoids in the COX-1 and COX-2 pathway and that COX-1 and COX-2 modulate pulmonary vasoconstrictor responses to angiotensin II and ventilatory hypoxia. The experiments in specific aims 1 and 2 involve the use of selective COX inhibitors which may be problematic, therefore, specific aim three is to determine the role of COX-1 and COX-2 in the generation of vasoactive prostanoids and in the regulation of the pulmonary vascular bed in COX-1 and COX-2 knockout mice. The results of these experiments will provide new information about the role of COX-1 and COX- 2 in the regulation of the pulmonary vascular bed and may lead to new strategies for the treatment of pulmonary hypertensive disorders.

拟议的研究的广泛的长期目标是提高我们目前对监管的理解， 肺血管床的体液因素，包括环氧合酶途径中的血管活性产物。 环氧合酶（考克斯）是前列腺素（PGs）和血栓素A2（前列腺素）形成的起始步骤。 前列腺素类药物对肺血管床有明显作用，PGI_2用于治疗肺动脉高压。 高血压已知在肺中存在两种考克斯同种型。考克斯-1被认为是一种组成性酶 参与生理调节，而考克斯-2是可诱导的同种型，可被炎性细胞因子上调。 虽然认为考克斯-2在正常组织中不存在或以低水平表达，但最近的研究表明，COX-2在正常组织中的表达水平较低。 文献和我们实验室研究表明，考克斯-1和考克斯-2在正常健康啮齿动物中大量表达 肺，并有能力产生血管活性前列腺素类的前体，花生四烯酸。我们假设 增加肺血管阻力和降低全身血管阻力的血管活性前列腺素 由考克斯-1和考克斯-2产生。第一个具体的目的是确定考克斯-1和考克斯-2在肿瘤细胞中的作用。 使用最近开发的右心导管术在完整胸部小鼠中产生血管活性前列腺素类 测量肺血管压力和血流的程序。这些研究将涉及使用选择性 考克斯-1和考克斯-2抑制剂、测定考克斯-1选择性的血小板聚集试验和酶免疫测定 来测量肺组织中的前列腺素水平第二个具体目的是确定考克斯-1和考克斯-2在肿瘤细胞中的作用。 当花生四烯酸通过药物或刺激从内源性池中释放时，血管活性前列腺素类的产生 据报道能从肺中释放三尖杉酯碱。在这些实验中，研究了考克斯-1和考克斯-2抑制剂对人结肠癌细胞的作用。 将在完整的胸部中研究血管紧张素II和离子载体A23187对呼吸性缺氧的反应 老鼠.这些实验将检验对离子载体A23187的反应是由形成的 前列腺素类在考克斯-1和考克斯-2途径中的作用，以及考克斯-1和考克斯-2调节肺血管收缩剂 对血管紧张素II和呼吸性缺氧的反应。具体目标1和2中的实验涉及使用 选择性考克斯抑制剂可能是有问题的，因此，具体目标三是确定考克斯-1和 考克斯-2在血管活性前列腺素类的产生和在考克斯-1和 考克斯-2敲除小鼠。这些实验的结果将提供关于考克斯-1和考克斯-2在肿瘤细胞中的作用的新信息。 2在调节肺血管床方面的作用，并可能导致肺动脉高压治疗的新策略。 高血压疾病