CARDIOPULMONARY SURGERY RESEARCH

心肺外科研究

• 批准号: 7465439
• 负责人: Philip J Kadowitz
• 金额: $ 34.08万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7465439
• 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

DESCRIPTION (provided by applicant): 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 released from 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.

描述（由申请人提供）：拟议研究的广泛长期目标是提高我们目前对体液因素（包括环氧合酶途径中的血管活性产物）调节肺血管床的理解。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。前列腺素类对肺血管床有显著作用，PGI 2用于治疗肺动脉高压。已知在肺中存在两种考克斯同种型。考克斯-1被认为是参与生理调节的组成型酶，而考克斯-2是由炎性细胞因子上调的诱导型同种型。尽管认为考克斯-2在正常组织中不存在或以低水平表达，但最近文献和我们实验室的研究表明，考克斯-1和考克斯-2在正常健康啮齿动物肺中大量表达，并且具有从前体花生四烯酸产生血管活性前列腺素类的能力。我们的假设是，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是由考克斯-1和考克斯-2产生的。第一个具体的目的是确定考克斯-1和考克斯-2的作用，在产生血管活性前列腺素类在完整的胸部小鼠使用最近开发的右心导管插入术程序，以测量肺血管压力和血流量。这些研究将涉及使用选择性考克斯-1和考克斯-2抑制剂，血小板聚集试验，以确定考克斯-1的选择性，和酶免疫测定，以测量肺组织中的前列腺素水平。第二个具体的目的是确定当花生四烯酸通过据报道从肺释放前列腺素的试剂或刺激物从内源性池释放时，考克斯-1和考克斯-2在血管活性前列腺素类产生中的作用。在这些实验中，将在完整胸部小鼠中研究考克斯-1和考克斯-2抑制剂对呼吸性缺氧、血管紧张素II和离子载体A23187的反应的影响。这些实验将检验对离子载体A23187的反应是通过在考克斯-1和考克斯-2途径中形成前列腺素类介导的，以及考克斯-1和考克斯-2调节对血管紧张素II和呼吸性缺氧的肺血管收缩反应的假设。具体目标1和2中的实验涉及使用可能存在问题的选择性考克斯抑制剂，因此，具体目标3是确定考克斯-1和考克斯-2在考克斯-1和考克斯-2敲除小鼠中血管活性前列腺素类的产生和肺血管床调节中的作用。这些实验的结果将提供有关考克斯-1和考克斯- 2在肺血管床调节中的作用的新信息，并可能导致肺动脉高压疾病的治疗的新策略。

项目成果

Role of nitric oxide in developmental biology in plants, bacteria, and man.

一氧化氮在植物、细菌和人类发育生物学中的作用。

• 发表时间: 2011
• 期刊: Current topics in pharmacology
• 作者: Allain,AlexanderV;Hoang,VanT;Lasker,GeorgeF;Pankey,EdwardA;Murthy,SubramanyamN;Kadowitz,PhilipJ
• 通讯作者: Kadowitz,PhilipJ

The selective Rho-kinase inhibitor azaindole-1 has long-lasting erectile activity in the rat.

• DOI: 10.1016/j.urology.2012.10.039
• 发表时间: 2013-02
• 期刊: Urology
• 影响因子: 2.1
• 作者: Lasker GF;Pankey EA;Allain AV;Murthy SN;Stasch JP;Kadowitz PJ
• 通讯作者: Kadowitz PJ

The role of the RhoA/rho-kinase pathway in pulmonary hypertension.

RhoA/rho 激酶通路在肺动脉高压中的作用。

• DOI: 10.2174/157016309787581057
• 发表时间: 2009
• 期刊: Current drug discovery technologies
• 作者: Nossaman,BobbyD;Kadowitz,PhilipJ
• 通讯作者: Kadowitz,PhilipJ

Intracavernosal administration of sodium nitrite as an erectile pharmacotherapy.

海绵体内给予亚硝酸钠作为勃起药物疗法。

• DOI: 10.1139/y10-032
• 发表时间: 2010
• 期刊: Canadian journal of physiology and pharmacology
• 影响因子: 2.1
• 作者: Lasker,GeorgeF;Matt,ChristopherJ;BadejoJr,AdelekeM;Casey,DavidB;Dhaliwal,JasdeepS;Murthy,SubramanyamN;Kadowitz,PhilipJ
• 通讯作者: Kadowitz,PhilipJ

Analysis of responses to glyceryl trinitrate and sodium nitrite in the intact chest rat.

• DOI: 10.1016/j.niox.2012.03.009
• 发表时间: 2012-05-15
• 期刊: Nitric oxide : biology and chemistry
• 作者: Nossaman BD;Pankey EA;Badejo AR Jr;Casey DB;Uppu S;Murthy SN;Kadowitz PJ
• 通讯作者: Kadowitz PJ