LUNG PERFUSION BY POSITRON EMISSSION TOMOGRAPHY

正电子发射断层扫描肺灌注

• 批准号: 6530628
• 负责人: Daniel P Schuster
• 金额: $ 40.32万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-04-01 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6530628
• 关键词: adult respiratory distress syndrome; bioimaging /biomedical imaging; clinical research; disease /disorder model; dogs; eicosanoid metabolism; human subject; lung injury; neutrophil; noninvasive diagnosis; phospholipase A2; platelet activating factor; positron emission tomography; prostacyclins; prostaglandin endoperoxide synthase; pulmonary circulation; pulmonary edema; pulmonary respiration; respiratory disorder diagnosis; thromboxanes; tumor necrosis factor alpha

Pulmonary edema, the most immediate consequence of acute injury to the pulmonary endothelium, is the principal cause of hypoxemia, respiratory distress, and the need for mechanical ventilatory support during the acute respiratory distress syndrome (ARDS). Recently, we reported that specific thromboxane receptor blockade could reduce experimental pulmonary edema accumulation. The severity of hypoxemia in ARDS is off-set by a redistribution of pulmonary blood flow away from edematous lung units. We also found recently, using the quantitative imaging technique of positron emission tomography, that perfusion redistribution could be prevented by pretreatment with low-dose endotoxin, which resulted in markedly increased endogenous prostacyclin production by a cyclooxygenase (COX)-2 dependent mechanism. The result was systemic hypotension as well as pulmonary vasodilation with severe hypoxemia. The dramatic increases in prostacyclin production after low-dose endotoxin were dependent on the presence of lung injury, implying a synergistic effect. Thus, we propose the following specific aims: Specific Aim 1: to determine the mechanisms responsible for the physiologic and biochemical synergistic effects of low-dose endotoxin with experimentally-induced acute lung injury. Specific Aim 2: to determine the relationship between changes in lung COX-2 expression and lung arachidonic acid utilization, and increased prostacyclin production, in patients with ARDS. Specific Aim 3: to determine the impact of specific thromboxane receptor blockade on pulmonary capillary pressures and extravascular lung water accumulation in patients with ARDS. To accomplish these specific aims, we will employ novel radiopharmaceuticals and highly specific inhibitors of key putative pathways in studies which will evaluate the role of neutrophils, tumor necrosis factor, platelet activating factor, phospholipase A2 activation, COX-2 expression, pulmonary venoconstriction, and altered arachidonic acid kinetics, in both experimental animals and patients with ARDS. These studies will help determine how changes in pulmonary perfusion affect the physiologic expression of acute lung injury. They will also extend previous work targeted toward improving outcomes associated with ARDS by limiting pulmonary edema accumulation.

肺水肿是肺部内皮急性损伤的最直接后果，是缺氧，呼吸窘迫的主要原因，以及在急性呼吸道遇险综合征（ARDS）期间需要机械通气支持的主要原因。最近，我们报道了特定的血栓烷受体阻滞可以减少实验性肺水肿的积累。 ARDS中低氧血症的严重程度是通过从水肿肺单位的肺部血流重新分布来偏离现场的。我们最近还发现，使用正电子发射断层扫描的定量成像技术，可以通过低剂量内毒素预处理可以预防灌注重新分布，从而导致环氧酶（COX）-2依赖机制通过环氧酶（COX）的内源性前列腺素产生显着增加。结果是全身性低血压以及严重低氧血症的肺血管舒张。低剂量内毒素后前列环蛋白产生的急剧增加取决于肺损伤的存在，这意味着协同作用。因此，我们提出以下特定目的：具体目的1：确定低剂量内毒素对实验诱导的急性肺损伤的生理和生化协同作用的机制。具体目标2：确定ARDS患者的肺Cox-2表达变化与肺蛛网膜酸利用率的变化与前列环蛋白的产生增加之间的关系。特定目标3：确定特定的血栓烷受体阻断对ARDS患者的肺毛细管压力和血管外肺水积累的影响。为了实现这些特定目标，我们将在研究中采用新型的放射性药物和高度特异性推定途径的抑制剂，这些途径将评估中性粒细胞，肿瘤坏死因子，血小板激活因子，磷脂酶A2激活，COX-2表达，肺泡静脉毒性和抗疗法的患者以及均具有实验性的患者。这些研究将有助于确定肺灌注的变化如何影响急性肺损伤的生理表达。他们还将通过限制肺水肿的积累来扩展针对改善与ARD相关的结果的先前工作。