ACTIVE THROMBOSIS, THROMBOLYSIS, AND STROKE OUTCOME

活动性血栓形成、血栓溶解和中风结果

• 批准号: 6045110
• 负责人: BRANT D WATSON
• 金额: $ 31.62万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-08-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6045110
• 关键词: antithrombins; brain circulation; cerebral artery; cerebral ischemia /hypoxia; disease /disorder model; enzyme inhibitors; fibrinolysis; fibrinolytic agents; gene expression; in situ hybridization; laboratory rat; lipid peroxides; malonaldehyde; monoclonal antibody; myeloperoxidase; neuropharmacology; nitric oxide synthase; outcomes research; pathologic process; reperfusion; selectins; stainings; stroke; thrombosis; tissue /cell culture; vascular endothelium

DESCRIPTION: Although thrombolysis by plasminogen activators is an accepted acute clinical treatment for stroke there is still a need to evaluate fully, in a relevant animal model, the consequences of the resultant reperfusion for metabolically compromised brain tissue. A reversible model of thrombotic stroke has been developed, in which the ictus is initiated by photochemically mediated (photothrombotic) occlusion of the rat middle cerebral artery, resulting in a fibrin-free platelet thrombus resistant to conventional (rt-PA) thrombolytic treatment. Such thrombi may account for the majority of recanalization failures seen clinically. Reperfusion is then achieve photophysically by a proprietary process that facilitates dethrombosis, evidently by enhanced penetration of antithrombotic plasma factors. For occlusion times less than 2 hr, cortical cerebral blood flow (CBF) is established within 5-30 min, but full flow restoration at later times will likely require thrombin inhibitor (or plasminogen activator) administration to clear stasis-induced distal secondary thrombi. Although tissue recovery is expected to coincide with flow recovery at early times, "reperfusion injury" concomitant with irreversible cellular changes presaging infarction may occur at later times, even if the microcirculation is preserved by antithrombin treatment via inhibition of the expression of P-selectin, which precedes leukocyte stasis. Indicators of developing reperfusion injury such as expression of P-selectin on endothelium and on thrombin-activated platelets, myeloperoxidase activity, and lipid peroxidation byproducts malondialdehyde and 4-hydroxy-2-nonenal will be monitored by immunostaining procedures at times up to 1 day. The effect of reperfusion on endothelial nitric oxide synthase protein and gene expression will be assessed by immunostaining and in situ hybridization. Outcome at 3 days, monitored by histological evaluation of regions of frank and incomplete infarction, will be correlated with the time course of reperfusion-inducing treatments and associated molecular changes.

描述：虽然纤溶酶原激活剂的溶栓是一种接受的 急性临床治疗中风仍然需要完全评估 相关的动物模型，结果再灌注的后果 代谢妥协的脑组织。血栓性中风的可逆模型 已经开发了，其中的ICTU是通过光化学介导的 大鼠中大脑中动脉的（光栓塞性）闭塞，导致A 无纤维蛋白的血小板血栓对常规（RT-PA）溶栓的抗性 治疗。这样的血栓可能解释了大部分的重新定性故障 在临床上看到。然后，再灌注是通过专有的 显然，通过增强 抗血栓血浆因子。在闭塞时间小于2小时，皮质大脑 血流（CBF）在5-30分钟内建立，但以后的全流量恢复 可能需要凝血酶抑制剂（或纤溶酶原激活剂）给药 清晰的暂停诱导的远端继发性血栓。尽管组织恢复是 预计将与早期的流量恢复相吻合，“再灌注损伤” 与不可逆的细胞变化伴随着可能发生梗塞的梗塞 在以后的时间，即使微循环通过抗凝血酶保存 通过抑制P-选择素的表达来治疗 白细胞停滞。发展再灌注损伤的指标，例如 p-选择素在内皮和凝血酶激活的血小板上的表达， 骨髓过氧化物酶活性和脂质过氧化副产品马发醛和 4-Hydroxy-2-nonenal将通过免疫染色程序有时监测 到1天。再灌注对内皮一氧化氮合酶的影响 蛋白质和基因表达将通过免疫染色和原位评估 杂交。 3天的结果，通过组织学评估监测 弗兰克和不完整的梗塞区域将与时间相关 再灌注诱导治疗和相关分子变化的过程。