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溶栓是公认的 中风的急性临床治疗仍然需要充分评估， 相关的动物模型，结果再灌注的后果， 代谢受损的脑组织可逆性血栓性脑卒中模型的建立 已经开发了，其中，冲击波是由光化学介导的 （光血栓形成）闭塞大鼠大脑中动脉，导致 对常规（rt-PA）溶栓抵抗的无纤维蛋白血小板血栓 治疗这种血栓可能是大多数再通失败的原因 临床观察再灌注然后通过专有的 促进去血栓形成的过程，显然是通过增强 抗血栓血浆因子。对于闭塞时间小于2小时，大脑皮质 血流（CBF）在5-30分钟内建立，但在稍后时间完全恢复 可能需要凝血酶抑制剂（或纤溶酶原激活剂）给药， 清除淤滞引起的远端继发血栓。虽然组织恢复是 预期与早期血流恢复一致，“再灌注损伤” 伴随着不可逆的细胞变化，预示着可能发生梗死 以后，即使抗凝血酶保留了微循环， 通过抑制P-选择素的表达进行治疗， 白细胞停滞发展再灌注损伤的指标，如 P-选择素在内皮和凝血酶活化的血小板上的表达， 髓过氧化物酶活性和脂质过氧化副产物丙二醛和 4-羟基-2-壬烯醛将通过免疫染色程序监测， 至1天。再灌注对内皮型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 杂交方法3天时的结果，通过组织学评价监测， 不完全性梗死和完全性梗死的区域与时间相关 诱导再灌注治疗的过程和相关的分子变化。