期刊
STROKE
卷 48, 期 6, 页码 1695-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.116.015956
关键词
blood-brain barrier; hemorrhage; inflammation; middle cerebral artery; stroke
资金
- Spanish Ministry of Economy and Competitiveness [SAF2014-52225, SAF2015-68632-R]
- Instituto de Salud Carlos III
- Fondo Europeo de Desarrollo Regional (FEDER) Una manera de hacer Europa [RETICS RD12/0014/0003]
Background and Purpose-Hemorrhagic transformation is the main complication of revascularization therapies after stroke. Toll-like receptor 4 (TLR4) is implicated in cerebral damage and inflammation in stroke. This study was designed to determine the role of TLR4 in hemorrhagic transformation development after tissue plasminogen activator (tPA) administration. Methods-Mice expressing (TLR4(+/+)) or lacking functional TLR4 (TLR4(-/-)) were subjected to middle cerebral artery occlusion using an in situ thromboembolic model by thrombin injection into the middle cerebral artery, and tPA (10 mg/kg) was administered 20 minutes or 3 hours after ischemia. Infarct size, hemorrhages, IgG extravasation, matrix metalloproteinase 9 expression, and neutrophil infiltration were assessed 24 hours after ischemia. Results-In TLR4(+/+), early reperfusion (tPA at 20 minutes) resulted infarct volume, whereas late recanalization (tPA at 3 hours) did not modify lesion size and increased the rate of the most severe hemorrhages. In TLR4(-/-) mice, both early and late reperfusion did not modify lesion size. Importantly, late tPA administration did not result in worse hemorrhages and in an increased bleeding area as occurred in TLR4(+/+) group. In TLR4(-/-) animals, late reperfusion produced a lesser increase in matrix metalloproteinase 9 expression when compared with TLR4(+/+) animals. Conclusions-Our results demonstrate TLR4 involvement in hemorrhagic transformation induced by delayed tPA administration, very likely by increasing matrix metalloproteinase 9 expression.
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