Toll-Like Receptor 4 Mediates Hemorrhagic Transformation After Delayed Tissue Plasminogen Activator Administration in In Situ Thromboembolic Stroke

作者：Garcia Culebras Alicia; Palma Tortosa Sara; Moraga Ana; Garcia Yebenes Isaac; Duran Laforet Violeta; Cuartero Maria I; de la Parra Juan; Barrios Munoz Ana L; Diaz Guzman Jaime; Pradillo Jesus M; Moro Maria A; Lizasoain Ignacio^*

来源：Stroke, 2017, 48(6): 1695-+.

DOI：10.1161/STROKEAHA.116.015956

• blood-brain barrier
• hemorrhage
• inflammation
• middle cerebral artery
• stroke

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.

• 出版日期2017-6