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Lipopolysaccharide-induced sepsis-like state compromises post-ischemic neurological recovery, brain tissue survival and remodeling via mechanisms involving microvascular thrombosis and brain T cell infiltration
Brain, Behavior, and Immunity ( IF 15.1 ) Pub Date : 2021-01-01 , DOI: 10.1016/j.bbi.2020.10.015
Maryam Sardari , Jelena Skuljec , Dongpei Yin , Kristina Zec , Tayana Silva de Carvalho , Dan Albers , Chen Wang , Refik Pul , Aurel Popa-Wagner , Thorsten R. Doeppner , Christoph Kleinschnitz , Egor Dzyubenko , Dirk M. Hermann

Sepsis predisposes for poor stroke outcome. This association suggests that sepsis disturbs post-ischemic tissue survival and brain remodeling. To elucidate this link, we herein exposed mice to 30 min intraluminal middle cerebral artery occlusion (MCAO) and induced a sepsis-like state at 72 hours post-ischemia by intraperitoneal delivery of Escherichia coli lipopolysaccharide (LPS; three doses of 0.1 or 1 mg/kg, separated by 6 hours), a major component of the bacterium's outer membrane. Neurological recovery, ischemic injury, brain remodeling and immune responses were evaluated over up to 56 days post-sepsis (dps) by behavioral tests, immunohistochemistry and flow cytometry. Delivery of 1 mg/kg but not 0.1 mg/kg LPS reduced rectal temperature over 48 hours, by up to 3.4±3.1°C, increased general and focal neurological deficits in the Clark score over 72 hours and increased motor-coordination deficits in the tight rope test over up to 21 days. Notably, 1 mg/kg, but not 0.1 mg/kg LPS increased intercellular adhesion molecule-1 abundance on ischemic microvessels, increased microvascular thrombosis and increased patrolling monocyte and T cell infiltrates in ischemic brain tissue at 3 dps. Infarct volume was increased by 1 mg/kg, but not 0.1 mg/kg LPS at 3 dps (that is, 6 days post-MCAO), as was brain atrophy at 28 and 56 dps. Microglial activation in ischemic tissue, evaluated by morphology analysis of Iba-1 immunostainings, was transiently increased by 0.1 and 1 mg/kg LPS at 3 dps. Our data provide evidence that neurological recovery and brain remodeling are profoundly compromised in the ischemic brain post-sepsis as a consequence of cerebral thromboinflammation.

中文翻译:

脂多糖诱导的败血症样状态通过涉及微血管血栓形成和脑 T 细胞浸润的机制损害缺血后神经恢复、脑组织存活和重塑

败血症易患中风预后不良。这种关联表明败血症会干扰缺血后组织的存活和大脑重塑。为了阐明这种联系,我们在此将小鼠暴露于腔内大脑中动脉闭塞 (MCAO) 30 分钟,并在缺血后 72 小时通过腹膜内递送大肠杆菌脂多糖 (LPS;三剂 0.1 或 1 mg) 诱导脓毒症样状态/kg,相隔 6 小时),细菌外膜的主要成分。通过行为测试、免疫组织化学和流式细胞术,评估了脓毒症后长达 56 天的神经恢复、缺血性损伤、脑重塑和免疫反应。递送 1 mg/kg 但不是 0.1 mg/kg LPS 在 48 小时内将直肠温度降低高达 3.4±3.1°C,在 72 小时内克拉克评分的一般和局部神经功能缺陷增加,在长达 21 天的紧绳测试中增加运动协调缺陷。值得注意的是,1 mg/kg,但不是 0.1 mg/kg LPS 增加了缺血微血管上的细胞间粘附分子 1 丰度,增加了微血管血栓形成,增加了在 3 dps 时缺血脑组织中的巡逻单核细胞和 T 细胞浸润。梗塞体积在 3 dps(即 MCAO 后 6 天)增加了 1 mg/kg,但没有增加 0.1 mg/kg LPS,在 28 dps 和 56 dps 时脑萎缩也是如此。通过 Iba-1 免疫染色的形态分析评估的缺血组织中的小胶质细胞活化在 3 dps 时瞬时增加了 0.1 和 1 mg/kg LPS。
更新日期:2021-01-01
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