The Neuroprotective Effect of Genetic Mannose-binding Lectin Deficiency is not Sustained in the Sub-acute Phase of Stroke.
The Neuroprotective Effect of Genetic Mannose-binding Lectin Deficiency is not Sustained in the Sub-acute Phase of Stroke.
复制标题
DOI：
10.1007/s12975-011-0104-2
复制
发表时间：
2011-12
影响因子：
6.9
通讯作者：
Connolly, E. Sander, Jr.
中科院分区：
文献类型：
--
作者：
Ducruet, Andrew F.;Sosunov, Sergey A.;Zacharia, Brad E.;Gorski, Justin;Yeh, Mason L.;DeRosa, Peter;Cohen, Gregory;Gigante, Paul R.;Connolly, E. Sander, Jr.
补体级联反应是脑缺血后炎症反应的关键介质。最近的研究表明，甘露糖结合凝集素（MBL）的遗传缺陷可改善再灌注损伤，改善中风急性期的预后。本研究旨在进一步阐明MBL在卒中中的致病作用，并检查与MBL缺乏相关的神经保护作用是否持续超过急性期。我们假设，遗传MBL缺陷会抑制补体激活，改善急性期再灌注损伤，但持续抑制补体进入亚急性期将有助于消除这种神经保护作用。采用免疫印迹和免疫组织化学方法对缺血后脑MBL和C3沉积的时间进程和定位进行了表征。MBL-a/c null（MBL-KO）小鼠在短暂性大脑中动脉闭塞（MCAO）后24小时和7天观察MBL基因缺失对小鼠组织学和功能的影响。MBL-a/c在急性期迅速存款在缺血内皮上并触发下游补体激活。MBL的遗传缺陷消除了C3裂解以及缺血区域中单核细胞的亚急性积累。尽管MBL-KO小鼠在24小时时表现出显著改善的结果，但与遗传MBL缺失相关的神经保护作用并不持续。开发成功的抗补体神经保护策略将需要精心定制的抑制，以及对中风恢复后期补体激活的功能效应的更好理解。
The complement cascade is a critical mediator of the inflammatory response following cerebral ischemia. Recent work has demonstrated that genetic-deficiency of Mannose-binding lectin(MBL) ameliorates reperfusion injury and improves outcome in the acute phase of stroke. The present study sought to further delineate the pathogenic role of MBL in stroke and to examine whether the neuroprotection associated with MBL-deficiency is sustained beyond the acute phase. We hypothesized that genetic MBL deficiency would suppress complement activation and ameliorate reperfusion injury in the acute phase, but that persistent inhibition of complement into the sub-acute phase would serve to abrogate this neuroprotective effect. The time-course and localization of post-ischemic cerebral MBL and C3 deposition were characterized using both Western-blot and immunohistochemistry. MBL-a/c null(MBL-KO) mice subjected to transient middle cerebral artery occlusion(MCAO) were then employed to investigate the histologic injury and functional outcome associated with genetic MBL deletion at both 24 hours and 7 days. MBL-a/c rapidly deposit on ischemic endothelium and trigger downstream complement activation in the acute phase. Genetic deficiency of MBL abrogates C3 cleavage as well as the sub-acute accumulation of mononuclear cells in the ischemic region. Although MBL-KO mice demonstrate significantly improved outcome at 24 hours, the neuroprotective effect associated with genetic MBL deletion is not sustained. Development of a successful anti-complement neuroprotective strategy will require carefully-tailored inhibition coupled with a greater understanding of the functional effects of complement activation during later phases of stroke recovery.
登录
查看更多内容
影响因子：
16.8
作者：
Mastellos, D;Lambris, JD
通讯作者：
Lambris, JD
影响因子：
6.3
作者：
Ducruet, Andrew F.;Hassid, Benjamin G.;Connolly, E. Sander
通讯作者：
Connolly, E. Sander
影响因子：
20.1
作者：
Mocco, J.;Mack, William J.;Connolly, E. Sander, Jr.
通讯作者：
Connolly, E. Sander, Jr.
影响因子：
8.3
作者：
Gelderblom, Mathias;Leypoldt, Frank;Magnus, Tim
通讯作者：
Magnus, Tim
影响因子：
4.8
作者：
Connolly, ES;Winfree, CJ;Pinsky, DJ
通讯作者：
Pinsky, DJ