HMGB1 Mediates Cognitive Impairment in Sepsis Survivors
HMGB1 Mediates Cognitive Impairment in Sepsis Survivors
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DOI：
10.2119/molmed.2012.00195
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发表时间：
2012-06-01
影响因子：
5.7
通讯作者：
Diamond, Betty
中科院分区：
文献类型：
--
作者：
Chavan, Sangeeta S.;Huerta, Patricio T.;Diamond, Betty
严重脓毒症是一种使感染和损伤复杂化的综合征，在美国每年影响75万人。急性死亡率约为30%，但令人惊讶的是，脓毒症幸存者有显著的残疾负担：高达25%的幸存者有认知和身体受损。为了研究脓毒症幸存者持续性认知障碍的机制，我们建立了盲肠结扎穿孔（CLP）后严重脓毒症幸存者的小鼠模型，以研究认知障碍。我们观察到高迁移率族蛋白1（HMGB 1），急性脓毒症病理生理学的关键介质，血清水平在脓毒症幸存者中增加。值得注意的是，CLP脓毒症幸存者在学习和记忆方面出现显著、持续的损伤以及与突触可塑性丧失相关的海马体解剖学变化后，这些水平至少在4周内保持升高。在腹膜炎发作后1周开始给予存活者中和性抗HMGB 1抗体，可显著改善记忆障碍和脑病理学。重组HMGB 1给药的幼稚小鼠重演的记忆障碍。总之，这些研究结果表明，升高的HMGB 1水平介导脓毒症幸存者的认知下降，并表明通过给予抗HMGB 1抗体可能预防或逆转脓毒症幸存者的认知障碍。在线地址：http://www.molmed.org doi：10.2119/molmed.2012.00195
Severe sepsis, a syndrome that complicates infection and injury, affects 750,000 annually in the United States. The acute mortality rate is approximately 30%, but, strikingly, sepsis survivors have a significant disability burden: up to 25% of survivors are cognitively and physically impaired. To investigate the mechanisms underlying persistent cognitive impairment in sepsis survivors, here we developed a murine model of severe sepsis survivors following cecal ligation and puncture (CLP) to study cognitive impairments. We observed that serum levels of high mobility group box 1 (HMGB1), a critical mediator of acute sepsis pathophysiology, are increased in sepsis survivors. Significantly, these levels remain elevated for at least 4 wks after CLP Sepsis survivors develop significant, persistent impairments in learning and memory, and anatomic changes in the hippocampus associated with a loss of synaptic plasticity. Administration of neutralizing anti-HMGB1 antibody to survivors, beginning 1 wk after onset of peritonitis, significantly improved memory impairments and brain pathology. Administration of recombinant HMGB1 to naive mice recapitulated the memory impairments. Together, these findings indicate that elevated HMGB1 levels mediate cognitive decline in sepsis survivors, and suggest that it may be possible to prevent or reverse cognitive impairments in sepsis survivors by administration of anti-HMGB1 antibodies. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00195