The role of Nox2-derived ROS in the development of cognitive impairment after sepsis.
The role of Nox2-derived ROS in the development of cognitive impairment after sepsis.
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DOI：
10.1186/1742-2094-11-36
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发表时间：
2014-02-27
影响因子：
9.3
通讯作者：
Bozza FA
中科院分区：
文献类型：
--
作者：
Hernandes MS;D'Avila JC;Trevelin SC;Reis PA;Kinjo ER;Lopes LR;Castro-Faria-Neto HC;Cunha FQ;Britto LR;Bozza FA
脓毒症相关脑病（SAE）是严重感染的早期常见特征。氧化应激是与 SAE 病理生理学相关的机制之一。本研究的目的是调查 NADPH 氧化酶与脓毒症幸存者的神经炎症和长期认知障碍的关系。通过盲肠结扎和穿刺（CLP）诱导粪便性腹膜炎，在 WT 和 gp91phox 敲除小鼠（gp91phox-/-）中诱导脓毒症。我们测量了脓毒症后 6 小时、24 小时和 5 天海马的氧化应激、Nox2 和 Nox4 基因表达以及神经炎症。小鼠还接受了 NADPH 氧化酶抑制剂罗布麻宁的治疗。脓毒症后 15 天，通过抑制性回避试验和 Morris 水迷宫对对照和罗布麻素治疗的 WT 小鼠的行为结果进行评估。脓毒症后 4-HNE 表达增加，同时 Nox2 基因表达增加，从而确定了海马的急性氧化损伤。用罗布麻素对Nox2进行药理抑制可完全抑制脓毒症动物的海马氧化应激。 gp91phox-/- 小鼠中的药理学抑制或 Nox2 的缺失可阻止神经胶质细胞活化，这是与 SAE 相关的核心机制之一。最后，在脓毒症急性期用罗布麻素治疗并抑制海马氧化应激可预防长期认知障碍的发展。我们的结果表明，Nox2 是参与 SAE 中海马氧化损伤的活性氧 (ROS) 的主要来源，并且 Nox2 衍生的 ROS 是脓毒症后认知障碍的决定因素。这些发现强调了 Nox2 衍生的 ROS 作为 SAE 相关神经炎症发展的核心机制的重要性。
Sepsis- associated encephalopathy (SAE) is an early and common feature of severe infections. Oxidative stress is one of the mechanisms associated with the pathophysiology of SAE. The goal of this study was to investigate the involvement of NADPH oxidase in neuroinflammation and in the long-term cognitive impairment of sepsis survivors. Sepsis was induced in WT and gp91phox knockout mice (gp91phox-/-) by cecal ligation and puncture (CLP) to induce fecal peritonitis. We measured oxidative stress, Nox2 and Nox4 gene expression and neuroinflammation in the hippocampus at six hours, twenty-four hours and five days post-sepsis. Mice were also treated with apocynin, a NADPH oxidase inhibitor. Behavioral outcomes were evaluated 15 days after sepsis with the inhibitory avoidance test and the Morris water maze in control and apocynin-treated WT mice. Acute oxidative damage to the hippocampus was identified by increased 4-HNE expression in parallel with an increase in Nox2 gene expression after sepsis. Pharmacological inhibition of Nox2 with apocynin completely inhibited hippocampal oxidative stress in septic animals. Pharmacologic inhibition or the absence of Nox2 in gp91phox-/- mice prevented glial cell activation, one of the central mechanisms associated with SAE. Finally, treatment with apocynin and inhibition of hippocampal oxidative stress in the acute phase of sepsis prevented the development of long-term cognitive impairment. Our results demonstrate that Nox2 is the main source of reactive oxygen species (ROS) involved in the oxidative damage to the hippocampus in SAE and that Nox2-derived ROS are determining factors for cognitive impairments after sepsis. These findings highlight the importance of Nox2-derived ROS as a central mechanism in the development of neuroinflammation associated with SAE.
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DOI：
10.1097/ta.0b013e3181dbb289
发表时间：
2010-12-01
影响因子：
--
作者：
Guerreiro, Marcio Osorio;Petronilho, Fabricia;Ritter, Cristiane
通讯作者：
Ritter, Cristiane
影响因子：
4.7
作者：
Choi SH;Aid S;Kim HW;Jackson SH;Bosetti F
通讯作者：
Bosetti F
影响因子：
8.8
作者：
Barichello, T;Fortunato, JJ;Dal-Pizzol, F
通讯作者：
Dal-Pizzol, F
影响因子：
8.8
作者：
Borrelli, E;RouxLombard, P;Suter, PM
通讯作者：
Suter, PM
脓毒症小鼠的细菌清除受到 MCP-1/CCL2 和一氧化氮的调节。
DOI：
10.1097/shk.0b013e31827802b5
发表时间：
2013-01
期刊：
Shock (Augusta, Ga.)
影响因子：
--
作者：
Gomes RN;Teixeira-Cunha MG;Figueiredo RT;Almeida PE;Alves SC;Bozza PT;Bozza FA;Bozza MT;Zimmerman GA;Castro-Faria-Neto HC
通讯作者：
Castro-Faria-Neto HC