Nerve agent exposure and physiological stress alter brain microstructure and immune profiles after inflammatory challenge in a long-term rat model of Gulf War Illness

IF 3.7 Q2 IMMUNOLOGY
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Abstract

Gulf War Illness (GWI) is a disorder experienced by many veterans of the 1991 Gulf War, with symptoms including fatigue, chronic pain, respiratory and memory problems. Exposure to toxic chemicals during the war, such as oil well fire smoke, pesticides, physiological stress, and nerve agents, is thought to have triggered abnormal neuroinflammatory responses that contribute to GWI. Previous studies have examined the acute effects of combined physiological stress and chemical exposures using GWI rodent models and presented findings related to neuroinflammation and changes in diffusion magnetic resonance imaging (MRI) measures, suggesting a neuroimmune basis for GWI. In the current study, using ex vivo MRI, cytokine mRNA expression, and immunohistological analyses of brain tissues, we examined the brain structure and immune function of a chronic rat model of GWI. Our data showed that a combination of long-term corticosterone treatment (to mimic high physiological stress) and diisopropyl fluorophosphate exposure (to mimic sarin exposure) primed the response to subsequent systemic immune challenge with lipopolysaccharide resulting in elevations of multiple cytokine mRNAs, an increased activated glial population, and disrupted brain microstructure in the cingulate cortex and hippocampus compared to control groups. Our findings support the critical role of neuroinflammation, dysregulated glial activation, and their relationship to disrupted brain microstructural integrity in the pathophysiology of GWI and highlight the unique consequences of long-term combined exposures on brain biochemistry and structural connectivity.
在长期海湾战争病大鼠模型中,神经毒剂暴露和生理应激改变了炎症挑战后的大脑微结构和免疫特征
海湾战争疾病(GWI)是许多参加过 1991 年海湾战争的退伍军人都经历过的一种疾病,症状包括疲劳、慢性疼痛、呼吸和记忆问题。战争期间接触的有毒化学物质,如油井火灾烟雾、杀虫剂、生理压力和神经毒剂,被认为引发了异常神经炎症反应,导致了海湾战争综合症。以前的研究利用 GWI 啮齿动物模型研究了生理应激和化学物质联合暴露的急性影响,并提出了与神经炎症和弥散磁共振成像(MRI)测量变化相关的研究结果,表明 GWI 的神经免疫基础。在本研究中,我们利用体外核磁共振成像、细胞因子 mRNA 表达和脑组织免疫组织学分析,研究了慢性 GWI 大鼠模型的大脑结构和免疫功能。我们的数据显示,与对照组相比,长期皮质酮处理(模拟高生理应激)和二异丙基氟磷酸酯暴露(模拟沙林暴露)的组合会引发对随后脂多糖全身免疫挑战的反应,从而导致多种细胞因子 mRNA 的升高、活化胶质群的增加以及扣带回皮层和海马的脑微结构破坏。我们的研究结果证明了神经炎症、失调的胶质细胞活化及其与大脑微结构完整性破坏之间的关系在 GWI 病理生理学中的关键作用,并强调了长期联合暴露对大脑生物化学和结构连通性造成的独特后果。
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来源期刊
Brain, behavior, & immunity - health
Brain, behavior, & immunity - health Biological Psychiatry, Behavioral Neuroscience
CiteScore
8.50
自引率
0.00%
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0
审稿时长
97 days
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