Acute neuropsychiatric impairments occur in over 70% of patients with acute lung injury. Mechanical ventilation is a well-known precipitant of acute lung injury and is strongly associated with the development of acute delirium and anxiety phenotypes. In prior studies, we demonstrated that IL-6 mediates neuropathological changes in the frontal cortex and hippocampus of animals with mechanical ventilation-induced brain injury; however, the effect of systemic IL-6 inhibition on structural and functional acute neuropsychiatric phenotypes is not known. We hypothesized that a murine model of mechanical ventilation-induced acute lung injury (VILI) would induce neural injury to the amygdala and hippocampus, brain regions that are implicated in diverse neuropsychiatric conditions, and corresponding delirium- and anxiety-like functional impairments. Furthermore, we hypothesized that these structural and functional changes would reverse with systemic IL-6 inhibition. VILI was induced using high tidal volume (35 cc/kg) mechanical ventilation. Cleaved caspase-3 (CC3) expression was quantified as a neural injury marker and found to be significantly increased in the VILI group compared to spontaneously breathing or anesthetized and mechanically ventilated mice with 10 cc/kg tidal volume. VILI mice treated with systemic IL-6 inhibition had significantly reduced amygdalar and hippocampal CC3 expression compared to saline-treated animals and demonstrated amelioration in acute neuropsychiatric behaviors in open field, elevated plus maze, and Y-maze tests. Overall, these data provide evidence of a pathogenic role of systemic IL-6 in mediating structural and functional acute neuropsychiatric symptoms in VILI and provide preclinical justification to assess IL-6 inhibition as a potential intervention to ameliorate acute neuropsychiatric phenotypes following VILI.

中文翻译：

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全身性白细胞介素 6 抑制可改善急性肺损伤小鼠模型中的急性神经精神表型

超过 70% 的急性肺损伤患者会出现急性神经精神障碍。机械通气是众所周知的急性肺损伤诱因，并且与急性谵妄和焦虑表型的发展密切相关。在先前的研究中，我们证明 IL-6 介导机械通气引起的脑损伤动物的额叶皮层和海马的神经病理学变化；然而，全身性 IL-6 抑制对结构和功能性急性神经精神表型的影响尚不清楚。我们假设机械通气诱导的急性肺损伤 (VILI) 的小鼠模型会导致杏仁核和海马体、与多种神经精神疾病相关的大脑区域以及相应的谵妄和焦虑样功能障碍的神经损伤。此外，我们假设这些结构和功能变化会随着全身性 IL-6 抑制而逆转。使用高潮气量 (35 cc/kg) 机械通气诱导 VILI。Cleaved caspase-3 (CC3) 表达被量化为神经损伤标志物，发现与具有 10 cc/kg 潮气量的自主呼吸或麻醉和机械通气小鼠相比，VILI 组的表达显着增加。与生理盐水治疗的动物相比，用全身性 IL-6 抑制治疗的 VILI 小鼠的杏仁核和海马 CC3 表达显着降低，并且在开阔视野、高架十字迷宫和 Y 迷宫测试中表现出急性神经精神行为的改善。全面的，