背景:急性肺损伤(ALI),传染病,在过去的几年里,神经系统的结果经常被讨论,特别是由于COVID-19大流行。然而,器官之间的许多交叉交流,尤其是肺和大脑,已经被研究不足。这里,在ALI模型中,我们重点研究了中性粒细胞在驱动脑内皮变化以及随后的小胶质细胞活化和神经元丢失中的作用.
方法:我们应用了10μg/40μl鼻内脂多糖(LPS)的三剂量范例,在成年C57BL/6小鼠的支气管肺泡灌洗液(BALF)中诱导中性粒细胞并伴有蛋白质性渗出物。脑内皮标记物,小胶质细胞激活,在最后一次鼻内剂量的LPS或盐水后24小时评估和神经元细胞结构。C57BL/6-Ly6g(tm2621(Cre-tdTomato)Arte(Catchup小鼠)用于测量LPS暴露后的嗜中性粒细胞和血脑屏障通透性,并进行活体2光子成像。
结果:三种剂量的鼻内LPS在BALF中诱导伴有蛋白质性渗出物的强烈中性粒细胞增多。ALI触发中枢神经系统病理,如脑血管内皮(VCAM1,CD31)的强烈激活所强调,血浆蛋白(纤维蛋白原)的积累,小胶质细胞活化(IBA1,CD68),海马腔隙层相关蛋白(PSD-95)的表达减少,内嗅皮层和海马CA1之间的中继站。Catchup小鼠的2光子成像显示,在最后一次鼻内治疗24小时后,中性粒细胞归巢到血脑屏障中的脑内皮,中性粒细胞从脑血管系统外渗。
结论:总体而言,这些数据证明了由ALI引起的脑病理学,强调中性粒细胞在驱动脑内皮变化和随后的神经炎症中的关键作用。这种范式可能对理解ALI的传染病如何导致神经变性有相当大的转化影响。尤其是老年人。
UNASSIGNED: Links between acute lung injury (ALI), infectious disease, and neurological outcomes have been frequently discussed over the past few years, especially due to the COVID-19 pandemic. Yet, much of the cross-communication between organs, particularly the lung and the brain, has been understudied. Here, we have focused on the role of neutrophils in driving changes to the brain endothelium with ensuing microglial activation and neuronal loss in a model of ALI.
UNASSIGNED: We have applied a three-dose paradigm of 10μg/40μl intranasal lipopolysaccharide (LPS) to induce
neutrophilia accompanied by proteinaceous exudate in bronchoalveolar lavage fluid (BALF) in adult C57BL/6 mice. Brain endothelial markers, microglial activation, and neuronal cytoarchitecture were evaluated 24hr after the last intranasal dose of LPS or saline. C57BL/6-Ly6g(tm2621(Cre-tdTomato)Arte (Catchup mice) were used to measure neutrophil and blood-brain barrier permeability following LPS exposure with intravital 2-photon imaging.
UNASSIGNED: Three doses of intranasal LPS induced robust
neutrophilia accompanied by proteinaceous exudate in BALF. ALI triggered central nervous system pathology as highlighted by robust activation of the cerebrovascular endothelium (VCAM1, CD31), accumulation of plasma protein (fibrinogen), microglial activation (IBA1, CD68), and decreased expression of proteins associated with postsynaptic terminals (PSD-95) in the hippocampal stratum lacunosum moleculare, a relay station between the entorhinal cortex and CA1 of the hippocampus. 2-photon imaging of Catchup mice revealed neutrophil homing to the cerebral endothelium in the blood-brain barrier and neutrophil extravasation from cerebral vasculature 24hr after the last intranasal treatment.
UNASSIGNED: Overall, these data demonstrate ensuing brain pathology resulting from ALI, highlighting a key role for neutrophils in driving brain endothelial changes and subsequent neuroinflammation. This paradigm may have a considerable translational impact on understanding how infectious disease with ALI can lead to neurodegeneration, particularly in the elderly.