Journal article
Herman Li, Linh Le, Mariah Marrero, Jennifer David-Bercholz, A. I. Caceres, Claire Lim, Wesley Chiang, A. Majewska, N. Terrando, Harris A Gelbard
bioRxiv, 2023
bioRxiv, 2023
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DOI
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APA
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Li, H., Le, L., Marrero, M., David-Bercholz, J., Caceres, A. I., Lim, C., … Gelbard, H. A. (2023). Neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury. BioRxiv.
Chicago/Turabian
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Li, Herman, Linh Le, Mariah Marrero, Jennifer David-Bercholz, A. I. Caceres, Claire Lim, Wesley Chiang, A. Majewska, N. Terrando, and Harris A Gelbard. “Neutrophilia with Damage to the Blood-Brain Barrier and Neurovascular Unit Following Acute Lung Injury.” bioRxiv (2023).
MLA
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Li, Herman, et al. “Neutrophilia with Damage to the Blood-Brain Barrier and Neurovascular Unit Following Acute Lung Injury.” BioRxiv, 2023.
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@article{herman2023a,
title = {Neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury},
year = {2023},
journal = {bioRxiv},
author = {Li, Herman and Le, Linh and Marrero, Mariah and David-Bercholz, Jennifer and Caceres, A. I. and Lim, Claire and Chiang, Wesley and Majewska, A. and Terrando, N. and Gelbard, Harris A}
}
Abstract
Background 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. Methods 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. Results 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. Conclusions 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.