Hypercapnia exacerbates the disruption of the blood‑brain barrier by inducing interleukin‑1β overproduction in the blood of hypoxemic adult rats

Ding,Hongguang; Liu,Xinqiang; Li,Xusheng; Wen,Miaoyun; Li,Ya; Han,Yongli; Huang,Linqiang; Liu,Mengting; Zeng,Hongke

doi:10.3892/ijmm.2020.4604

Hypercapnia exacerbates the disruption of the blood‑brain barrier by inducing interleukin‑1β overproduction in the blood of hypoxemic adult rats

Authors:
- Hongguang Ding
- Xinqiang Liu
- Xusheng Li
- Miaoyun Wen
- Ya Li
- Yongli Han
- Linqiang Huang
- Mengting Liu
- Hongke Zeng
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Affiliations: Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, P.R. China
Published online on: May 14, 2020 https://doi.org/10.3892/ijmm.2020.4604
Pages: 762-772
Copyright: © Ding et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Refractory hypoxemia is the main symptom of acute respiratory distress syndrome (ARDS). Low tidal volume ventilation is routinely applied in clinical practice to correct hypoxemia, which aims to prevent ventilator‑induced lung injury. However, this ventilation strategy inevitably leads to hypercapnia. Our previous study demonstrated that hypercapnia aggravated cognitive impairment in hypoxemic rats; however, the underlying mechanism remains unclear. The aim of the present study was to investigate whether hypercapnia exacerbates the blood‑brain barrier (BBB) disruption through inducing interleukin (IL)‑1β overproduction in the blood of hypoxemic rats. The BBB permeability in a rat model of hypercapnia/hypoxemia was evaluated. The levels of IL‑1β in the blood of rats and human whole‑blood cultures were assessed. The expression of IL‑1 receptor 1 (IL‑1R1), phosphorylated IL‑1R1‑associated kinase (p‑IRAK‑1) and tight junctional proteins in cerebral vascular endothelial cells was examined in vitro and in vivo. In addition, IL‑1Ra, an IL‑1 receptor antagonist, was used to determine whether hypercapnia affects tight junctional protein expression in hypoxic cerebral vascular endothelial cells through inducing IL‑1β overproduction. It was observed that hypercapnia alone did not disrupt the BBB, but aggravated the damage to the BBB integrity in hypoxemic rats. Hypercapnia increased IL‑1β expression in the blood of hypoxemic rats as well as in hypoxic human whole‑blood cultures. IL‑1R1 and p‑IRAK‑1 expression was increased, while that of tight junctional proteins was reduced by hypercapnia in hypoxemic cerebral vascular endothelial cells in vitro and in vivo. Additionally, the expression of tight junctional proteins was markedly increased following treatment with IL‑1Ra. These results suggest that hypercapnia‑induced IL‑1β overproduction in the hypoxemic blood may decrease tight junctional protein expression in cerebrovascular endothelial cells via the IL‑1R1/p‑IRAK‑1 pathway, further disrupting BBB integrity, and eventually resulting in increased BBB permeability.

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