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<p>Vascular hyperpermeability drives the pathogenesis of acute lung injury (ALI) during sepsis. Although γ-aminobutyric acid type A receptors (<i>GABAARs</i>) are classically recognized as central nervous system ion channels, we identified an unexpected, essential requirement for the GABA<sub>A</sub> receptor α1 subunit (<i>GABRA1</i>) in preserving pulmonary endothelial integrity. To investigate the translational relevance of our findings in vivo, we utilized a cecal ligation and puncture (CLP)-induced sepsis mouse model. Analysis of pulmonary microvascular endothelial cells (PMVECs) isolated from these septic mice revealed a profound depletion of <i>GABRA1</i>. This reduction was consistently observed in cultured endothelial cells following LPS challenge. Furthermore, targeted silencing of <i>GABRA1</i> in Human Umbilical Vein Endothelial Cell (HUVEC) significantly exacerbated LPS-induced barrier dysfunction, as indicated by a marked decrease in transendothelial electrical resistance and increased expression of adhesion molecules (<i>ICAM-1</i> and <i>VCAM-1</i>). These results suggest that <i>GABRA1</i> may act as a regulatory element in the pulmonary vasculature, offering a potential therapeutic avenue for managing septic endothelial leakage.</p>

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Activation of endothelial GABAA receptor α1 subunit protects against barrier dysfunction in acute lung injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月28日

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  • Shuting Zhou,
  • Xudong He,
  • Xinzhe Ni,
  • Aizhong Wang,
  • Xiaotao Xu

摘要

Vascular hyperpermeability drives the pathogenesis of acute lung injury (ALI) during sepsis. Although γ-aminobutyric acid type A receptors (GABAARs) are classically recognized as central nervous system ion channels, we identified an unexpected, essential requirement for the GABAA receptor α1 subunit (GABRA1) in preserving pulmonary endothelial integrity. To investigate the translational relevance of our findings in vivo, we utilized a cecal ligation and puncture (CLP)-induced sepsis mouse model. Analysis of pulmonary microvascular endothelial cells (PMVECs) isolated from these septic mice revealed a profound depletion of GABRA1. This reduction was consistently observed in cultured endothelial cells following LPS challenge. Furthermore, targeted silencing of GABRA1 in Human Umbilical Vein Endothelial Cell (HUVEC) significantly exacerbated LPS-induced barrier dysfunction, as indicated by a marked decrease in transendothelial electrical resistance and increased expression of adhesion molecules (ICAM-1 and VCAM-1). These results suggest that GABRA1 may act as a regulatory element in the pulmonary vasculature, offering a potential therapeutic avenue for managing septic endothelial leakage.