Activation of endothelial GABA A α1 receptor protects against barrier dysfunction in acute lung injury

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 GABA _A α 1 subunit (GABRA1) in preserving pulmonary endothelial integrity. Analysis of pulmonary microvascular endothelial cells (PMVECs) isolated from mice with polymicrobial sepsis (CLP) revealed a profound depletion of GABRA1. This suppression was faithfully mirrored in cultured endothelial cells following endotoxin (LPS) challenge. Crucially, targeted silencing of GABRA1 in HUVECs severely aggravated LPS-triggered barrier dysfunction, characterized by a precipitous drop in transendothelial electrical resistance and exaggerated upregulation of adhesion molecules (ICAM-1, VCAM-1). These results re-define GABRA1 as a vital structural gatekeeper in the pulmonary vasculature, offering a non-canonical therapeutic avenue for managing septic endothelial leakage.