Acute pulmonary inflammation is a common disease on intensive care. Due to the lack of specific treatments, lethality is still very high. The ionotropic GABAA-receptors are known from the central nervous system (CNS) and have recently been detected in the lung. These receptors have been shown to influence inflammatory processes. Opposing data has been reported, where both, GABA site agonists and antagonists achieved anti-inflammatory effects. The distribution of the 19 known GABAA-receptor subunits (α1-6, β1-3, γ1-3, δ, ε, π, θ and ρ1-3) and their role in inflammation remain unclear. In murine models of LPS- and bacteria-induced inflammation, Muscimol (GABAA-receptor agonist) and Bicuculline (antagonist) were administered before the onset of inflammation. Transcription of GABAA-receptor subunits was evaluated by real-time polymerase chain reaction. Neutrophil counts and adhesion molecule expression in wild type and GABAα1 knock-in mice were determined by flow-cytometry. Myeloperoxidase, neutrophil extracellular traps and cytokines were determined. In a model of ventilator-induced lung injury, blood gas analysis was performed using arterial blood. A multiplex western blot was done to assess signaling proteins. Muscimol and Bicuculline inhibited neutrophil influx in the bronchoalveolar lavage but did not change neutrophil activation. Both altered surface expression of adhesion molecules on neutrophils and reduced release of interleukin-6 (IL-6). The increased α1 subunit expression on lung epithelium and endothelium after inflammation was abolished by Muscimol and Bicuculline. In GABAα1-knock-in mice the protective effects of both agents were no longer observed. Only Muscimol lowered protein extravasation, improved blood gas analysis and lung function. A multiplex assay ascribed these anti-inflammatory effects to the influence of the IL-6 and phosphoinositide 3-kinase signaling pathways. In conclusion, Muscimol and Bicuculline exert various protective effects in two murine models of acute pulmonary inflammation. The multiple effects of Muscimol were linked to the inhibition of the proinflammatory signaling pathways IL-6 and PI3K.
© 2025. The Author(s).