Effects of anesthetic regimes on inflammatory responses in a rat model of acute lung injury

Purpose: Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter through activation of GABA receptors. Volatile anesthetics activate type-A (GABA_A) receptors resulting in inhibition of synaptic transmission. Lung epithelial cells have been recently found to express GABA_A receptors that exert anti-inflammatory properties. We hypothesized that the volatile anesthetic sevoflurane (SEVO) attenuates lung inflammation through activation of lung epithelial GABA_A receptors. Methods: Sprague-Dawley rats were anesthetized with SEVO or ketamine/xylazine (KX). Acute lung inflammation was induced by intratracheal instillation of endotoxin, followed by mechanical ventilation for 4 h at a tidal volume of 15 mL/kg without positive end-expiratory pressure (two-hit lung injury model). To examine the specific effects of GABA, healthy human lung epithelial cells (BEAS-2B) were challenged with endotoxin in the presence and absence of GABA with and without addition of the GABA_A receptor antagonist picrotoxin. Results: Anesthesia with SEVO improved oxygenation and reduced pulmonary cytokine responses compared to KX. This phenomenon was associated with increased expression of the π subunit of GABA_A receptors and glutamic acid decarboxylase (GAD). The endotoxin-induced cytokine release from BEAS-2B cells was attenuated by the treatment with GABA, which was reversed by the administration of picrotoxin. Conclusion: Anesthesia with SEVO suppresses pulmonary inflammation and thus protects the lung from the two-hit injury. The anti-inflammatory effect of SEVO is likely due to activation of pulmonary GABA_A signaling pathways.