Purpose: Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter through activation of GABA receptors. Volatile anesthetics activate type-A (GABAA) receptors resulting in inhibition of synaptic transmission. Lung epithelial cells have been recently found to express GABAA receptors that exert anti-inflammatory properties. We hypothesized that the volatile anesthetic sevoflurane (SEVO) attenuates lung inflammation through activation of lung epithelial GABAA 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 GABAA 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 GABAA 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 GABAA signaling pathways.
Bibliographical noteFunding Information:
Acknowledgments The authors are indebted to Julie Khang, BSc for technical assistance. The study was supported by Canadian Institutes of Health Research (CIHR) grants to WYL, Arthur S. Slutsky, and Haibo Zhang, Ontario Thoracic Society (OTS) Grant-in-Aid and McLaughlin Foundation to Haibo Zhang. Spyri-don Fortis was supported by the Alexander S. Onassis Public Benefit Foundation. Peter M. Spieth was supported by the German Research Foundation (DFG SP 1222/3-1). Peter M. Spieth is a recipient of the University of Toronto Eli Lilly Critical Care Fellowship Award.
- Mechanical ventilation
- Volatile anesthetics