GABA receptor ameliorates ventilator-induced lung injury in rats by improving alveolar fluid clearance

Abstract

IntroductionMechanical ventilators are increasingly used in critical care units. However, they can cause lung injury, including pulmonary edema. Our previous studies indicated that γ-aminobutyric acid (GABA) receptors are involved in alveolar-fluid homeostasis. The present study investigated the role of GABA receptors in ventilator-induced lung injury.MethodsAdult female Sprague-Dawley rats were subjected to high-tidal-volume ventilation of 40 ml/kg body weight for 1 hour, and lung injuries were assessed.ResultsHigh-tidal-volume ventilation resulted in lung injury, as indicated by an increase in total protein in bronchoalveolar fluid, wet-to-dry ratio (indication of pulmonary edema), and Evans Blue dye extravasation (indication of vascular damage). Intratracheal administration of GABA before ventilation significantly reduced the wet-to-dry ratio. Further, histopathologic analysis indicated that GABA reduced ventilator-induced lung injury and apoptosis. GABA-mediated reduction was effectively blocked by the GABAA-receptor antagonist, bicuculline. The GABA-mediated effect was not due to the vascular damage, because no differences in Evans Blue dye extravasation were noted. However, the decrease in alveolar fluid clearance by high-tidal-volume ventilation was partly prevented by GABA, which was blocked by bicuculline.ConclusionsThese results suggest that GABA reduces pulmonary edema induced by high-tidal-volume ventilation via its effects on alveolar fluid clearance and apoptosis.

Role of posterior hypothalamus in hypobaric hypoxia induced pulmonary edema

“…While NO-ergic mechanism may have a limited contribution, the GABA-ergic mechanism in the posterior hypothalamus has a significant role to play in alleviating pulmonary edema. It is interesting to mention here that in rats, intratracheal administration of GABA has already been reported to reduce the pulmonary edema associated with ventilator induced lung injury by promoting alveolar fluid clearance mechanisms (Chintagari and Liu, 2012). The present findings demonstrate that central GABA has an additional beneficial effect in the pulmonary edema associated with hypobaric hypoxia namely a reduction in pulmonary vascular permeability as evidenced by a decrease in Evans blue leakage.…”

Resolvin D1 Stimulates Alveolar Fluid Clearance through Alveolar Epithelial Sodium Channel, Na,K-ATPase via ALX/cAMP/PI3K Pathway in Lipopolysaccharide-Induced Acute Lung Injury

“…Thus, both ENaC and Na,K-ATPase are accredited with key roles in the resolution of pulmonary edema (10). Several recent in vivo studies have demonstrated vasopressin-2 receptor antagonist (11), GABA receptor (12), b-adrenergic (13), triiodo-L-thyronine (14), and leukotriene D 4 (15) could markedly upregulate AFC in experimental animal models. We previously reported that treatment with lipoxin A 4 , an anti-inflammatory and proresolution mediator, and lipoxin receptor agonist (BML-111) significantly stimulated AFC in oleic acid-induced lung injury and decreased pulmonary edema (16).…”

Sevoflurane Abolishes Oxygenation Impairment in a Long-term Rat Model of Acute Lung Injury

“…However, 1 possible link is the pulmonary γ-aminobutyric acid type A (GABA A )-receptor (GABAAR). 38 Current studies suggest that modifying or blocking GABAAR might lead to an improved alveolar fluid clearance in ALI 39 and that GABAAR function may be modulated by isoflurane. 39 Further work is needed to better understand the role of GABAAR in volatile-mediated immunomodulation and alveolar fluid clearance.…”

“…38 Current studies suggest that modifying or blocking GABAAR might lead to an improved alveolar fluid clearance in ALI 39 and that GABAAR function may be modulated by isoflurane. 39 Further work is needed to better understand the role of GABAAR in volatile-mediated immunomodulation and alveolar fluid clearance. Another potential mediator for the sevoflurane effect we observed is downregulation of toll-like receptor 2 and toll-like receptor 4 resulting in an attenuation of proinflammatory cytokines.…”