D-W Cao1, M-X Hou, X-R Zhang. 1. Department of Respiratory Medicine, The First Hospital of Shanxi Medical University, Taiyuan, China. ykdzxr61@163.com.
Abstract
OBJECTIVE: Ventilator-induced lung injury (VILI) remains a challenge. This study was designed to investigate the effects of ambroxol on VILI and the underlying mechanisms in a rodent model. MATERIALS AND METHODS: Male Wistar rats weighing 310-380 g were divided into four groups (n=8 per group): 1) saline only, 2) ventilation plus saline, 3) ventilation plus ambroxol (2 mg/kg), and 4) ventilation plus ambroxol (50 mg/kg). Rats in groups 1 and 2 were treated (i.p.) with 2.5 ml of saline once a day for six days and last injected 1 h prior to tracheotomy. Rats in groups 3 and 4 received ambroxol on the same schedule. Rats were ventilated for 90 minutes at a tidal volume (VT) of 30 ml/kg. The expression levels of c-Jun, a component of activator protein-1 (AP-1), and gamma-glutamylcysteine synthetase (γ-GCS), the rate-limiting enzyme in the synthesis of glutathione (gamma-glutamyl-cysteinyl-glycine, GSH), an endogenous antioxidant, were measured with immunohistochemical staining and in situ hybridization. Both AP-1 and GSH are involved in VILI. RESULTS: Ambroxol at 50 mg/kg inhibited ventilation-induced lung inflammation, significantly elevated the ventilation-induced down-regulation of γ-GCS mRNA and protein, and significantly decreased the ventilation-induced up-regulation of c-Jun mRNA and protein. It has been reported that reactive oxygen species (ROS) can activate AP-1, leading to the production of pro-inflammatory cytokines and lung inflammation. CONCLUSIONS: Ambroxol increases γ-GCS to promote GSH production, which in turn, inhibits ROS-dependent AP-1 activation and inflammation.
OBJECTIVE: Ventilator-induced lung injury (VILI) remains a challenge. This study was designed to investigate the effects of ambroxol on VILI and the underlying mechanisms in a rodent model. MATERIALS AND METHODS: Male Wistar rats weighing 310-380 g were divided into four groups (n=8 per group): 1) saline only, 2) ventilation plus saline, 3) ventilation plus ambroxol (2 mg/kg), and 4) ventilation plus ambroxol (50 mg/kg). Rats in groups 1 and 2 were treated (i.p.) with 2.5 ml of saline once a day for six days and last injected 1 h prior to tracheotomy. Rats in groups 3 and 4 received ambroxol on the same schedule. Rats were ventilated for 90 minutes at a tidal volume (VT) of 30 ml/kg. The expression levels of c-Jun, a component of activator protein-1 (AP-1), and gamma-glutamylcysteine synthetase (γ-GCS), the rate-limiting enzyme in the synthesis of glutathione (gamma-glutamyl-cysteinyl-glycine, GSH), an endogenous antioxidant, were measured with immunohistochemical staining and in situ hybridization. Both AP-1 and GSH are involved in VILI. RESULTS:Ambroxol at 50 mg/kg inhibited ventilation-induced lung inflammation, significantly elevated the ventilation-induced down-regulation of γ-GCS mRNA and protein, and significantly decreased the ventilation-induced up-regulation of c-Jun mRNA and protein. It has been reported that reactive oxygen species (ROS) can activate AP-1, leading to the production of pro-inflammatory cytokines and lung inflammation. CONCLUSIONS:Ambroxol increases γ-GCS to promote GSH production, which in turn, inhibits ROS-dependent AP-1 activation and inflammation.