Effects of Dexmedetomidine on Regulating Pulmonary Inflammation in a Rat Model of Ventilator-induced Lung Injury

Abstract

We sought to elucidate the effects of dexmedetomidine, a selective alpha2-adrenergic receptor agonist, on the regulation of pulmonary inflammation in ventilator-induced lung injury (VILI) in a rat model. A total of 64 adult male Sprague-Dawley rats were assigned to receive either standard ventilation (tidal volume 10 mL/kg; respiratory rate 50 breaths/minute), high-tidal volume ventilation (HVT: tidal volume 20 mL/kg; respiratory rate 50 breaths/minute), HVT plus dexmedetomidine (0.5, 2.5 or 5.0 microg/kg per hour), or HVT plus dexmedetomidine (0.5, 2.5 or 5.0 microg/kg per hour) and yohimbine (the alpha2-adrenergic receptor antagonist) (n = 8 in each group). The doses of dexmedetomidine were chosen to correspond to 1, 5 and 10 times the clinical dose (0.5 microg/kg per hour). After maintaining ventilation for 4 hours, rats were sacrificed and pulmonary inflammatory changes as well as the upregulation of pulmonary inflammatory molecules were evaluated. Histological and arterial blood gas analyses confirmed that HVT induced significant lung injury. HVT also significantly increased the pulmonary concentrations of chemokines (e.g. macrophage inflammatory protein-2), cytokines (e.g. tumor necrosis factor-alpha, interleukin [IL]-1beta, and IL-6), inducible nitric oxide synthase/nitric oxide, cyclooxygenase-2/prostaglandin E2. Dexmedetomidine at the dose of 5.0 microg/kg per hour, but not at 0.5 and 2.5 microg/kg per hour, significantly attenuated the effects of HVT. Moreover, these effects of dexmedetomidine were significantly attenuated by yohimbine. Dexmedetomidine at clinically relevant doses had no significant effect in attenuating VILI. In contrast, dexmedetomidine at a dose approximately 10 times higher than the clinical dose significantly attenuated VILI. These effects of dexmedetomidine were mediated, at least in part, by the alpha2-adrenergic receptor.