Dexmedetomidine Attenuates Bilirubin-Induced Lung Alveolar Epithelial Cell Death In Vitro and In Vivo*

Hepatopulmonary syndrome (HPS) is a serious complication frequently observed in patients with chronic liver disease (1, 2). Previous studies have shown that pathological changes occurring in the lungs of animals with HPS included nonspecific pneumonia and epithelial cells injury (3). The tidal volume, minute ventilation, and mean inspiratory flow were significantly decreased, and chest wall pressure dissipation against the resistive and viscoelastic components and elasticity were reduced (4). All of these changes result in ventilation-perfusion (V/Q) mismatch, diffusion limitation of oxygen, and, less commonly, arteriovenous shunt. Orthotropic liver transplantation was considered the favorable method to improve the survival rate of patients with HPS (5). Many other operations have been performed on patients with HPS in clinics to improve hepatic function, such as endoscopic sphincterotomy, multiple bile duct stone extraction, and hilar tumor resection. Hyperbilirubinemia is the typical feature of most severe liver disease and was considered the main cause of HPS (6). Previous studies have identified that high concentration of bilirubin leads to release of inflammatory cytokines from glial cells or neuronal cell apoptosis in the brain (7). In the lung, pulmonary vascular dilatation and high permeability of the pulmonary vascular barrier were found in rats undergoing common bile duct ligation (CBDL) surgery (8). Following destruction of the vascular endothelial barrier, high concentrations of bilirubin can enter interstitial tissue and, therefore, could be in direct contact with pulmonary alveolar epithelial cells, but the potential effect of bilirubin on the lung epithelial cells remains incompletely understood. Dexmedetomidine, a potent α2 adrenergic agonist, has been commonly used in operating room and ICU for its sparing effect of other anesthetics or sedation (9, 10). Recent studies have demonstrated that dexmedetomidine could reduce systemic inflammation in animals and improves the gas exchange in patients (11, 12). An elegant previous study has shown that dexmedetomidine confers a remote lung acute injury following kidney ischemia reperfusion injury in mice (13). In addition, it has been found that dexmedetomidine has potent renoprotective effects against renal ischemia reperfusion injuries, which is very likely associated with p-Akt and Janus kinase/signal transducer and activator of transcription signaling activation in mice and rats (14, 15).Taken together, these studies indicate that dexmedetomidine possesses cytoprotective effects. Thus, we hypothesized that dexmedetomidine might alleviate the epithelial cell injury in HPS. In this study, we aim to investigate whether dexmedetomidine protects the lung alveolar epithelium against injury associated with hyperbilirubinemia both in vivo and in vitro.