Effects of dexmedetomidine pretreatment on cell apoptosis induced by endoplasmic reticulum stress and c-Jun N-terminal kinase pathway during one-lung ventilation in rats

Abstract

Objective To evaluate the effects of dexmedetomidine (DEX) on cell apoptosis induced by endoplasmic reticulum stress and c-Jun N-terminal kinase (JNK) pathway during one-lung ventilation (OLV) in rats. Methods Sixty male Sprague-Dawley rats were randomly allocated into 6 groups (n=10 each): sham operation group (Sham group), OLV group, OLV + atipamezole (α2 receptor antagonist) group (AD group), OLV + atipamezole + DEX group (DEX+ AD group), OLV + low-dose DEX group (DEX-L group) and OLV + high-dose DEX group (DEX-H group). The animals were anesthetized with 10% chloral hydrate 4.5 ml/kg, tracheostomized and mechanically ventilated.Bilateral lungs were ventilated for 2.5 h in Sham group.The right lung was ventilated for 2.0 h followed by 0.5 h two-lung ventilation in OLV group.In DEX-L and DEX-H groups, DEX was infused intravenously for 1 h at a rate of 2.5 μg·kg-1·h-1 and 5.0 μg·kg-1·h-1, respectively, starting from 1 h prior to OLV.Atipamezole 250 μg/kg was injected intravenously at 1 h prior to OLV in AD group.Atipamezole 250 μg/kg was injected intravenously at the onset of DEX infusion (5.0 μg·kg-1·h-1) in DEX+ AD group.The rats were sacrificed and left lungs were removed for determination of weight to dry lung weight ratio (W/D), cell apoptosis in lung tissues (by TUNEL), and expression of glucose-regulated protein 78 (GRP78)mRNA and protein, JNK mRNA and phosphorylated JNK (p-JNK) protein (by RT-PCR and Western blot). Pathological changes of lungs were examined and the injured alveolus rate (IAR) was counted under light microscope.The changes in ultrastructure of lung tissues were observed under transmission electron microscope.Apoptosis index (AI) was calculated. Results W/D, AI and IAR were significantly higher in OLV, AD and DEX+ AD group than in Sham group, while lower in DEX-L and DEX-H groups than in OLV, AD and DEX+ AD groups.The pathological changes of the structure of lung tissues were observed in OLV, AD and DEX+ AD groups, while the pathological changes were significantly alleviated in DEX-L and DEX-H groups.In OLV, AD and DEX+ AD groups, there was apoptosis in lots of pulmonary vascular endothelial cells and alveolar epithelial cells, while cell apoptosis was significantly reduced after administration of DEX.The expression of GRP78 mRNA and protein, JNK mRNA and p-JNK protein was significantly higher in OLV, AD and DEX+ AD groups than in Sham group, and lower in DEX-L and DEX-H groups than in OLV, AD and DEX+ AD groups. Conclusion DEX pretreatment can protect lungs during OLV, and inhibited JNK signaling pathway and reduced cell apoptosis induced by endoplasmic reticulum stress may be involved in the mechanism. Key words: Dexmedetomidine; Respiration, artifical; Endoplasmic reticulum; JNK mitogen-activated protein kinases; Apoptosis