Role of endogenous heme oxygenase-1/carbon monoxide signaling pathway in endoplasmic reticulum stress during endotoxin-induced acute lung injury in rats

Abstract

Objective To evaluate the role of endogenous heme oxygenase-1/carbon monoxide (HO-1/CO) signaling pathway in endoplasmic reticulum stress during endotoxin-induced acute lung injury(ALI) in rats. Methods Forty healthy clean-grade male Sprague-Dawley rats, aged 8 weeks, weighing 190-210 g, were divided into 4 groups (n=10 each) using a random number table method: control group (group C), ALI group, ALI plus ZnPP-IX group (group AZ), and ALI plus vehicle sodium bicarbonate group (group AV). ALI was induced by intravenously injecting lipopolysaccharide 5 mg/kg in anesthetized rats.At 30 min before establishing the model, ZnPP-IX 10 μmol/kg (diluted to 1 ml in 50 mmol/L sodium bicarbonate) was intraperitoneally injected in group AZ, and 50 mmol/L sodium bicarbonate 1 ml was intraperitoneally injected in group AV.After injecting lipopolysaccharide for 6 h, blood samples were collected from the common carotid artery for determination of plasma CO concentration, the rats were then sacrificed, and lungs were removed for microscopic examination of the pathological changes which were scored and for determination of CO level, wet to dry weight ratio (W/D ratio), cell apoptosis (by TUNEL), and expression of heme oxygenase-1 (HO-1), glucose-regulated protein 78 (GRP78), phosphorylated protein kinase R-like endoplasmie reticulum kinase (p-PERK), phosphorylated eukaryotic translation initiation factor 2 alpha (p-elF2), CCAAT/enhancer-binding protein homologous protein (CHOP) and caspase-12 in lung tissues (by Western blot). Apoptosis index (AI) was calculated. Results Compared with group C, the lung injury scores, W/D ratio, AI and CO levels in plasma and lung tissues were significantly increased, and the expression of HO-1, GRP78, p-PERK, p-elF2, CHOP and caspase-12 was up-regulated in the other three groups (P 0.05). Conclusion HO-1/CO signaling pathway produces endogenous protection possibly through inhibiting endoplasmic reticulum stress during endotoxin-induced ALI in rats. Key words: Heme oxygenase-1; Carbon monoxide; Endotoxins; Acute lung injury; Endoplasmic reticulum stress