Effect of extracellular signal-regulated kinases signaling pathway on the expression of heme oxygenase-1 in the lung during endotoxic shock in rats

Abstract

Objective To investigate the effects of extracellular signal-regulated kinases (ERK1/2) signaling pathway on the expression of heme oxygenase-1 (HO-1) in acute lung injury of endotoxic shock induced by lipopolysaccharide (LPS) in rats.Methods Forty-eight pathogen-free male SD rats weighing 180 g-200 g were randomly divided into 4 groups (n=12 each):sham operation group (group S),endotoxic shock group (group SS),endotoxic shock and PD98059 group (group SE) and PD98059 group (group E).Rats in group S and group SS were administrated with DMSO 0.1 ml intravenously.Rats in Group SE and group E were injected with the inhibitor of ERK1/2 (PD98059) in 0.1 ml DMSO intravenously.30 min later,rats in Group S and group E received 0.5 ml normal saline intravenously while rats in group SS and group SE received LPS 10 mg/kg in 0.5 ml normal saline intravenously.The invasive arterial pressure was monitored,if there was an initial 25％ decrease in mean arterial pressure,then the model can be put to use.The lung injury degree was judged by microscopic examination,moisture content,malondialdehyde (MDA) content and superoxide dismutase (SOD) activity.The ERK1/2 protein,p-ERK1/2 protein and HO-1 protein were measured by Western blot.HO-1 mRNA level were measured by RT-PCR.Results The grade of the pathology (4.5 ±2.1),MDA content (3.12±1.30) nmol/mg,moisture content(81±6)％ in group SS were significantly higher than that in group S (2.0±1.0),(78±5)％,(1.79±0.12) nmol/mgand group E (2.1±1.1),(77±4)％,(1.83±-0.20) nmol/mg,(P＜0.05).But significantly lower than that in group SE(6.4±1.3),(87±5)％,(4.62±0.92) nmol/mg (P＜0.05).The SOD activity in group SS (20.2±2.4) NU/mg were significantly lower than that in group S (30.9± 2.9) NU/mgand group E (32.2±1.2) NU/mg(P＜0.05),but significantly higher than that in group SE(14.9±3.2) NU/mg(P＜0.05).ERK1/2 protein (0.43±0.09) and p-ERK1/2 protein (1.46 ±0.22),HO-1mRNA (1.834± 0.023) and HO-1 protein (1.17± 0.25) in group SS were significantly higher than that in group S,group SE and group E (P＜0.05).And there were no significant difference in group S and group P among all the indexes (P＞0.05).Conclusions Using the inhibitor of ERK1/2 signaling pathway in endotoxic shock rats worsened lung injury,and its mechanism may be related to decreased HO-1 expression by inhibition of ERK1/2 signaling pathway. Key words: Extracellular signal-regulated kinases; Endotoxic shock; Lung; Heme oxygenase-1