Role Of P38MAPK And ERK1/2Signaling Pathway In The Regulation Of Heme Oxygenase-1Expression In The Lung Tissue During Endotoxic Shock Induced ALI In Rats

Endotoxic shock is a common symptom in clinical critical patients, which can cause multiple organ injury, especially common in acute lung injury, further may lead to acute respiratory distress syndrome. The pathogenesis of lung injury caused by endotoxin shock is very complicated. To explore the pathogenesis and treatment of reasonably and effectively is still a focus of research at home and abroad.We have previously demonstrated that the induction of HO-1in injured lung during endotoxic shock was increased and which can protected the lung from injured. And it is important to know its mechanism. P38MAPK and ERK1/2are two important signaling pathways among MAPKs family, which play an important role in differentiation and apoptosis of cells and inflammation. Studys have shown that HO-1was induced by various stimuli via activation of the ERK1/2signaling pathway in kidney cells. It has also been found that HO-1induction increased via P38mapk in vitro vascular smooth muscle cell.But there has not been reported whether P38MAPK and ERK1/2signaling pathways mediated the HO-1induction in injured lung during endotoxic shock.Part1:Effect of P38MAPK signaling pathway on the expression of heme oxygenase-1in the lung during endotoxic shock induced ALI in ratsObjective To investigate the effect of P38MAPK signaling pathway on expression of heme oxygenase-1(HO-1) on acute lung injury of endotoxic shock induced by lipopolysaccharide(LPS) in rats.Methods Forty-eight pathogen-free male SD rats weighing180g-200g were randomly divided into4groups (n=12each):Group Ⅰ sham operation (group C) Group Ⅱ endotoxic shock (group LS); Group Ⅲ endotoxic shock and S8203580(group LSS)and Group Ⅳ SB203680(group B). Rats in group C and group LS were administrated with DMSO0.1ml intravenously; Rats in Group LSS and group B were injected with the inhibitor of P38MAPK (SB203580) in0.1ml DMSO intravenously.30min later, Rats in Group C and group B received0.5ml normal saline intravenously while rats in group LS and group LSS received LPS10mg/kg in 0.5ml normal saline intravenously. Connected with arterial pressure monitor,if an initial25%decrease in mean arterial pressure, the model can be put to use. The lung injury degree was judged by microscopic examination and moisture content、SOD activity, MDA content. The P38MAPK protein and HO-1protein were measured by Western blot. HO-1mRNA level were measured by RT-PCR.Results Compared with group C, the SOD activity were significantly decreased, the pathological injury score,moisture content and MDA content were significantly increased,the expression of HO-1mRNA and protein and P38MAPK protein was significantly up-regulated in group LS and LSS, and no change was found in above indexes in group SB. Compared with group LS,the SOD activity were significantly increased, the pathological injury score,moisture content and MDA content were significantly decreased, the expression of HO-1mRNA and protein was significantly up-regulated, P38MAPK protein expression was down-regulated in group LSS.Conclusions The inhibition of P38MAPK signaling pathway can lead to the up-regulation of HO-1expression in lung tissue during endotoxic shock induced ALI in rats.Part2:Effect of ERK1/2signaling pathway on the expression of heme oxygenase-1in the lung during endotoxic shock induced ALI in ratsObjective To investigate the effect of ERK1/2signaling pathway on expression of HO-1on acute lung injury of endotoxic shock induced by lipopolysaccharide(LPS) in rats.Methods Forty-eight pathogen-free male SD rats weighing180g-200g were randomly divided into4groups (n=12each):Group Ⅰ sham operation (group S) Group Ⅱ endotoxic shock (group SS); Group Ⅲ endotoxic shock and PD98059(group SE)and Group Ⅳ PD98059(group E). Rats in group S and group SS were administrated with DMSO0.1ml intravenously; Rats in Group SE and group E were injected with the inhibitor of ERK1/2(PD98059) in0.1ml DMSO intravenously.30min later, Rats in Group S and group E received0.5ml normal saline intravenously while rats in group SS and group SE received LPS10mg/kg in0.5ml normal saline intravenously. Connected with arterial pressure monitor,if an initial25%decrease in mean arterial pressure, the model can be put to use. The lung injury degree was judged by microscopic examination and moisture content and MDA content, SOD activity. The ERK1/2protein and HO-1protein were measured by Western blot. HO-1mRNA level were measured by RT-PCR.Results The grade of the pathology,MDA content, moisture content in group SS were significantly higher than in group S and group E (P<0.05).but significantly lower than in group SE (P<0.05);The SOD activity in group SS were significantly lower than in group S and group E (P<0.05),but significantly higher than in group SE (P<0.05);ERKl/2protein and HO-1mRNA and HO-1protein in group SS were significantly higher than in group S, group SE and group E (P<0.05);And there were no significant difference in group S and group E among all the indexes(P>0.05).Conclusions Using the inhibitor of ERK1/2signaling pathway in endotoxic shock rats enhanced lung injury,and its mechanism may be related to decreased HO-1expression by inhibition of ERK1/2signaling pathway.