Role of extracellular regulated kinase pathway in the lipopolysaccharide-induced acute lung injury in rat

Abstract

bjective To investigate the role of extracellular signal-regulated kinases（ERK） signal pathway in the lipopolysaccharide（LPS）-induced acute lung injury（ALI） in rats. Methods One hundred and twenty male SD rats were randomly divided into four groups（n=30）： Saline group, LPS group, LSP＋U group and Saline＋U group. Each group was divided into five subgroups at 1, 3, 6, 12 h and 24 h time point respectively. Western blot was used to detect the expression of phosphorylation of ERK1/2 and high-mobility group box 1（HMGB-1） in lung tissues, nuclear factor-κB（NF-κB）p65 in the nuclear extracts, which reflected the extent of lung injury. Additionally we examined the concentration of tumor necrosis factor（TNF）-α, interleukin（IL）-10 and inducible nitric oxide synthase（iNOS） in bronchoalveolar lavage fluid（BALF）, the lung water content and the histopathologic changes of lung. In addition, survival rate was investigated between LPS group and LSP＋U group,and each group with other 10 rats. Results With the administration of LPS, the phospho？蛳ERK1/2 substantially increased immediately and subsequently the expression of NF？蛳κB in the nuclear extracts was increased significantly and reached its peak level at 3 h and 12 h. Moreover, HMGB-1, one of the key mediators in the development of sepsis increased significantly after LPS administration. The concentrations of TNF？蛳α,iNOS and IL-10 were also increased. Pathological examination showed that the normal structure of lung was destroyed badly after LPS injection. U0126 effectively inhibited the activation of ERK1/2, blocked LPS-induced NF-κB activation and HMGB-1 expression in lung tissue, reduced the lung water content[（4.59±0.51） vs （5.19±0.10）, P〈0.05], the concentration of TNF-α, iNOS and IL-10[TNF-α, reached a peak at 3 h,（28±3） vs （70±10）（P〈0.05）. iNOS, reached a peak at 12 h, （7 771±957） vs （10 679±1 641）,P〈0.05. IL-10,reached a peak at 6 h,（59±10） vs（91±11）, P〈0.05], and prevented LPS-induced lung injury. Conclusions ERK1/2 plays an important role in the development of LPS-induced ALI, and the activation of ERK1/2 may be one of the mechanisms of LPS-induced ALI. Key words: Extracellular signal-regulated kinases; Nuclear factor-κB; Acute lung injury; Tumor necrosis factor-α; Interleukin-10; Inducible nitric oxide synthase; Lipopolysaccharide