The Effect Of PI3K/Akt/Nrf2 Signaling Pathway In Endotoxin-induced Acute Lung Injury In Rabbits

The effect of PI3K/Akt/Nrf2 signaling pathway in endotoxin-induced acute lung injury in rabbitsWe all know that Endotoxic shock often cause multiple organ dysfunctions,and the lung is one of the most commonly involved organs,which can be led to ALI,or ARDS,Up to now,It is not yet completely clear that the mechanism of ALI induced by endotoxic shock and complicated etiology.Therefore,it is very important to clarify the pathogenesis of lung injury induced by endotoxin shock and to find a reasonable and effective treatment.PI3 K,a lipid kinase that exists in mammalian cells,is a member that can recruit and activate the downstream signaling protein,of which can launched to expand the cascade reaction[1].Akt,a kind of serine / threonine protein kinase,is a molecular mass of 60000,a s an important downstream target protein of P13 K signal pathway,PKB [2].Nrf2/ARE signaling pathway is an important endogenous antioxidant stress pathway.According to Research Report,Nrf2 and many other alpha signaling pathways,for example,PI3K/AKT,PKC,MAPK,involved in the activation.and those can cause the dissociation from the Keapl,promotion its nuclear translocation,recognization and binding the antioxidant response element.As a result,regulating gene expression happen in the end [3,4].HO-1 is an important protein in the regulation of Nrf2/ARE pathway.It is confirmed that HO-1 Nrf2/ pathway has an protective effect on endotoxin organ damage in the role of transcription factor with endogenous.Akt/Nrf2/P13 K signaling pathway,which is one of the important pathways for promoting cell survival,can promote cell proliferation,inhibit apoptosis,and participate in the reorganization of the cytoskeleton and other functions[5].Objective To investigate the effect of PI3K/Akt/Nrf2 signal transduction pathway in acute lung injury in rabbits.Methods Fifty healthy male New Zealand white rabbits,weighing 1.5-2.0 kg,aged 2 months,were randomly divided into 5 groups(n=10/ each): normal control group(Group C),endotoxic shock group(Group L),wortmannin group(Group W),dimethyl sulfoxide(DMSO)group(Group D),wortmannin+ endotoxic shock group(WL).Group C and group L were injected with 0.08ml/kg 0.9% sodium chloride,W group and WL group were injected with 0.6 w ortmannin mg/kgvia auricular vein(dissolved in0.08ml/kg DMSO).The group D was injected with DMSO with the concentration of 0.08ml/ kg.30 min later,LPS 5 mg/kg was injected intravenously in groups L and WL,while the equal amount of normal saline was administered in group C,W and D.The rabbits were sacrificed by bloodletting at 6 hours after LPS or normal saline injection.Blood sample(4ml)was collected and the lung tissue was taken for the examination.Then,We evaluate the pathological changes of lung tissue,determinate lung W/D ratio,serum levels of TNF-? and IL-10 concentration,the activities of SOD and the contents of MDA,and detect the expressions of p-Akt protein,HO-1 protein,Nrf2 nuclear and total protein,as well as HO-1 m RNA and Nrf2 m RNA expressions.Results Compared with group C,W/D ratio,l ung injury scores,serum TNF-?concentration,IL-10 concentration and MDA contents were increased,the expressions of p-Akt protein,HO-1 protein,Nrf2 nuclear and total protein,Nrf2 m RNA and HO-1 m RNA were up-regulated,while SOD activities were decreased in group L and WL(both P<0.05).No significant difference w as found in the parameters mentioned above in groups D and W(both P>0.05).Compared with group L,lung injury scores,W/D ratio,serum TNF-?concentration and MDA contents were increased,while IL-10 concentration and SOD activities were decreased,the expressions of p-Akt protein,HO-1 protein,Nrf2 nuclear and total protein,HO-1 m RNA and Nrf2 m RNA were significantly down-regulated in group WL(both P<0.05).Conclusion The activation of PI3 K / Akt / Nrf2 signaling pathway can reduce the acute lung injury induced by endotoxic shock in rabbits.It may be caused by the activation of this signaling pathway or up-regulation of HO-1 gene transcription or expression to enhance endogenous antioxidant Injury.Perhaps it is one of the mechanisms of endotoxin-induced acute lung injury...