SIRT1 Regulates Nrf2/HO-1 Signaling Pathway In Sepsis-induced Acute Lung Injury

Objective : To investigate whether silence information regulator 1(SIRT1)could regulate nuclear factor E2 related factor 2(Nrf2)/ heme oxygenase-1(HO-1)signaling pathway and its role in acute lung injury(ALI)in sepsis rats.Methods:Twenty-four male SD rats were randomly divided into sham operation group(Sham group),cecal ligation and puncture group(CLP group),CLP + SIRT1 specific agonist group(CLP+SRT1720group),CLP + SIRT1 specific inhibitor group(CLP+EX527 group),with 6 rats in each group,10mg/kg SRT1720 and EX527 were intraperitoneally injected 2 hours before CLP.The rats were killed 24 hours after modeling and their lung tissues were taken.The pathological changes of lung tissues were observed under light microscope and the pathological score of lung tissues(Smith score)was calculated.The activity of superoxide dismutase(SOD),the content of reduced glutathione(GSH),malondialdehyde(MDA)and8-hydroxydeoxyguanosine(8-OHd G)in lung tissues were detected;ELISA was used to detect tumor necrosis factor alpha(TNF-α),interleukin-6(IL-6),interleukin-1β(IL-1β);Western Blotting was used to detect the levels of SIRT1,Nrf2 and HO-1 in rat lung tissue;The m RNA expression of SIRT1,Nrf2 and HO-1 was detected by real-time quantitative polymerase chain reaction(RT-q PCR).Results : Compared with the Sham group,the alveolar structure of the CLP group was severely damaged,the alveolar interval was widened,a large number of inflammatory cells infiltrated into the alveolar cavity,and there was hyperemia in the pulmonary capillary,and the lung injury score were significantly increased(all P<0.05).The levels of IL-6 and IL-1β were significantly increased(all P<0.05),SOD activity and GSH content decreased,the content of MDA and 8-OHd G increased(all P<0.05);the m RNA and protein expressions of SIRT1,Nrf2 and HO-1 in lung tissue were decreased(all P<0.05).Compared with the CLP group,the lung tissue damage in the CLP+SRT1720 group was significantly relieved,and the specific manifestations were: Smith score and lung tissue TNF-α,IL-6,and IL-1β levels were significantly decreased(all P<0.05),SOD activity and GSH content increased,MDA and 8-OHd G contents decreased(all P<0.05),the m RNA and protein expressions of SIRT1,Nrf2 and HO-1 in lung tissue were Increased(all P<0.05);while the CLP+EX527group had significantly aggravated lung tissue damage,specifically: Smith score And lung tissue TNF-α,IL-6,IL-1β levels were significantly increased(all P<0.05),SOD activity and GSH content decreased,the contents of MDA and 8-OHd G were increased(all P<0.05),the m RNA and protein expressions of SIRT1,Nrf2 and HO-1 in lung tissue were decreased(all P<0.05).Conclusion:In the rat model of acute lung injury by sepsis,SIRT1 can be activated to regulate the activation of Nrf2/HO-1 signaling pathway,upregulate the expression of downstream antioxidant enzymes,reduce oxidative stress injury,and then alleviate the ALI induced by sepsis in rats.