SRT2104 Protects Against Cigarette Smoke-Induced Premature Senescence In Mice Via SIRT1 Signaling Pathway

Objective The purpose of this study is to investigate whether SIRT1 selective against SRT2104 can protect the senescence of mouse alveolar epithelial cells in the model of cigarette smoke induced emphysema,reveal the senescence mechanism of promoting the development of COPD,and provide a new drug target for the treatment of COPD.Methods Clean male C57 BL / 6J and Sirt1-deficient heterozygous /haploinsufficient C57 BL / 6J mice were randomly divided into six groups: group A1,C57 BL / 6J mice control group;group A2,C57 BL / 6J mice emphysema model group;group A3,C57BL/ 6J mice emphysema model + SRT2104;group B1,Sirt1-deficient heterozygous /haploinsufficient control group;group B2,Sirt1-deficient heterozygous/haploinsufficient emphysema model group;group B3,Sirt1-deficient heterozygous mice lung Emphysema model + SRT2104 group.The model of emphysema in mice was established by passive smoking method.The lung histopathology of mice in each group was measured.SIRT1,p53,FOXO3 a,p21,MMP-9 and TIMP-1 m RNA expression levels were detected by q RT-PCR.The expression levels of SIRT1,p53,FOXO3 a,p21,MMP-9 and TIMP-1 protein in lung tissue of mice were analyzed by blotting and immunohistochemistry,and the activity of SA β-galactosidase(SA β-gal)in lung tissue of mice in each group was detected.Results Compared with group A1 and B1,group A2 and group B2,the alveoli cavity of mice were enlarged,part of alveoli were fused,the number of alveoli was decreased,the capillary of alveoli septum was congested and the infiltration of focal lymphocytes and plasma cells was consistent with the pathological changes of emphysema.Compared with group A2,the number of alveoli in group A3 increased,inflammatory cells decreased,and lung tissue damage was significantly reduced;group B3 was less inflammatory than group B2,but the alveoli cavity was still significantly enlarged.The results of immunohistochemistry,QRT PCR and Western blot showed that the expression of SIRT1,FOXO3 a and TIMP-1 in lung tissue of smoking induced emphysema mice was significantly lower than that of the control group(P < 0.05),while the expression of p53,p21 and MMP-9 was significantly higher(P < 0.05).After srt2104 treatment,compared with SIRT1 knockout mice,there was no significant change in the expression of FOXO3 a,p53,p21 and MMP-9 m RNA in the lung tissue of srt2104 treated mice(P > 0.05),but the expression of TIMP-1 m RNA was significantly increased(P < 0.05).Compared with the normal control group,the activity of SA-βgal in lung tissue of smoking induced emphysematous mice increased significantly(P <0.05),and the activity of SA-β gal in lung tissue of srt2104 treated emphysematous mice decreased significantly(P < 0.05).The activity of SA-β gal in lung tissue of SIRT1 knockout mice was also significantly increased(P < 0.05).After srt2104 treatment,there was no significant change in SA-β gal activity in lung tissue of SIRT1 knockout mice(P > 0.05).Conclusion SIRT1 selective against srt2104 may reduce the lung tissue damage induced by smoking through SIRT1 / FOXO3 a and SIRT1 / p53 signaling pathway,but it can not delay the development of pulmonary emphysema in SIRT1 specific knockout mice.