Increased TXNIP Mediates Bronchial Epithelial Cell Senescence In Chronic Obstructive Pulmonary Disease

【Background】Accelerated aging and increased cellular senescence occur in the lungs of chronic obstructive pulmonary disease(COPD)patients and contributes to disease pathogenesis.The mechanisms of senescence in COPD have not been elucidated.Thioredoxin interacting protein(TXNIP)is an essential intracellular regulator of redox signaling and involved in the regulation of oxidative stress,inflammation,apoptosis and autophagy.Recently,TXNIP has been reported to be upregulated in senescent cells and organs,revealing a potential role in the pathogenesis of COPD and other age-related diseases.【Objective】To investigate the expression of TXNIP in COPD lungs and elucidate its role in cigarette smoke extract(CSE)-induced airway epithelial cell senescence and cellular dysfunction.【Methods】Immunohistochemical(IHC)staining and Western blotting(WB)were performed to examine TXNIP expression and cellular senescence in resected lungs from COPD patients.The effects of CSE and oxidative stress on TXNIP expression were studied in primary human bronchial epithelial cells(HBEC)and in a ozone-exposed mouse model.The effects of TXNIP overexpression and knockdown on CSE-induced airway epithelial cellular senescence,inflammation,autophagy and epithelial dysfunction ex vivo was examined.Pharmacological inhibitors of autophagic flux(chloroquine)and autophagy(Wortmannin)were used to to assess the role of TXNIP in regulating autophagy upstream of cellular senescence.【 Results 】 TXNIP is increased and accompanied with cellular senescence in airway epithelium of COPD patients.CSE-induced TXNIP expression was attenuated by N-acetylcysteine treatment in HBEC.Ozone-induced oxidative stress also enhanced airway epithelial TXNIP expression of mice in vivo.TXNIP knockdown protected against CSE-evoked senescence,autophagy and theproduction of inflammatory mediators(interleukin(IL)-8,tumor necrosis factor(TNF)-α and IL-1β).TXNIP overexpression enhanced the senescent phenotype leading to epithelial cell growth arrest and loss of epithelial barrier function.Autophagy was induced by CSE exposure of HBEC as indicated by increased LC3B-II and p62 levels and was prevented by TXNIP gene silencing.LC3B-II expression decreased in TXNIP knockdown cells and increased in TXNIP-overexpressing cells after treatment with chloroquine.LC3 B puncta immunostaining and blue staining of MDC also enhanced in TXNIP-overexpressing cells upon chloroquine treatment.Moreover,TXNIP-induced cellular senescence was normalized by the treatment of Wortmannin,an inhibitor of autophagy.【Conclusion】Increased epithelial TXNIP expression induced by oxidative stress of cigarette smoking regulates autophagy and promotes senescence,highlighting the critical role of airway epithelial cell senescence in COPD pathogenesis.