PD-L1 Upregulation In Lung Epithelial Cells In COPD And The Hydrogen Intervention Research

[Background]In clinical practice,a high lung cancer prevalence is observed in chronic obstructive pulmonary disease(COPD)patients.However,the underlying connection between these two diseases still remains unclear.Therefore,research on the possible mechanism of this correlation will be helpful in the risk factors determination and prevention of lung cancer,the identification of susceptible populations,and the early disease monitoring and intervention.It has been reported that the overexpression of programmed death-ligand 1(PD-L1)is associated with risk of lung cancer initiation.PD-L1 is a transmembrane protein in epithelial cells,generally overexpressed in tumor cells and inhibits the functions of cytotoxic CD 8+T cells on tumor cells clearance by binding with programmed death 1(PD-1).The expression of PD-L1 is reportedly modulated by ERK1/2andSTAT1/3 axis.However,no study has yet delved into the presence of ERK1/2 or STAT1/3 signaling pathways regulating PD-L1 expression in the context of COPD pathogenesis.Hydrogen gas(H2)has anti-inflammatory,antioxidant,anti-tumor and signaling pathway modulating effects.H2 inhalation exhibited effects on improving COPD symptoms.However,it is inconclusive whether H2 inhalation affects pulmonary PD-L1 expression,especially on lung tissue PD-L1 expression in COPD patients.[Objectives]To investigate the altered expression of PD-L1 in lung epithelial cells of COPD animal models caused by cigarette smoke(CS)or motor vehicle exhaust(MVE)and to reveal its molecular mechanism,and to evaluate the effects of H2 inhalation on COPD treatment and PD-L1 expression in lung epithelial cells[Methods]In this study,we established COPD animal models in mice and rats by exposing to cigarette smoke(CS)or motor vehicle exhaust(MVE)with or without the assistance of LPS inhalation.The expressions of PD-L1 and phosphorylated ERK1/2 and STAT1/3 in COPD lung tissues were evaluated.The epithelial cells derived from human bronchial,BEAS-2B,were used to verified the PD-L1 expression changes upon cigarette smoke extract(CSE)or diesel-related particulate matter 2.5(PM2.5)treatments.Hydrogen gas(H2)inhalation exhibited effects on improving COPD symptoms.Here the effects of hydrogen gas inhalation on PD-L1 overexpression were evaluated.[Results]We successfully established COPD animal models,manifested by loss of body weights,lung functions decline,chronic lung inflammation and emphysema-like phenotypes.The activation of ERK1/2 and STAT1/3,and PD-L1 upregulations were found in COPD animals’ lung.In BEAS-2B cells,PD-L1 upregulation induced by CSE or PM2.5 were paralleled with proinflammatory cytokines production and could be abolished by ERK1/2orSTAT1/3 signaling inhibition.H2 inhalation inhibited activation of ERK1/2andSTAT1/3 axis and PD-L1 upregulation in COPD mice lung.[Conclusion]CS or MVE exposure cause upregulation of PD-L1 expression in airway epithelial cells associated with inflammatory responses,and the ERK1/2 and STAT1/3 pathways are involved in PD-L1 regulation.H2 were observed on relieving COPD symptoms and inhibiting PD-L1 upregulation,which might consequently reduce the lung cancer initiation risk in COPD patients.