期刊
FRONTIERS IN PHARMACOLOGY
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2020.584637
关键词
mitochondria; cellular senescence; telomere; DNA damage; aging; smokers; idiopathic pulmonary fibrosis; chronic obstructive pulmonary diseases
资金
- NIH [R01 HL1377380, R01 HL135613, R01 ES 029177]
- University of Rochester CTSA of the NIH [UL1 TR002001]
Background Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Here, we determined how aging contributes to the altered gene expression related to mitochondrial function, cellular senescence, and telomeric length processes that play an important role in the progression of COPD and idiopathic pulmonary fibrosis (IPF). Methods Total RNA from the human lung tissues of non-smokers, smokers, and patients with COPD and IPF were processed and analyzed using a Nanostring platform based on their ages (younger: 55 years). Results Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1,FEN1,COX18,COX10,UCP2 & 3), cellular senescence (PCNA,PTEN,KLOTHO,CDKN1C,TNKS2,NFATC1 & 2,GADD45A), and telomere replication/maintenance (PARP1,SIRT6,NBN,TERT,RAD17,SLX4,HAT1) target genes. Interestingly,NOX4andTNKS2were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and quality control mechanisms likeFIS1andRHOT2were decreased in young IPF compared to their age matched COPD subjects. ERCC1 andGADD45Bwere higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases including the SARS-CoV-2 infection. Lung immunoblot analysis of smokers, COPD and IPF subjects revealed increased abundance of proteases and receptor/spike protein like TMPRSS2, furin, and DPP4 in association with a slight increase in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor ACE2 levels. Conclusions Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition in the pathobiology of lung aging in COPD and IPF is associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis as pharmacological targets for COVID-19.
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