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Lung cellular senescence is independent of aging in a mouse model of COPD/emphysema.

ABSTRACT: Cigarette smoke (CS) induces lung cellular senescence that plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). How aging influences cellular senescence and other molecular hallmarks, and increases the risk of CS-induced damage remains unknown. We hypothesized that aging-associated changes in lungs worsen the COPD/emphysema by CS exposure. Younger and older groups of C57BL/6J mice were exposed to chronic CS for 6 months with respective age-matched air-exposed controls. CS caused a decline in lung function and affected the lung structure of both groups of mice. No alterations were observed in the induction of inflammatory mediators between the air-exposed younger and older controls, but aging increased the severity of CS-induced lung inflammation. Aging per se increased lung cellular senescence and significant changes in damage-associated molecular patterns marker S100A8. Gene transcript analysis using the nanoString nCounter showed a significant upregulation of key pro-senescence targets by CS (Mmp12, Ccl2, Cdkn2a, Tert, Wrn, and Bub1b). Aging independently influenced lung function and structure, as well as increased susceptibility to CS-induced inflammation in emphysema, but had a negligible effect on cellular senescence. Thus, aging solely does not contribute to the induction of cellular senescence by CS in a mouse model of COPD/emphysema.

SUBMITTER: Rashid K

PROVIDER: S-EPMC5998122 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Lung cellular senescence is independent of aging in a mouse model of COPD/emphysema.

Rashid Kahkashan K Sundar Isaac K IK Gerloff Janice J Li Dongmei D Rahman Irfan I

Scientific reports 20180613 1

Cigarette smoke (CS) induces lung cellular senescence that plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). How aging influences cellular senescence and other molecular hallmarks, and increases the risk of CS-induced damage remains unknown. We hypothesized that aging-associated changes in lungs worsen the COPD/emphysema by CS exposure. Younger and older groups of C57BL/6J mice were exposed to chronic CS for 6 months with respective age-matched air-expo ...[more]

PMID: 29899396

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Project description:BackgroundThe aging lung is a complex process and influenced by various stressors, especially airborne pathogens and xenobiotics. Additionally, a lifetime exposure to antigens results in structural and functional changes of the lung; yet an understanding of the cell type specific responses remains elusive. To gain insight into age-related changes in lung function and inflammaging, we evaluated 89 mouse and 414 individual human lung genomic data sets with a focus on genes mechanistically linked to extracellular matrix (ECM), cellular senescence, immune response and pulmonary surfactant, and we interrogated single cell RNAseq data to fingerprint cell type specific changes.ResultsWe identified 117 and 68 mouse and human genes linked to ECM remodeling which accounted for 46% and 27%, respectively of all ECM coding genes. Furthermore, we identified 73 and 31 mouse and human genes linked to cellular senescence, and the majority code for the senescence associated secretory phenotype. These cytokines, chemokines and growth factors are primarily secreted by macrophages and fibroblasts. Single-cell RNAseq data confirmed age-related induced expression of marker genes of macrophages, neutrophil, eosinophil, dendritic, NK-, CD4+, CD8+-T and B cells in the lung of aged mice. This included the highly significant regulation of 20 genes coding for the CD3-T-cell receptor complex. Conversely, for the human lung we primarily observed macrophage and CD4+ and CD8+ marker genes as changed with age. Additionally, we noted an age-related induced expression of marker genes for mouse basal, ciliated, club and goblet cells, while for the human lung, fibroblasts and myofibroblasts marker genes increased with age. Therefore, we infer a change in cellular activity of these cell types with age. Furthermore, we identified predominantly repressed expression of surfactant coding genes, especially the surfactant transporter Abca3, thus highlighting remodeling of surfactant lipids with implications for the production of inflammatory lipids and immune response.ConclusionWe report the genomic landscape of the aging lung and provide a rationale for its growing stiffness and age-related inflammation. By comparing the mouse and human pulmonary genome, we identified important differences between the two species and highlight the complex interplay of inflammaging, senescence and the link to ECM remodeling in healthy but aged individuals.

Dataset Information

Lung cellular senescence is independent of aging in a mouse model of COPD/emphysema.

Publications

Lung cellular senescence is independent of aging in a mouse model of COPD/emphysema.

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