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.
Highlights
Aging is defined as a result of the progressive breakdown of tissues and organs, an imbalance in physiological processes, and a reduced response to environmental challenges[1]
These results show that the characteristic of aging itself is involved in lung cellular senescence, but does not increase the susceptibility of cigarette smoke (CS)-induced lung cellular senescence in a mouse model of chronic obstructive pulmonary disease (COPD)
It has been proposed that the pathology of COPD is associated with accelerated lung aging[1,6,28,29]
Summary
Aging is defined as a result of the progressive breakdown of tissues and organs, an imbalance in physiological processes, and a reduced response to environmental challenges[1]. Normalized nanoString mRNA counts were used to represent selected genes from the cellular senescence and aging panel that was differentially expressed among younger and older chronic air and CS-exposed mouse lungs. Cytokine array analysis showed a significant increase in IL-1ra and MCP-1 release in BAL fluid of CS-exposed younger and older mice as compared to their respective air-exposed controls.
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