Researchers publishing in Aging Cell have described how treating the increased senescent cell burden that comes with cigarette smoke exposure can repair some of the damage.
Senescent cells and COPD
Chronic obstructive pulmonary disorder (COPD) and idiopathic pulmonary fibrosis (IPF), both of which are well-known consequences of regular exposure to cigarette smoke, have been associated with senescent cells [1]. Cellular senescence and cigarette smoke have been directly linked as well [2]. However, while the relationship between IPF and cellular senescence has been relatively well explained [3], COPD is less well-understood.
As p16 expression is strongly associated with cellular senescence in this context [2], this research team sought to learn more by employing a mouse model that has easily controllable and visible p16-expressing cells.
Smoking for mice
For this study, the researchers used both male and female mice between the ages of 4 and 12 months. These animals were obtained from Judith Campisi of the Buck Institute for Research on Aging.
One group was exposed to normal air, another group was exposed to a model of environmental tobacco smoke (ETS) to reflect second-hand smoke exposure, and a third group was exposed to cigarette smoke (CS). This smoke exposure lasted for two months. Five days before the end of the experiment, some mice from each group were administered ganciclovir (GCV), a known senolytic.
Many biomarkers are affected
As expected, CS and ETS strongly affected cellular senescence according to the p16 reporter mechanisms in these model mice. CS also significantly increased cellular senescence according to the well-known senescence biomarker SA-ß-gal. ETS also significantly increased the amount of nicotine metabolites.
Ganciclovir successfully reversed these senescence biomarkers, reducing them to non-significant levels between the treated mice and mice that had never been exposed to smoke. It also significantly restored biomarkers of mitochondrial function, suggesting that critical parts of energy transport were restored.
However, it could not reverse all of the effects of smoking. One consequence of cigarette smoke is neutrophil infiltration in the lungs. While five days of ganciclovir was able to slightly but significantly reduce this in younger mice, it had no significant effect in older mice. KC, a cytokine associated with neutrophils, was doubled by CS and reduced back to baseline levels by ganciclovir. Other biomarkers of inflammation were mostly unaffected.
Most critically, the changes to lung morphology caused by CS were largely reverted with ganciclovir, including unhealthy airspace enlargement. As before, young mice were better affected by this treatment than older mice were.
Positive but incomplete
This data shows many positive effects of senolytics in treating exposure to cigarette smoke and demonstrates that it has potential as a treatment. However, this was only still a mouse model, there was only two months of exposure and five days of treatment, and many of the experiments did not return significant results. In the future, removing or repairing senescent cells might be part, but only one part, of a complete treatment for smoking-induced COPD.
As always, the best treatment is prevention. If nothing else, experiments like this once again show that exposure to cigarette smoke is a very bad idea.
Literature
[1] Barnes, P. J., Baker, J., & Donnelly, L. E. (2019). Cellular senescence as a mechanism and target in chronic lung diseases. American journal of respiratory and critical care medicine, 200(5), 556-564.
[2] Cottage, C. T., Peterson, N., Kearley, J., Berlin, A., Xiong, X., Huntley, A., … & Lemaire, R. (2019). Targeting p16-induced senescence prevents cigarette smoke-induced emphysema by promoting IGF1/Akt1 signaling in mice. Communications Biology, 2(1), 307.
[3] Kellogg 3rd, D. L., Kellogg Jr, D. L., Musi, N., & Nambiar, A. M. (2021). Cellular senescence in idiopathic pulmonary fibrosis. Current Molecular Biology Reports, 7(3), 31-40.
