Senescent Cells Mediate Much of the Pulmonary Dysfunction Generated by Smoking

Cells become senescent in response to a toxic, damaging environment. This is a first line of defense against the possibility of cancer. Senescent cells cease replication and begin to secrete a potent inflammatory mix of signals that usually serves to attract immune cells to destroy them, if they don't manage to self-destruct via their own programmed cell death processes. Unfortunately, the immune system becomes ever less functional with age, and thus lingering senescent cells will accumulate in ever greater numbers. This is probably why many of the progressive lung conditions arising from a toxic environment, such as that produced by smoking, tend to arise at a later age.

Researchers here show that a sizable fraction of the pulmonary dysfunction arising from smoking is mediated by the actions of senescent cells in lung tissue, which in turn suggests that senolytic therapies presently under development for age-related diseases will greatly reduce the consequences of smoking and other forms of particulate exposure. Not that is will ever make it smart to stab yourself repeatedly, just because you know that hospital staff can patch up the injury.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States, and can be characterized as a disease of accelerated pulmonary aging. Characteristics of COPD include inflammation, tissue remodeling, and emphysematous alveolar destruction, leading to enlarged air spaces with less surface area capable of gas exchange. Lung exposure to contaminants and pollutants are risk factors for COPD, including cigarette smoking (CS). Aside from smoking cessation, no therapeutic intervention has been identified and research continues to investigate the molecular mechanisms driving disease progression.

Many of the pathological processes identified in COPD are mediated by CS, including altered homeostatic apoptosis proliferation, production of extracellular matrix (ECM)-degrading proteases and oxidative stress, as well as telomere dysfunction, leading to the activation of the DNA damage response pathway and ultimately cellular senescence. Senescent cells produce and secrete numerous harmful pro-inflammatory and degrading mediators, collectively called the senescence-associated secretory phenotype (SASP). SASP proteins have been shown to be upregulated in pathologies related to accelerated aging and are known to perpetuate inflammation and tissue remodeling in COPD. Development of effective therapeutics to combat senescent cells may provide clinical benefit.

A universal marker for cell senescence does not exist but most senescent cells express p16 (p16ink4A), a cell cycle inhibitor that targets cyclin-dependent kinases (CDKs) and is important in wound healing and tumor suppression. Removal of p16+ senescent cells has been shown to be an efficient way of extending healthspan and reversing senescence-associated pathologies. In the current study, we hypothesized that p16 plays a role in the pathological processes associated with smoking and COPD, and that deletion of p16 protects the lung from the development of emphysematous-like tissue remodeling. We examined human lung tissue from COPD patients and normal control subjects, and found a substantial increase in p16-expressing alveolar cells in COPD patients. Using a transgenic mouse deficient for p16, we demonstrated that lungs of mice lacking p16 were structurally and functionally resistant to CS-induced emphysema due to activation of IGF1/Akt regenerative and protective signaling.