Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Abstract

Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly COPD and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16 INK4a respectively, leading to activation of p21 CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype (SASP), leading to low grade chronic inflammation, which further drives senescence. Loss of key anti-aging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN, thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a, which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6 and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing SASP and reversing cell cycle arrest in epithelial cells from peripheral airways of COPD patients. MiR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 MAP kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.

Monocyte-derived Prostaglandin E2 inhibits antigen-specific cutaneous immunity during ageing

“…Relevant to our current observations, it has been shown that senescent cells increase in the 569 lungs with age-dependent pathology (Barnes et al, 2019) and it will be important to 570 understand if these cells are involved with the recruitment of these inflammatory monocytes 571 in patients with severe COVID-19 infection. Although CCR2 + monocytes can contribute to the 572 inflammatory environment in the skin, they are also actively involved in the resolution of 573 inflammation, for example in in the gut (Farro et al, 2017).…”

Animal Models Reflecting Chronic Obstructive Pulmonary Disease and Related Respiratory Disorders: Translating Pre-Clinical Data into Clinical Relevance

“…Evidence suggests emphysema is caused by accelerated ageing of lung tissues and is associated with flawed endogenous antiageing (sirtuins) and autophagy mechanisms [106][107][108]. This process leads to eventual telomere shortening, cellular senescence, and the development of COPD [109,110]. Oxidative stress is another key driver of COPD pathogenesis.…”

COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

“…Accumulating evidence shows that senescence accelerates the progression of a variety of diseases, such as atherosclerosis, neurodegeneration venereal diseases, and PF . Especially, cellular senescence is considered as an important driving mechanism for chronic lung diseases . At present, it is reasonable to believe that abnormalities in the process of the alveolar epithelial cell (AEC) injury and repair play a critical role in the genesis and development of PF .…”