Cellular senescence and radiation-induced pulmonary fibrosis

Abstract

Radiation-induced pulmonary fibrosis (RIPF) is a serious treatment complication that affects about 9-30% cancer patients receiving radiotherapy for thoracic tumors. RIPF is characterized by progressive and irreversible destruction of lung tissues and deterioration of lung function, which can compromise quality of life and eventually lead to respiratory failure and death. Unfortunately, the mechanisms by which radiation causes RIPF have not been well established nor has an effective treatment for RIPF been developed. Recently, an increasing body of evidence suggests that induction of senescence by radiation may play an important role in RIPF and clearance of senescent cells (SnCs) with a senolytic agent, small molecule that can selectively kill SnCs, has the potential to be developed as a novel therapeutic strategy for RIPF. This review discusses some of these new findings to promote further study on the role of cellular senescence in RIPF and the development of senolytic therapeutics for RIPF.

Activation of p21 limits acute lung injury and induces early senescence after acid aspiration and mechanical ventilation

“… 35 Therefore, main features of abnormal lung repair after acute injury (limited cell proliferation, chronic inflammation and fibrosis) could be explained by a persistent senescent response. 36 Inhibition of this response by selective deletion of Tp53 in Club cells ameliorated lung damage related to chronic inflammation, 33 suggesting a novel mechanism amenable to treatment of lung diseases.…”

Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies

“…Another way in which senescence may be a clinically important part of radiotherapy response is in causing radiation-induced fibrosis. This can be a potentially severe complication of radiotherapy, especially in the lung where pulmonary fibrosis may occur [ 74 ]. Senescent cells also appear to be linked to skin fibrosis and ulceration following radiotherapy [ 75 ].…”

Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

“…SnCs exert their deleterious effects in part via a senescence‐associated secretory phenotype (SASP) (Tchkonia, Zhu, Deursen, Campisi, & Kirkland, ). Therefore, selectively clearing SnCs and suppressing the SASP have emerged as attractive therapeutic strategies to extend health span (Baker et al, ), treat age‐related diseases (Baker et al, ; Childs et al, ; Jeon et al, ), and ameliorate chemotherapy‐induced toxicity (Demaria et al, ; He et al, ). However, SnCs are resistant to the induction of programmed cell death (apoptosis) (Marcotte, Lacelle, & Wang, ).…”