Zhu Y, Doornebal EJ, Pirtskhalava T, et al

Zhu Y, Doornebal EJ, Pirtskhalava T, et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. to be developed as a novel therapeutic strategy for RIPF. This review discusses some of these new findings to promote further study around the role of cellular senescence in RIPF and the development of senolytic therapeutics for RIPF. Introduction Thoracic radiotherapy (RT) is an WM-8014 essential treatment modality for lung, breast and esophageal cancers, and various mediastinal tumors. Despite the increasing use of highly conformal RT techniques, many patients treated with thoracic RT remain at risk of developing radiation-induced pulmonary fibrosis (RIPF).1C3 The necessity of avoiding pneumonitis and RIPF limits the dose and intensity of irradiation and thus reduces the efficacy of RT. In addition, RIPF is usually a latent disease that may occur several years after exposure to ionizing radiation (IR). Therefore, long-term malignancy survivors who were previously treated with standard RT or preconditioned with total body irradiation (TBI) for bone marrow transplantation are still at risk to develop RIPF. However, RIPF is not a universal end result of RT and there is no reliable prognosticator to predict which patients are at risk of developing RIPF after thoracic RT. Treating all patients after thoracic RT with a radiation protectant/mitigator to WM-8014 prevent and mitigate RIPF would unnecessarily expose a tremendous number of patients to the risk of drug toxicity and incur great cost. Furthermore, RIPF is usually insidious and most patients with RIPF have a significant fibrotic burden at the time of clinical presentation, limiting treatment to mitigants that would likely only slow the progression of RIPF. Currently, pirfenidone and nintedanib are the only drugs that have been approved to treat idiopathic pulmonary fibrosis (IPF) but their effectiveness against RIPF has yet to be decided.4,5 In addition, there is no therapeutics that can halt or reverse the disease progression of IPF and RIPF. Without an effective treatment, RIPF can continue progressing to chronic pulmonary insufficiency that not only affects the quality of life but may eventually lead to or death. Therefore, new strategies that can quit and even reverse the WM-8014 course of the disease are urgently needed. An accumulating body of evidence suggests that induction of senescence by radiation may play an important role in RIPF and clearance WM-8014 of senescent cells (SnCs) with senolytic brokers, a class of small molecules that can selectively kill SnCs has the potential to be developed as a novel therapeutic strategy for RIPF.6,7 Therefore, in this evaluate we discuss some of these new findings to promote further study around the role of cellular senescence in RIPF and the development of senolytic therapeutics for RIPF. RIPF RIPF is usually a late effect of radiation around the lungs.8 It evolves in the third phase of RT-induced lung tissue damage. The first phase is usually asymptomatic. The second phase, called the radiation-induced IgM Isotype Control antibody (APC) pneumonitis, occurs within a few weeks up to several months after radiation, resulting in a noninfectious inflammation of the lungs. Although post-radiation pneumonitis is usually often radiographically obvious and asymptomatic, in some patients, it WM-8014 may progress to oxygen dependence, requirement for mechanical ventilation, respiratory failure, and, in some cases, death. With or without anti-inflammatory treatment, most patients can recover from radiation-induced pneumonitis but some may proceed to the third phase, i.e. fibrotic phase, which is usually characterized by progressive and irreversible pulmonary fibrosis that causes destruction of lung tissues and deterioration of lung function and eventually results in respiratory failure and death.2 Extensive efforts have been devoted to elucidate the mechanisms by which IR induces RIPF. The suggested mechanisms include increased production of reactive oxygen species (ROS), induction of chronic inflammation, activation of the TGF- signaling pathway, and dysregulation of extracellular matrix degradation.6 However, therapeutics targeting each of these individual causes of RIPF have some effects on preventing and mitigating the disease but have limited effectiveness in retarding and reversing the progression of the disease if they cannot be given to patients before or shortly after RT. The lack of an effective.

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