Radiotherapy is used in more than half of all cancer patients, both for curative and palliative purposes [
66]. Although modern and precise radiotherapy techniques substantially improved the delivery of energy (summarized as ionizing radiation) in the form of electromagnetic waves (gamma- or X-rays) or particles (neutrons, beta or alpha) used for cancer eradication, damage healthy cells and can lead to severe early and late complications in the tumor microenvironment with an increased risk of morbidity in patients after radiotherapy (RT) [
67]. Radiation-induced lung disease (inflammation and fibrosis) is a major hurdle in the successful treatment of thorax-associated tumors [
68,
69]. Radiation-induced pulmonary fibrosis affects up to 25% of cancer patients receiving radiotherapy to tumors of the thoracic region [
70]. The radiosensitivity of lung tissue is also dose-limiting when the whole body is irradiated prior bone marrow transplantation [
71,
72]. The mechanism of radiation-induced normal tissue damage, however, is not fully understood; no causal strategy for the prevention or treatment of radiation-induced damage to the lungs is available so far [
73,
74]. Highly conformal radiation techniques such as stereotactic body radiation therapy (SBRT) or intensity-modulated radiotherapy (IMRT) are suited to minimize the irradiated lung volume. For example, SBRT is applied to patients with early stage inoperable non-small cell lung cancer [
75]. Through image-guided precise targeting of very small volumes, relatively high dose-per-fraction sizes were delivered to the tumors. However, persisting adverse effects such as chest wall pain, rib fracture, esophagitis, brachial plexopathy, and in particular pneumonitis and fibrosis were reported [
75,
76]. In contrast to conventional dose rates (1–4 Gy/min), the so called ‘‘Flash” radiotherapy (>40 Gy/s; Flash-RT) was shown to enhance the differential effect between normal tissue and tumor in lung models [
77]. Herein, it was hypothesized that the protective effect of Flash irradiation was related to the high dose rate delivery. Indeed, Flash irradiation was shown to minimize persistent DNA damage, to reduce the inflammatory response and to facilitate radiation recovery [
78].
Senescence of Lung Epithelial Cells
Repetitive injury, especially to the pulmonary epithelium, is considered a central factor in the development of various lung diseases. Herein, the senescence of the respiratory epithelium either of the ciliated pseudostratified columnar epithelium, the cuboidal epithelium or the squamous epithelium in the alveolar ducts and alveoli is regarded as a central process for the initiation and progression of related lung diseases, particularly in pulmonary fibrosis and experimental lung fibrosis models [
10,
20,
35]. Human lung tissues from lung fibrosis (IPF) patients were shown to harbor numerous senescent epithelial cells as revealed by prominent SA-β-gal and p16 staining [
35]. IPF related epithelial senescence was closely associated with the SASP factors IL-1β, IL-6, IL-8 and TNF-α, which were already correlated with pulmonary fibrogenesis [
98]. Of note, using an in vitro model of (bleomycin) stress-induced epithelial cell senescence, senescent lung epithelial cells-derived SASP factors were able to mediate the activation of pulmonary fibroblasts [
35]. Therefore, the current hypothesis is that alveolar epithelial injury imposed on senescent epithelial cells leads to aberrant wound healing and the secretion of high levels of growth factors and chemokines that foster the activation of adjacent cells, including endothelial cells and fibroblasts, and the deposition of the extreacellular matrix [
99]. Among the ‘activating’ epithelial-derived SAPS factors, increased levels of MMP12, SERPINE1, SPP1, and fibrotic mediator Wnt-inducible signaling protein (WISP) 1 were determined [
100]. Moreover, pharmacological clearance of senescent lung epithelial cells by the induction of apoptosis in fibrotic alveolar (type II) epithelial cells or ex vivo three-dimensional lung tissue cultures (using dasatinib and quercetin) reduced SASP factors and extracellular matrix markers (e.g., collagen1a1, collagen5a3 and fibronectin) clearly indicating that senolytic drugs may be a viable therapeutic option for IPF [
100].
In a preclinical model of radiation-induced pneumopathy, clearance of senescent cells with a senolytic drug (ABT-263) efficiently reduced senescent cells and reversed pulmonary fibrosis [
26]. This, of course, would even limit the diminishing epithelial regenerative capacity, as well as associated SASP-mediated effects on adjacent lung cells as a central aspect in the development of lung injury. Therefore, targeting particularly senescent lung epithelial cells was suggested as a promising option for pulmonary fibrosis. Furthermore, radiation-induced senescence of lung epithelial cells was also closely connected to radiation-induced vascular dysfunction and associated extravasation of pre-metastatic immune and circulating tumor cells in a mouse model of radiation-induced pneumopathy [
20,
101]. Adoptive transfer of mesenchymal stem cells during the early phase after irradiation efficiently counteracted epithelial senescence (as well as vascular dysfunction) [
21,
101]. RT-induced senescence of bronchial-alveolar epithelial cells was further accompanied by the up-regulation of the SASP factor CCL2 [
101]. Importantly, abrogation of certain aspects of the secretome of senescent lung cells, in particular signaling inhibition of the SASP factor CCL2, secreted predominantly by RT-induced senescent epithelial cells, limited inflammation as well as fibrosis progression [
20]. This radioprotective action by addressing or modulating the SASP phenotype or senescent lung cells can have important implications in oncology, because higher doses of radiation might improve both local tumor control and survival. Moreover, treatment of thoracically irradiated mice with ABT-263 almost completely reversed pulmonary fibrosis, even when the initiation of ABT-263 treatment was delayed until fibrosis was established [
26]. This means that unlike other known radiation protectants and mitigators, which were usually needed to be applied before or shortly after RT, senolytic drugs such as ABT-263 have the potential to be used as an effective, novel treatment of radiation-induced side complications such as inflammation and fibrosis, even after the lung injury develops into a progressive disease [
70].
Although studies in animal models and patient samples show a complex response with multiple interactions between resident epithelial cells, fibroblasts and endothelial cells, and, in addition, infiltrating immune cells to radiation-induced diseased lung states, senescent epithelial cells and accompanied SASP contribute to the alteration and ‘activation’ of the lung microenvironment. Persistent or irreparable DNA damage following XRT in lung epithelial cells in turn can induce an irreversible cell cycle arrest that lead to apoptosis or to the establishment of cellular senescence. Radiation-induced epithelial senescence leads to increased SASP factor production. Very close by, the hitherto quiescent healthy endothelium that usually provides an efficient barrier to liquids or cell extravasation becomes activated and/or “angiogenic” phenotype (acute effect) in response to certain SASP factors. Increased endothelial permeability associated with increased leakage of blood stream components into the lung interstitium then fosters inflammation and/or metastasis formation. Normal fibroblasts will also be activated by SASP factors potentially resulting in a phenotypic change into pro-fibrotic myofibroblasts and/or cancer-associated fibroblasts that foster tissue remodeling by extracellular matrix deposition and thus fibrosis progression.
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