Role of Type II Pneumocyte Senescence in Radiation-Induced Lung Fibrosis

Citrin, Deborah E.; Shankavaram, Uma; Horton, Jason A.; Shield, William P.; Zhao, Shuping; Asano, Hiroaki; White, Ayla O.; Sowers, Anastasia L.; Thetford, Angela; Chung, Eun Joo

doi:10.1093/jnci/djt212

Cited by 134 publications

(187 citation statements)

References 37 publications

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“…In the bleomycin model of lung injury, AOSHIBA et al [257] reported a senescence-associated secretory phenotype. Similarly, pneumocyte senescence has been observed in radiation-induced lung fibrosis in mice [258].…”

Section: Cellular Senescencementioning

confidence: 67%

Hallmarks of the ageing lung

2015

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Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. @ERSpublications Hallmarks of ageing are selecting factors for the pathogenesis of COPD, lung cancer and IPF

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Section: Cellular Senescencementioning

confidence: 67%

Hallmarks of the ageing lung

2015

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“…Primary pneumocytes were isolated from C57BL/6J mice using a modified version of a previously described method (22–24). Briefly, mice were anesthetized 10 min after intraperitoneal injection of heparin sodium (12.5 u/g body weight).…”

Section: Methodsmentioning

confidence: 99%

Transforming Growth Factor Alpha is a Critical Mediator of Radiation Lung Injury

et al. 2014

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Radiation fibrosis of the lung is a late toxicity of thoracic irradiation. Epidermal growth factor (EGF) signaling has previously been implicated in radiation lung injury. We hypothesized that TGF-α, an EGF receptor ligand, plays a key role in radiation-induced fibrosis in lung. Mice deficient in transforming growth factor (TGF-α−/−) and control C57Bl/ 6J (C57-WT) mice were exposed to thoracic irradiation in 5 daily fractions of 6 Gy. Cohorts of mice were followed for survival (n ≥ 5 per group) and tissue collection (n = 3 per strain and time point). Collagen accumulation in irradiated lungs was assessed by Masson’s trichrome staining and analysis of hydroxyproline content. Cytokine levels in lung tissue were assessed with ELISA. The effects of TGF-α on pneumocyte and fibroblast proliferation and collagen production were analyzed in vitro. Lysyl oxidase (LOX) expression and activity were measured in vitro and in vivo. Irradiated C57-WT mice had a median survival of 24.4 weeks compared to 48.2 weeks for irradiated TGF-α−/− mice (P = 0.001). At 20 weeks after irradiation, hydroxyproline content was markedly increased in C57-WT mice exposed to radiation compared to TGF-α−/− mice exposed to radiation or unirradiated C57-WT mice (63.0, 30.5 and 37.6 µg/lung, respectively, P = 0.01). C57-WT mice exposed to radiation had dense foci of subpleural fibrosis at 20 weeks after exposure, whereas the lungs of irradiated TGF-α−/− mice were largely devoid of fibrotic foci. Lung tissue concentrations of IL-1β, IL-4, TNF-α, TGF-β and EGF at multiple time points after irradiation were similar in C57-WT and TGF-α−/− mice. TGF-α in lung tissue of C57-WT mice rose rapidly after irradiation and remained elevated through 20 weeks. TGF-α−/− mice had lower basal LOX expression than C57-WT mice. Both LOX expression and LOX activity were increased after irradiation in all mice but to a lesser degree in TGF-α−/− mice. Treatment of NIH-3T3 fibroblasts with TGF-α resulted in increases in proliferation, collagen production and LOX activity. These studies identify TGF-α as a critical mediator of radiation-induced lung injury and a novel therapeutic target in this setting. Further, these data implicate TGF-α as a mediator of collagen maturation through a TGF-β independent activation of lysyl oxidase.

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“…Fibrosis is considered a disease induced by recurrent and/or nonresolving injury to lung epithelium that results in cell death and/or phenotypic alterations to surviving cells, which leads to generation of myofibroblasts/fibrocytes and deposition of extracellular matrix (64–71). Radiation-induced pulmonary injury can be characterized by endothelium and pneumocyte apoptosis and senescence (71, 72) that are followed by recruitment of NADPH oxidase-expressing inflammatory cells and myofibroblasts to sites of injury, which in turn contribute to oxidative and cytokine stress. In published studies, it has been shown that suppression of TGF-β/Smad signaling, or overexpression of superoxide dismutase and/or overexpression of catalase abrogates development of radiation-induced pulmonary fibrosis (73–76).…”

Section: Nrf2 and Radiation-associated Pulmonary Injurymentioning

confidence: 99%

The Role of Nrf2 in the Response to Normal Tissue Radiation Injury

et al. 2018

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The transcription factor Nrf2 is an important modulator of antioxidant and drug metabolism, carbohydrate and lipid metabolism, as well as heme and iron metabolism. Regulation of Nrf2 expression occurs transcriptionally and post-transcriptionally. Post-transcriptional regulation entails ubiquitination followed by proteasome-dependent degradation. Additionally, Nrf2-mediated gene expression is subject to negative regulation by ATF3, Bach1 and cMyc. Nrf2-mediated gene expression is an important regulator of a cell’s response to radiation. Although a majority of studies have shown that Nrf2 deficient cells are radiosensitized and Nrf2 over expression confers radioresistance, Nrf2’s role in mediating the radiation response of crypt cells is controversial. The Nrf2 activator CDDO attenuates radiation-mediated crypt injury, whereas intestinal crypts in Nrf2 null mice are radiation resistant. Further investigation is needed in order to define the relationship between Nrf2 and radiation sensitivity in Lgr5+ and Bmi1+ cells that regulate regeneration of crypt stem cells. In hematopoietic compartments Nrf2 promotes the survival of irradiated osteoblasts that support long-term hematopoietic stem cell (LT-HSC) niches. Loss of Nrf2 in LT-HSCs increases stem cell intrinsic radiosensitivity, with the consequence of lowering the LD5030. An Nrf2 deficiency drives LT-HSCs from a quiescent to a proliferative state. This results in hematopoietic exhaustion and reduced engraftment after myoablative irradiation. The question of whether induction of Nrf2 in LT-HSC enhances hematopoietic reconstitution after bone marrow transplantation is not yet resolved. Irradiation of the lung induces pulmonary pneumonitis and fibrosis. Loss of Nrf2 promotes TGF-β/Smad signaling that induces ATF3 suppression of Nrf2-mediated target gene expression. This, in turn, results in elevated reactive oxygen species (ROS) and isolevuglandin adduction of protein that impairs collagen degradation, and may contribute to radiation-induced chronic cell injury. Loss of Nrf2 impairs ΔNp63 stem/progenitor cell mobilization after irradiation, while promoting alveolar type 2 cell epithelial-mesenchymal transitions into myofibroblasts. These studies identify Nrf2 as an important factor in the radiation response of normal tissue.

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Role of Type II Pneumocyte Senescence in Radiation-Induced Lung Fibrosis

Abstract: These studies identify senescence as an important process in AECII in vivo and indicate that NOX is a critical mediator of radiation-induced AECII senescence and pulmonary fibrosis.

Cited by 134 publications

References 37 publications

Hallmarks of the ageing lung

Hallmarks of the ageing lung

Transforming Growth Factor Alpha is a Critical Mediator of Radiation Lung Injury

The Role of Nrf2 in the Response to Normal Tissue Radiation Injury

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