NRF2 deficiency reduces life span of mice administered thoracic irradiation

Abstract

Subsets of cancer survivors who have been subjected to thoracic irradiation face the prospect of developing pulmonary injury. Radiation-induced pulmonary fibrosis is an insidious injury that presents 6 to 24 months after irradiation and continues to progress over a period of years. TGF-β and reactive oxygen species contribute significantly to the pathogenesis of this injury. The transcription factor NRF2 controls antioxidant gene expression and therefore regulates the cellular oxidant burden. This work demonstrates an additional paradigm for NRF2: suppression of TGF-β-mediated signaling, assessed by measuring expression of a surrogate TGF-β1 target gene (PAI-1) in lung fibroblasts. Thoracic irradiation of Nfe2l2 (−/−) mice resulted in rapid expression of PAI-1 and FSP-1 compare to irradiated wild type mice. Examination of lung tissue 16 weeks after thoracic irradiation of Nfe2l2 (−/−) mice revealed the presence of distended alveoli and decreased numbers of alveoli compared to wild type mice. Suppression of NRF2 expression shortened life span in mice administered 16 Gy to the thorax. Nfe2l2 (+/−) and (−/−) mice exhibited a mean life span of 176 days compared to wild type mice that lived an average of 212 days. These novel results identify NRF2 as a susceptibility factor for development of late tissue injury.

Inhibition of serine palmitoyltransferase delays the onset of radiation-induced pulmonary fibrosis through the negative regulation of sphingosine kinase-1 expression

“…Such a possibility can be inferred from the fact that synthetic ␣ -mannosyl ceramide analogs with myriocin instead of sphingosine as the backbone unit were shown to stimulate a particular V ␣ 19 subset of NKT cells ( 46 ). In view of the important role played by the immune system in the development of RIF and RILI ( 9,10,(47)(48)(49)(50)(51)(52)(53), it becomes critical to identify criteria for a timely switch from the enforcement of SphK1-S1P/DHS1P-S1PR signaling network at early stages of RILI progression to its inhibition in order to prevent the development of RIF. The ability of myriocin to defer radiation-induced SphK1 activation and RIF progression and to counteract TGF-␤ -induced signaling identifi es SPT as a novel therapeutic target for the management of RIF that can potentially lead to improvements in the outcomes in patients receiving radiotherapy for thoracic malignancies.…”

Noblesse Oblige: NRF2 Functions in the Airways

“…12 for early studies). For example, Nrf2 2/2 mice had enhanced pulmonary fibrosis and lethality after bleomycin or thoracic radiation treatment relative to wild-type controls (12,13). Airway toxicity caused by air pollutant ultrafine particles and ozone, as well as allergic airway inflammation and hyperresponsiveness caused by allergens, were also further augmented in Nrf2 2/2 mice compared with Nrf2 1/1 mice (12, 14, 15).…”

NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation

“…Nuclear factor erythroid-2-related factor 2 (NRF2) regulates an adaptive cytoprotective response to counteract the deleterious effects of ROS, such as DNA damage and apoptosis, and confers cytoprotection following exposure to environmental oxidants (17)(18)(19)(20)(21)(22). Upon activation, NRF2 dissociates from its cytosolic inhibitor KEAP1 and mediates transcriptional activation of its target genes, which include multiple antioxidants and electrophile detoxification enzymes (17,19,23).…”