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

ABSTRACT: 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-?/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 ?Np63 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.

SUBMITTER: Cameron BD

PROVIDER: S-EPMC6093213 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Cameron Brent D BD Sekhar Konjeti R KR Ofori Maxwell M Freeman Michael L ML

Radiation research 20180525 2

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 reg ...[more]

PMID: 29799319

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Project description:PurposeFor decades, Dr. John Moulder has been a leading radiation biologist and one of the few who consistently supported the study of normal tissue responses to radiation. His meticulous modeling and collaborations across the field have offered a prime example of how research can be taken from the bench to the bedside and back, with the ultimate goal of providing benefit to patients. Much of the focus of John's work was on mitigating damage to the kidney, whether as the result of accidental or deliberate clinical exposures. Following in his footsteps, we offer here a brief overview of work conducted in the field of radiation-induced bladder injury. We then describe our own preclinical experimental studies which originated as a response to reports from a clinical genome-wide association study (GWAS) investigating genomic biomarkers of normal tissue toxicity in prostate cancer patients treated with radiotherapy. In particular, we discuss the use of Renin-Angiotensin System (RAS) inhibitors as modulators of injury, agents championed by the Moulder group, and how RAS inhibitors are associated with a reduction in some measures of toxicity. Using a murine model, along with precise CT-image guided irradiation of the bladder using single and fractionated dosing regimens, we have been able to demonstrate radiation-induced functional injury to the bladder and mitigation of this functional damage by an inhibitor of angiotensin-converting enzyme targeting the RAS, an experimental approach akin to that used by the Moulder group. We consider our scientific trajectory as a bedside-to-bench approach because the observation was made clinically and investigated in a preclinical model; this experimental approach aligns with the exemplary career of Dr. John Moulder.ConclusionsDespite the differences in functional endpoints, recent findings indicate a commonality between bladder late effects and the work in kidney pioneered by Dr. John Moulder. We offer evidence that targeting the RAS pathway may provide a targetable pathway to reducing late bladder toxicity.

Dataset Information

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

Publications

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

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