Elsevier

Radiotherapy and Oncology

Volume 160, July 2021, Pages 125-131
Radiotherapy and Oncology

Review Article
Nrf2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS): Novel mechanistic considerations

https://doi.org/10.1016/j.radonc.2021.04.015Get rights and content

Highlights

  • LDRT shows clinical response for COVID-19-induced pneumonia and ARDS via Nrf-2.

  • Nrf2-activation creates optimal redox environment for anti-inflammatory phenotype.

  • Nrf2-mediated response suppresses cytokine storm preventing COVID-19 deaths.

  • Activation of Nrf2 is highly dose dependent and conforms to a hormetic response.

  • LDRT can be regarded as safe and effective for use at any stage of COVID-19.

Abstract

Novel mechanistic insights are discussed herein that link a single, nontoxic, low-dose radiotherapy (LDRT) treatment (0.5–1.0 Gy) to (1) beneficial subcellular effects mediated by the activation of nuclear factor erythroid 2-related transcription factor (Nrf2) and to (2) favorable clinical outcomes for COVID-19 pneumonia patients displaying symptoms of acute respiratory distress syndrome (ARDS). We posit that the favorable clinical outcomes following LDRT result from potent Nrf2-mediated antioxidant responses that rebalance the oxidatively skewed redox states of immunological cells, driving them toward anti-inflammatory phenotypes. Activation of Nrf2 by ionizing radiation is highly dose dependent and conforms to the features of a biphasic (hormetic) dose–response. At the cellular and subcellular levels, hormetic doses of <1.0 Gy induce polarization shifts in the predominant population of lung macrophages, from an M1 pro-inflammatory to an M2 anti-inflammatory phenotype. Together, the Nrf2-mediated antioxidant responses and the subsequent shifts to anti-inflammatory phenotypes have the capacity to suppress cytokine storms, resolve inflammation, promote tissue repair, and prevent COVID-19-related mortality. Given these mechanistic considerations—and the historical clinical success of LDRT early in the 20th century—we opine that LDRT should be regarded as safe and effective for use at almost any stage of COVID-19 infection. In theory, however, optimal life-saving potential is thought to occur when LDRT is applied prior to the cytokine storms and before the patients are placed on mechanical oxygen ventilators. The administration of LDRT either as an intervention of last resort or too early in the disease progression may be far less effective in saving the lives of ARDS patients.

Keywords

SARS-Cov 2
LDRT
Nrf2
Hormesis
Cytokine storm
COVID-19

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