Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung

Geri Traver, Stacey Mont, David Gius, William E. Lawson, George X. Ding, Konjeti R. Sekhar, Michael L. Freeman*

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The development of radiation-induced pulmonary fibrosis represents a critical clinical issue limiting delivery of therapeutic doses of radiation to non-small cell lung cancer. Identification of the cell types whose injury initiates a fibrotic response and the underlying biological factors that govern that response are needed for developing strategies that prevent or mitigate fibrosis. C57BL/6 mice (wild type, Nrf2 null, Nrf2flox/flox, and Nrf2Δ/Δ; SPC-Cre) were administered a thoracic dose of 12 Gy and allowed to recover for 250 days. Whole slide digital and confocal microscopy imaging of H&E, Masson's trichrome and immunostaining were used to assess tissue remodeling, collagen deposition and cell renewal/mobilization during the regenerative process. Histological assessment of irradiated, fibrotic wild type lung revealed significant loss of alveolar type 2 cells 250 days after irradiation. Type 2 cell loss and the corresponding development of fibrosis were enhanced in the Nrf2 null mouse. Yet, conditional deletion of Nrf2 in alveolar type 2 cells in irradiated lung did not impair type 2 cell survival nor yield an increased fibrotic phenotype. Instead, radiation-induced ΔNp63 stem/progenitor cell mobilization was inhibited in the Nrf2 null mouse while the propensity for radiation-induced myofibroblasts derived from alveolar type 2 cells was magnified. In summary, these results indicate that Nrf2 is an important regulator of irradiated lung's capacity to maintain alveolar type 2 cells, whose injury can initiate a fibrotic phenotype. Loss of Nrf2 inhibits ΔNp63 stem/progenitor mobilization, a key event for reconstitution of injured lung, while promoting a myofibroblast phenotype that is central for fibrosis.

Original languageEnglish (US)
Pages (from-to)578-586
Number of pages9
JournalFree Radical Biology and Medicine
Volume112
DOIs
StatePublished - Nov 2017

Keywords

  • Alveolar type 2 cell
  • Nrf2
  • Pulmonary fibrosis
  • Radiation
  • ΔNp63

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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