Publication
Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung.
Authors Traver G, Mont S, Gius D, Lawson WE, Ding GX, Sekhar KR, Freeman ML
Submitted By Submitted Externally on 10/8/2017
Status Published
Journal Free radical biology & medicine
Year 2017
Date Published 11/1/2017
Volume : Pages 112 : 578 - 586
PubMed Reference 28870520
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, Nrf2(flox/flox), and Nrf2(?/?); SPC-Cre)
were administered a thoracic dose of 12Gy 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 ?Np63 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 ?Np63 stem/progenitor mobilization, a key event for
reconstitution of injured lung, while promoting a myofibroblast phenotype that
is central for fibrosis.