The molecular mechanisms of
pulmonary fibrosis are poorly understood, although
reactive oxygen species are thought to have an important role. NRF2 is a
transcription factor that protects cells and tissues from oxidative stress by activating protective
antioxidant and detoxifying
enzymes. We hypothesized that NRF2 protects lungs from injury and
fibrosis induced by
bleomycin, an anti-neoplastic agent that causes
pulmonary fibrosis in susceptible patients. To test this hypothesis, mice with targeted deletion of Nrf2 (Nrf2-/-) and wild-type (Nrf2+/+) mice were treated with
bleomycin or vehicle, and
pulmonary injury and fibrotic responses were compared.
Bleomycin-induced increases in lung weight, epithelial cell death, and
inflammation were significantly greater in Nrf2-/- mice than in Nrf2+/+ mice. Indices of lung
fibrosis (
hydroxyproline content,
collagen accumulation, fibrotic score, cell proliferation) were significantly greater
in bleomycin-treated Nrf2-/- mice, compared with Nrf2+/+ mice. NRF2 expression and activity were elevated in Nrf2+/+ mice by
bleomycin.
Bleomycin caused greater up-regulation of several NRF2-inducible
antioxidant enzyme genes and
protein products in Nrf2+/+ mice compared with Nrf2-/- mice. Further,
bleomycin-induced transcripts and
protein levels of
lung injury and
fibrosis markers were significantly attenuated in Nrf2+/+ mice compared with Nrf2-/- mice. Results demonstrated that NRF2 has a critical role in protection against
pulmonary fibrosis, presumably through enhancement of cellular
antioxidant capacity. This study has important implications for the development of intervention strategies against
fibrosis.