Nrf2 protects against pulmonary fibrosis by regulating the lung oxidant level and Th1/Th2 balance

摘要

Background: Pulmonary fibrosis is a progressive and lethal disorder. Although the precise mechanisms ofpulmonary fibrosis are not fully understood, oxidant/antioxidant and Th1/Th2 balances may play an important rolein many of the processes of inflammation and fibrosis. The transcription factor Nrf2 acts as a critical regulator forvarious inflammatory and immune responses by controlling oxidative stress. We therefore investigated theprotective role of Nrf2 against the development of pulmonary fibrosis.Methods: To generate pulmonary fibrosis, both wild-type C57BL/6 mice and Nrf2-deficient mice of the samebackground were administered bleomycin intratracheally.Results: The survival of Nrf2-deficient mice after bleomycin administration was significantly lower than that of wildtypemice. The degree of bleomycin-induced initial pulmonary inflammation and pulmonary fibrosis was muchmore severe in Nrf2-deficient mice than in wild-type mice. The expression of antioxidant enzymes and phase IIdetoxifying enzymes was significantly reduced in the lungs of Nrf2-deficient mice, concomitant with an elevationof lung 8-isoprostane level, compared with wild-type mice. The expression of Th2 cytokines, such as interleukin-4and interleukin-13, was significantly elevated in the lungs of Nrf2-deficient mice with an increase in the number ofTh2 cells that express GATA-binding protein 3.Conclusions: The results indicated that Nrf2 protects against the development of pulmonary fibrosis by regulatingthe cellular redox level and lung Th1/Th2 balance. Thus, Nrf2 might be an important genetic factor in thedetermination of susceptibility to pulmonary fibrosis.