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

Abstract

BackgroundPulmonary fibrosis is a progressive and lethal disorder. Although the precise mechanisms of pulmonary fibrosis are not fully understood, oxidant/antioxidant and Th1/Th2 balances may play an important role in many of the processes of inflammation and fibrosis. The transcription factor Nrf2 acts as a critical regulator for various inflammatory and immune responses by controlling oxidative stress. We therefore investigated the protective role of Nrf2 against the development of pulmonary fibrosis.MethodsTo generate pulmonary fibrosis, both wild-type C57BL/6 mice and Nrf2-deficient mice of the same background were administered bleomycin intratracheally.ResultsThe survival of Nrf2-deficient mice after bleomycin administration was significantly lower than that of wild-type mice. The degree of bleomycin-induced initial pulmonary inflammation and pulmonary fibrosis was much more severe in Nrf2-deficient mice than in wild-type mice. The expression of antioxidant enzymes and phase II detoxifying enzymes was significantly reduced in the lungs of Nrf2-deficient mice, concomitant with an elevation of lung 8-isoprostane level, compared with wild-type mice. The expression of Th2 cytokines, such as interleukin-4 and interleukin-13, was significantly elevated in the lungs of Nrf2-deficient mice with an increase in the number of Th2 cells that express GATA-binding protein 3.ConclusionsThe results indicated that Nrf2 protects against the development of pulmonary fibrosis by regulating the cellular redox level and lung Th1/Th2 balance. Thus, Nrf2 might be an important genetic factor in the determination of susceptibility to pulmonary fibrosis.

Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function

“…The role of Nrf2 as a critical mediator of the antioxidant response has been well studied. Previous studies demonstrate that Nrf2 deficiency exacerbates inflammation and oxidative stress in a variety of disease models, including emphysema (38), COPD exacerbations (13), acute lung injury (31,42), pulmonary fibrosis (6,22), and sepsis (53). Alternatively, activation of Nrf2 in these disease models reduces oxidative stress and inflammation (24,43,49).…”

Functions of Galectin-3 and Its Role in Fibrotic Diseases

“…In patients with severe chronic obstructive pulmonary disease, there were increased Gal-3 expression and neutrophil accumulation in the small airway epithelium, along with epithelial proliferation and airway obstruction (Pilette et al, 2007). Other research demonstrated that Gal-3 knockdown mice developed a lower Th2 response but a higher Th1 response, which played a significant role in the processes of inflammation and fibrosis (Zuberi et al, 2004;Kikuchi et al, 2010).…”

Involvement of Kruppel-like factor 9 in bleomycin-induced pulmonary toxicity

“…The chemotherapeutic agent, BLM, has been demonstrated to cause oxidative lung injuries in mice, and BLM-treated mice are considered to be a classical model of idiopathic pulmonary fibrosis (25). Currently, only a few genes involved in the control of ROS have been implicated in the pathogenesis of pulmonary fibrosis in mouse knockout models (18), including Nrf2 as a sole transcription factor among these genes (12). Furthermore, Nrf2 was activated and its targets, including Nqo1, were upregulated in mice treated with BLM (23).…”

“…Klf9 is a ubiquitously expressed member of the Sp1 C2H2-type zinc finger family of transcription factors (12). The expression of Klf9 can be increased by several stress-inducing agents, including the proteasomal inhibitor, bortezomib, and the histone deacetylase inhibitor, panobinostat, and Klf9 in turn mediates their cytotoxicity (13).…”