Sulforaphane prevents bleomycin-induced pulmonary fibrosis in mice by inhibiting oxidative stress via nuclear factor erythroid 2-related factor-2 activation

Abstract

Lung fibrosis is associated with inflammation, apoptosis and oxidative damage. The transcription factor nuclear factor erythroid 2-related factor-2 (Nrf2) prevents damage to cells from oxidative stress by regulating the expression of antioxidant proteins. Sulforaphane (SFN), an Nrf2 activator, additionally regulates excessive oxidative stress by promoting the expression of endogenous antioxidants. The present study investigated if SFN protects against lung injury induced by bleomycin (BLM). The secondary aim of the present study was to assess if this protection mechanism involves upregulation of Nrf2 and its downstream antioxidants. Pulmonary fibrosis was induced in C57/BL6 mice by intratracheal instillation of BLM. BLM and age-matched control mice were treated with or without a daily dose of 0.5 mg/kg SFN until sacrifice. On days 7 and 28, mice were assessed for induction of apoptosis, inflammation, fibrosis, oxidative damage and Nrf2 expression in the lungs. The lungs were investigated with histological techniques including haematoxylin and eosin staining, Masson's trichrome staining and terminal deoxynucleotidyl transferase UTP nick end labeling. Inflammatory, fibrotic and apoptotic processes were confirmed by western blot analysis for interleukin-1β, tumor necrosis factor-α, transforming growth factor-β and caspase-3 protein expressions. Furthermore, protein levels of 3-nitro-tyrosine, 4-hydroxynonenal, superoxide dismutase 1 and catalase were investigated by western blot analysis. It was demonstrated that pulmonary fibrosis induced by BLM significantly increased apoptosis, inflammation, fibrosis and oxidative stress in the lungs at days 7 and 28. Notably, SFN treatment significantly attenuated the infiltration of the inflammatory cells, collagen accumulation, epithelial cell apoptosis and oxidative stress in the lungs. In addition, SFN treatment increased expression of the Nrf2 gene and its downstream targets. In conclusion, these results suggested that SFN treatment of pulmonary fibrosis mouse models may attenuate alveolitis, fibrosis, apoptosis and lung oxidative stress by increasing the expression of antioxidant enzymes, including NAPDH quinone oxidoreductase, heme oxygenase-1, superoxide dismutase and catalase, via upregulation of Nrf2 gene expression. Thus, the results from the present study may facilitate the development of therapies for BLM-toxicity and pulmonary fibrosis.

Activation of Nrf2/ARE pathway alleviates the cognitive deficits in PS1V97L‐Tg mouse model of Alzheimer’s disease through modulation of oxidative stress

“…It upregulates the expression of endogenous antioxidant proteins against oxidative stress and damage via Nrf2 activation. In previous studies, sulforaphane was shown to rapidly cross the BBB in mice, leading to an increase in Nrf2 expression in the striatum and cortex (Alfieri et al, ; Bai et al, ; Tarozzi et al, ; Wang, Wu, et al, ; Yan et al, ; Zhao, Moore, Clifton, & Dash, ). SF is a potent activator of Nrf2 activator, which induces antioxidative effects through the Nrf2/ARE pathway in many diseases.…”

Oxidative stress and cellular and tissue damage in organogenic outbred mouse embryos after moderate perigestational alcohol intake

“…Catalase protects against oxidative stress-induced cell damage. Its activity and expression has been linked to many pathological processes, such as lung fibrosis (Yan et al, 2017). Catalase also activates this study may be due to the lower blood-alcohol concentration in maternal-fetal circulation and/or in the embryo than the other studies, which failed to activate SOD but was still high enough to achieve neural tube dysmorphogenesis in ethanol-exposed embryos.…”

“…Catalase protects against oxidative stress‐induced cell damage. Its activity and expression has been linked to many pathological processes, such as lung fibrosis (Yan et al, ). Catalase also activates Extracellular signal‐regulated kinase, thus stimulating cell growth that would otherwise be inhibited during oxidative stress.…”

The protective effect of activating Nrf2 / HO-1 signaling pathway on cardiomyocyte apoptosis after coronary microembolization in rats

“…The apoptotic pathways mainly include intrinsic and extrinsic pathways [ 43 ]. Some studies have confirmed that Nrf2/HO-1 mainly regulated apoptosis through intrinsic pathway, but relative studies about extrinsic pathway of Nrf2/HO-1 were few [ 44 , 45 ].In our study, Nrf2/HO-1 could suppress the expression of caspase-9 and caspase-3, and caspase-9 is the key factor of intrinsic pathway and active caspase-3 to induce apoptosis. Nrf2/HO-1 is probably concluded in the process of myocardial apoptosis after CME through the intrinsic pathway.…”