Sulforaphane ameliorates steroid insensitivity through an Nrf2-dependent pathway in cigarette smoke-exposed asthmatic mice

Sakurai, Hirofumi; Morishima, Yuko; Ishii, Yukio; Yoshida, Kazufumi; Nakajima, Masayuki; Tsunoda, Yoshiya; Hayashi, Shih Yuan; Kiwamoto, Takumi; Matsuno, Yosuke; Kawaguchi, Mio; Yamamoto, Masayuki; Hizawa, Nobuyuki

doi:10.1016/j.freeradbiomed.2018.10.400

Cited by 27 publications

(29 citation statements)

References 51 publications

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“…7b). Recent studies demonstrated that the isothiocyanate sulforaphane (SFN) reversed corticosteroid resistance by modulating NRF2 pathway in cigarette smoke-exposed asthmatic mice [49] and in a mixed granulocyte mouse model of asthma [50]. AITC is known to be a structurally related compound of SFN and has a similar effect in activating NRF2/HO-1 pathway [41,42].…”

Section: Discussionmentioning

confidence: 99%

AITC inhibits fibroblast-myofibroblast transition via TRPA1-independent MAPK and NRF2/HO-1 pathways and reverses corticosteroids insensitivity in human lung fibroblasts

et al. 2021

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Background Little is known on the role of transient receptor potential ankyrin 1 (TRPA1) in fibroblast—myofibroblast transition (FMT) that can lead to airway remodeling which is a major problem for severe asthma and fibrosis. Thus, this study investigated the effect of TRPA1 modulators on transforming growth factor beta 1(TGF-β1) -treated lung fibroblasts. Methods MRC-5 cells were preincubated with TGF-β1 for 24 h. TRPA1 agonist or antagonist were added and further incubated for 24 h. The changes in TRPA1 and alpha-smooth muscle actin (α-SMA) expressions by stimuli were evaluated using qRT-PCR, western blot and immunohistochemical analyses. Statistical significance was determined by using one- or two-way ANOVA, followed by Bonferroni’s post hoc analysis for comparison of multiple groups and paired 2-tailed Student’s t-test between 2 groups. Results MRC-5 cells treated by TGF-β1 significantly upregulated α-SMA mRNA expressions (P < 0.01), but downregulated TRPA1 gene expression (P < 0.001). Post-treatment of TRPA1 activator, allyl isothiocyanate (AITC), after TGF-β1 significantly downregulated the α-SMA gene induction (P < 0.01 at 24 h), protein expression (P < 0.05) and immunoreactivity with stress fibers (P < 0.05). On the other hand, TRPA1 antagonist HC-030031 did not prevent this effect, and instead tended to facilitate the suppressive effect of AITC when co-stimulated. AITC significantly increased phosphorylated- extracellular signal-regulated kinase (ERK) 1/2 and heme oxygenase (HO)-1 protein expressions (P < 0.05) in TGF-β1-treated cells. Combined inhibition with ERK1/2 mitogen-activated protein kinase (MAPK) and nuclear factor erythroid 2-related factor (NRF2) almost completely reversed AITC-induced α-SMA suppression (P < 0.05). Dexamethasone was not able to inhibit the upregulated α-SMA induction by TGF-β1. However, AITC improved dexamethasone-insensitive myodifferentiation in the presence of the corticosteroid (P < 0.01). Conclusion We found that AITC exerts protective effect on TGF-β1-induced α-SMA induction by activating ERK1/2 MAPK and NRF2/HO-1 pathways in lung fibroblasts. It also overcomes corticosteroids insensitivity in TGF-β1-induced α-SMA induction. TRPA1 antagonist modulates the suppressive effect, but not prevent it. AITC and TRPA1 antagonist may be therapeutic agents in treating chronic respiratory diseases.

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Section: Discussionmentioning

confidence: 99%

AITC inhibits fibroblast-myofibroblast transition via TRPA1-independent MAPK and NRF2/HO-1 pathways and reverses corticosteroids insensitivity in human lung fibroblasts

et al. 2021

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“…Airway hyperresponsiveness and inflammation by chlorine gas was also resolved by sulforaphane in Nrf2 +/+ mice but not in Nrf2 −/− mice (Ano et al, 2017). In a ovalbumin and cigarette smoke model of refractory asthma, sulforaphane restored steroid therapy sensitivity through activation of histone deacetylase 2 in an Nrf2-dependent manner (Sakurai et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane enriched transcriptome of lung mitochondrial energy metabolism and provided pulmonary injury protection via Nrf2 in mice

Cho

Miller-DeGraff

Blankenship-Paris

et al. 2019

Toxicology and Applied Pharmacology

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Nrf2 is essential to antioxidant response element (ARE)-mediated host defense. Sulforaphane (SFN) is a phytochemical antioxidant known to affect multiple cellular targets including Nrf2-ARE pathway in chemoprevention. However, the role of SFN in non-malignant airway disorders remain unclear. To test if pre-activation of Nrf2-ARE signaling protects lungs from oxidantinduced acute injury, wild-type (Nrf2 +/+) and Nrf2-deficient (Nrf2 −/−) mice were given SFN orally or as standardized broccoli sprout extract diet (SBE) before hyperoxia or air exposure. Hyperoxiainduced pulmonary injury and oxidation indices were significantly reduced by SFN or SBE in Nrf2 +/+ mice but not in Nrf2 −/− mice. SFN upregulated a large cluster of basal lung genes that are

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“…In COPD models, sulforaphane promotes a robust antioxidant response, inhibits lung inflammation, and protects from cellular damage [ 289 , 290 , 291 ]. Treatment with sulforaphane improves corticosteroid sensitivity in mice challenged with cockroach allergen extract or exposed to cigarette smoke [ 292 , 293 ]. These effects were absent in Nrf2 knockout mice, suggesting that sulforaphane requires Nrf2 to enhance corticosteroid sensitivity [ 293 ].…”

Section: Targeting Oxidative Stress To Improve Corticosteroid Sensitivitymentioning

confidence: 99%

“…Treatment with sulforaphane improves corticosteroid sensitivity in mice challenged with cockroach allergen extract or exposed to cigarette smoke [ 292 , 293 ]. These effects were absent in Nrf2 knockout mice, suggesting that sulforaphane requires Nrf2 to enhance corticosteroid sensitivity [ 293 ]. Further, recently developed Nrf2-enhancing drugs such as RTA-408 have reduced airway hyperresponsiveness, oxidant stress, and inflammatory responses in mouse models of asthma [ 294 ].…”

Section: Targeting Oxidative Stress To Improve Corticosteroid Sensitivitymentioning

confidence: 99%

Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD

et al. 2021

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Corticosteroid insensitivity is a key characteristic of patients with severe asthma and COPD. These individuals experience greater pulmonary oxidative stress and inflammation, which contribute to diminished lung function and frequent exacerbations despite the often and prolonged use of systemic, high dose corticosteroids. Reactive oxygen and nitrogen species (RONS) promote corticosteroid insensitivity by disrupting glucocorticoid receptor (GR) signaling, leading to the sustained activation of pro-inflammatory pathways in immune and airway structural cells. Studies in asthma and COPD models suggest that corticosteroids need a balanced redox environment to be effective and to reduce airway inflammation. In this review, we discuss how oxidative stress contributes to corticosteroid insensitivity and the importance of optimizing endogenous antioxidant responses to enhance corticosteroid sensitivity. Future studies should aim to identify how antioxidant-based therapies can complement corticosteroids to reduce the need for prolonged high dose regimens in patients with severe asthma and COPD.

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Sulforaphane ameliorates steroid insensitivity through an Nrf2-dependent pathway in cigarette smoke-exposed asthmatic mice

Cited by 27 publications

References 51 publications

AITC inhibits fibroblast-myofibroblast transition via TRPA1-independent MAPK and NRF2/HO-1 pathways and reverses corticosteroids insensitivity in human lung fibroblasts

AITC inhibits fibroblast-myofibroblast transition via TRPA1-independent MAPK and NRF2/HO-1 pathways and reverses corticosteroids insensitivity in human lung fibroblasts

Sulforaphane enriched transcriptome of lung mitochondrial energy metabolism and provided pulmonary injury protection via Nrf2 in mice

Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD

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