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Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice.

ABSTRACT: Oxidative stress has been postulated to play an important role in the pathogenesis of asthma; although a defect in antioxidant responses has been speculated to exacerbate asthma severity, this has been difficult to demonstrate with certainty. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive basic leucine zipper transcription factor that is involved in the transcriptional regulation of many antioxidant genes. We show that disruption of the Nrf2 gene leads to severe allergen-driven airway inflammation and hyperresponsiveness in mice. Enhanced asthmatic response as a result of ovalbumin sensitization and challenge in Nrf2-disrupted mice was associated with more pronounced mucus cell hyperplasia and infiltration of eosinophils into the lungs than seen in wild-type littermates. Nrf2 disruption resulted in an increased expression of the T helper type 2 cytokines interleukin (IL)-4 and IL-13 in bronchoalveolar lavage fluid and in splenocytes after allergen challenge. The enhanced severity of the asthmatic response from disruption of the Nrf2 pathway was a result of a lowered antioxidant status of the lungs caused by lower basal expression, as well as marked attenuation, of the transcriptional induction of multiple antioxidant genes. Our studies suggest that the responsiveness of Nrf2-directed antioxidant pathways may act as a major determinant of susceptibility to allergen-mediated asthma.

SUBMITTER: Rangasamy T

PROVIDER: S-EPMC2212893 | biostudies-literature | 2005 Jul

REPOSITORIES: biostudies-literature

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Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice.

Rangasamy Tirumalai T Guo Jia J Mitzner Wayne A WA Roman Jessica J Singh Anju A Fryer Allison D AD Yamamoto Masayuki M Kensler Thomas W TW Tuder Rubin M RM Georas Steve N SN Biswal Shyam S

The Journal of experimental medicine 20050701 1

Oxidative stress has been postulated to play an important role in the pathogenesis of asthma; although a defect in antioxidant responses has been speculated to exacerbate asthma severity, this has been difficult to demonstrate with certainty. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive basic leucine zipper transcription factor that is involved in the transcriptional regulation of many antioxidant genes. We show that disruption of the Nrf2 gene leads to severe allergen-dr ...[more]

PMID: 15998787

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Project description:Endogenous redox systems not only counteract oxidative damage induced by high levels of hydroxyl radicals (OH·) under pathological conditions, but also shape redox signaling as a key player in the regulation of physiological processes. Second messengers like hydrogen peroxide and nitric oxide, as well as redox enzymes of the Thioredoxin (Trx) family, including Trxs, glutaredoxins (Grxs), and peroxiredoxins (Prxs) modulate reversible, oxidative modifications of proteins. Thereby redox regulation is part of various cellular processes such as the immune response and Trx proteins have been linked in different disorders including inflammatory diseases. Here, we have analyzed the protein distribution of representative oxidoreductases of the Trx fold protein family-Trx1, Grx1, Grx2, and Prx2-in a murine model of allergic asthma bronchiale, as well as their potential therapeutic impact on type-2 driven airway inflammation. Ovalbumin (OVA) sensitization and challenge using the type-2 prone Balb/c mouse strain resulted in increased levels of all investigated proteins in distinct cellular patterns. While concomitant treatment with Grx1 and Prx2 did not show any therapeutic impact on the outcome of the disease, Grx2 or Trx1 treatment before and during the OVA challenge phase displayed pronounced protective effects on the manifestation of allergic airway inflammation. Eosinophil numbers and the type-2 cytokine IL-5 were significantly reduced while lung function parameters profoundly improved. The number of macrophages in the bronchoalveolar lavage (BAL) did not change significantly, however, the release of nitric oxide that was linked to airway inflammation was successfully prevented by enzymatically active Grx2 ex vivo. The Grx2 Cys-X-X-Ser mutant that facilitates de-/glutathionylation, but does not catalyze dithiol/disulfide exchange lost the ability to protect from airway hyper reactivity and to decrease NO release by macrophages, however, it reduced the number of infiltrating immune cells and IL-5 release. Altogether, this study demonstrates that specific redox proteins and particular enzyme activities protect against inflammatory damage. During OVA-induced allergic airway inflammation, administration of Grx2 exerts beneficial and thus potentially therapeutic effects.

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Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice.

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Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice.

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