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Free Radic Biol Med. 2017 Jan;102:1-15. doi: 10.1016/j.freeradbiomed.2016.11.017. Epub 2016 Nov 13.

Inflammation and airway hyperresponsiveness after chlorine exposure are prolonged by Nrf2 deficiency in mice.

Author information

1
Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
2
Department of Respiratory Medicine, University of Tsukuba, Tsukuba, Japan.
3
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
4
Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: james.martin@mcgill.ca.

Abstract

RATIONALE:

Chlorine gas (Cl2) is a potent oxidant and trigger of irritant induced asthma. We explored NF-E2-related factor 2 (Nrf2)-dependent mechanisms in the asthmatic response to Cl2, using Nrf2-deficient mice, buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis and sulforaphane (SFN), a phytochemical regulator of Nrf2.

METHODS:

Airway inflammation and airway hyperresponsiveness (AHR) were assessed 24 and 48h after a 5-min nose-only exposure to 100ppm Cl2 of Nrf2-deficient and wild type Balb/C mice treated with BSO or SFN. Animals were anesthetized, paralyzed and mechanically ventilated (FlexiVentâ„¢) and challenged with aerosolized methacholine. Bronchoalveolar lavage (BAL) was performed and lung tissues were harvested for assessment of gene expression.

RESULTS:

Cl2 exposure induced a robust AHR and an intense neutrophilic inflammation that, although similar in Nrf2-deficient mice and wild-type mice at 24h after Cl2 exposure, were significantly greater at 48h post exposure in Nrf2-deficient mice. Lung GSH and mRNA for Nrf2-dependent phase II enzymes (NQO-1 and GPX2) were significantly lower in Nrf2-deficient than wild-type mice after Cl2 exposure. BSO reduced GSH levels and promoted Cl2-induced airway inflammation in wild-type mice, but not in Nrf2-deficient mice, whereas SFN suppressed Cl2-induced airway inflammation in wild-type but not in Nrf2-deficient mice. AHR was not affected by either BSO or SFN at 48h post Cl2 exposure.

CONCLUSIONS:

Nrf2-dependent phase II enzymes play a role in the resolution of airway inflammation and AHR after Cl2 exposure. Moderate deficiency of GSH affects the magnitude of acute inflammation but not AHR.

KEYWORDS:

Buthionine sulfoximine; Irritant induced asthma; Nrf2; Phase II enzymes; Sulforaphane

[Indexed for MEDLINE]

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