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

Satoshi Ano, Alice Panariti, Benoit Allard, Michael O'Sullivan, Toby K. McGovern, Yoichiro Hamamoto, Yukio Ishii, Masayuki Yamamoto, William S. Powell, James G. Martin

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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 48 h after a 5-min nose-only exposure to 100 ppm Cl2 of Nrf2-deficient and wild type Balb/C mice treated with BSO or SFN. Animals were anesthetized, paralyzed and mechanically ventilated (FlexiVent™) 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 24 h after Cl2 exposure, were significantly greater at 48 h 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 48 h 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.

Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalFree Radical Biology and Medicine
Volume102
DOIs
Publication statusPublished - 2017 Jan 1

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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