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Role of Nrf2 in host defense against influenza virus in cigarette smoke-exposed mice.

Abstract
Influenza virus is a common respiratory tract viral infection. Although influenza can be fatal in patients with chronic pulmonary diseases such as chronic obstructive pulmonary disease, its pathogenesis is not fully understood. The Nrf2-mediated antioxidant system is essential to protect the lungs from oxidative injury and inflammation. In the present study, we investigated the role of Nrf2 in protection against influenza virus-induced pulmonary inflammation after cigarette smoke exposure with both in vitro and in vivo approaches. For in vitro analyses, peritoneal macrophages isolated from wild-type and Nrf2-deficient mice were treated with poly(I:C) and/or cigarette smoke extract. For in vivo analysis, these mice were infected with influenza A virus with or without exposure to cigarette smoke. In Nrf2-deficient macrophages, NF-κB activation and the induction of its target inflammatory genes were enhanced after costimulation with cigarette smoke extract and poly(I:C) compared with wild-type macrophages. The induction of antioxidant genes was observed for the lungs of wild-type mice but not those of Nrf2-deficient mice after cigarette smoke exposure. Cigarette smoke-exposed Nrf2-deficient mice showed higher rates of mortality than did wild-type mice after influenza virus infection, with enhanced peribronchial inflammation, lung permeability damage, and mucus hypersecretion. Lung oxidant levels and NF-κB-mediated inflammatory gene expression in the lungs were also enhanced in Nrf2-deficient mice. Our data indicate that the antioxidant pathway controlled by Nrf2 is pivotal for protection against the development of influenza virus-induced pulmonary inflammation and injury under oxidative conditions.
AuthorsYuichi Yageta, Yukio Ishii, Yuko Morishima, Hironori Masuko, Satoshi Ano, Tadahiro Yamadori, Ken Itoh, Kaoru Takeuchi, Masayuki Yamamoto, Nobuyuki Hizawa
JournalJournal of virology (J Virol) Vol. 85 Issue 10 Pg. 4679-90 (May 2011) ISSN: 1098-5514 [Electronic] United States
PMID21367886 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
Topics
  • Animals
  • Inflammation (pathology)
  • Influenza A virus (immunology, pathogenicity)
  • Lung (pathology)
  • Macrophages, Peritoneal (immunology, virology)
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 (deficiency, immunology, metabolism)
  • Orthomyxoviridae Infections (immunology, mortality, pathology)
  • Smoking (adverse effects)
  • Survival Analysis

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