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.

• Authors: Yuichi Yageta, Yukio Ishii, Yuko Morishima, Hironori Masuko, Satoshi Ano, Tadahiro Yamadori, Ken Itoh, Kaoru Takeuchi, Masayuki Yamamoto, Nobuyuki Hizawa
• Journal: Journal of virology (J Virol) Vol. 85 Issue 10 Pg. 4679-90 (May 2011) ISSN: 1098-5514 [Electronic] United States
• PMID: 21367886 (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