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.