Antiviral activity of Nrf2 in a murine model of respiratory syncytial virus disease

Hye Youn Cho, Farhad Imani, Laura Miller-DeGraff, Dianne Walters, Guillermina A. Melendi, Masayuki Yamamoto, Fernando P. Polack, Steven R. Kleeberger

Research output: Contribution to journalArticlepeer-review

117 Citations (Scopus)

Abstract

Rationale: Respiratory syncytial virus (RSV) is the most frequent cause of significant lower respiratory illness in infants and young children, but its pathogenesis is not fully understood. The transcription factor Nrf2 protects lungs from oxidative injury and inflammation via antioxidant response element (ARE)-mediated gene induction. Objectives: The current study was designed to determine the role of Nrf2-mediated cytoprotective mechanisms in murine airway RSV disease. Methods: Nrf2-deficient (Nrf2-/-) and wild-type (Nrf2+/+) mice were intranasally instilled with RSV or vehicle. In a separate study, Nrf2+/+ and Nrf2-/- mice were treated orally with sulforaphane (an Nrf 2-ARE inducer) or phosphate-buffered saline before RSV infection. Measurements and Main Results: RSV-induced bronchopulmonary inflammation, epithelial injury, and mucus cell metaplasia as well as nasal epithelial injury were significantly greater in Nrf2-/- mice than in Nrf2+/+ mice. Compared with Nrf2+/+ mice, significantly attenuated viral clearance and IFN-γ, body weight loss, heightened protein/lipid oxidation, and AP-1/NF-κB activity along with suppressed antioxidant induction was found in Nrf2-/- mice in response to RSV. Sulforaphane pretreatment significantly limited lung RSV replication and virus-induced inflammation in Nrf2+/+ but not in Nrf2-/- mice. Conclusions: The results of this study support an association of oxidant stress with RSV pathogenesis and a key role for the Nrf 2-ARE pathway in host defense against RSV.

Original languageEnglish
Pages (from-to)138-150
Number of pages13
JournalAmerican journal of respiratory and critical care medicine
Volume179
Issue number2
DOIs
Publication statusPublished - 2009 Jan 15

Keywords

  • Airway
  • Antioxidant response element
  • Inflammation
  • Oxidative stress
  • Sulforaphane

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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