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Published ahead of print on October 17, 2008, doi:10.1164/rccm.200804-535OC

Am. J. Respir. Crit. Care Med., Volume 179, Number 2, January 2009, 138-150

A more recent version of this article appeared on January 15, 2009
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Submitted on April 9, 2008
Accepted on October 15, 2008

Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus (RSV) Disease

Hye-Youn Cho1*, Farhad Imani1, Laura Miller-Degraff1, Dianne Walters1, Guillermina A Melendi2, Masayuki Yamamoto3, Fernando P Polack2, and Steven R Kleeberger1

1 Laboratory of Respiratory Biology, NIEHS, RTP, North Carolina, United States, 2 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States; INFANT Foundation, Buenos Aires, Argentina, 3 Graduate School of Medicine, Tohoku University, Sendai, Japan

* To whom correspondence should be addressed. E-mail: cho2{at}niehs.nih.gov.

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 mechanism in airway RSV disease in mice. 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 Nrf2-ARE inducer) or PBS 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 to Nrf2+/+ mice, significantly attenuated viral clearance and IFN-{gamma}, body weight loss, heightened protein/lipid oxidation and AP-1/NF-{kappa}B activity along with suppressed antioxidant induction was found in Nrf2-/- mice in response to RSV. Sulforaphane pre-treatment significantly limited lung RSV replication and virus-induced inflammation in Nrf2+/+ but not in Nrf2+/+ mice. Conclusions: Results supported an association of oxidant stress in RSV pathogenesis and a key role for Nrf2-ARE pathway in host defense against RSV.


Key words: airway • oxidative stress • antioxidant response element • inflammation • sulforaphane




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[Abstract] [Full Text] [PDF]


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