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

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 Nrf2-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-gamma, body weight loss, heightened protein/lipid oxidation, and AP-1/NF-kappaB 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 Nrf2-ARE pathway in host defense against RSV.

• Authors: Hye-Youn Cho, Farhad Imani, Laura Miller-DeGraff, Dianne Walters, Guillermina A Melendi, Masayuki Yamamoto, Fernando P Polack, Steven R Kleeberger
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 179 Issue 2 Pg. 138-50 (Jan 15 2009) ISSN: 1535-4970 [Electronic] United States
• PMID: 18931336 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Anticarcinogenic Agents
• Buffers
• Isothiocyanates
• NF-E2-Related Factor 2
• Phosphates
• Sulfoxides
• Thiocyanates
• Sodium Chloride
• sulforaphane

Topics

• Animals
• Anticarcinogenic Agents (administration & dosage)
• Bronchoalveolar Lavage Fluid
• Buffers
• Disease Models, Animal
• Drug Therapy, Combination
• Isothiocyanates
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-E2-Related Factor 2 (metabolism)
• Oxidative Stress (drug effects)
• Phosphates (administration & dosage)
• Respiratory Syncytial Virus Infections (drug therapy, metabolism)
• Respiratory Syncytial Virus, Human (drug effects, metabolism)
• Sodium Chloride (administration & dosage)
• Sulfoxides
• Thiocyanates (administration & dosage)