Published ahead of print on February 14, 2008, doi:10.1164/rccm.200708-1243OC Am. J. Respir. Crit. Care Med., Volume 177, Number 10, May 2008, 1111-1121 A more recent version of this article appeared on May 15, 2008
Submitted on August 22, 2007 Human Rhinovirus 1B Exposure Induces PI 3-kinase-dependent Airway Inflammation in MiceDawn C Newcomb1,1 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA, 2 Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA, 3 Department of Pathology, University of Michigan, Ann Arbor, MI, USA, 4 Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom, 5 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA * To whom correspondence should be addressed. E-mail: mhershen{at}umich.edu.
Rationale: Infection with rhinovirus (RV) triggers exacerbations of asthma and chronic obstructive lung disease.
Objective: We sought to develop a mouse model of RV employing RV1B, a minor group serotype which binds to the low-density lipoprotein receptor.
Methods: C57BL/6 mice were inoculated intranasally with RV1B, replication-deficient UVirradiated RV1B, or RV39, a major group virus.
Measurements and Main Results: Viral RNA was present in the lungs of RV1B-treated mice, but not those exposed to UV-irradiated RV1B or RV39. Lung homogenates of RV-treated mice contained infectious RV four days after inoculation. RV1B exposure induced neutrophilic and lymphocytic airway inflammation, as well as increased lung expression of KC, macrophageinflammatory protein-2 and interferons- Key words: asthma, COPD, Akt, low-density lipoprotein receptor
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. RV1B-exposed mice showed airways hyperresponsiveness 1 and 4 d after inoculation. UV-irradiated RV1B induced modest neutrophilic airway inflammation and hyperresponsiveness 1 d after exposure. Both RV1B and UV-irradiated RV1B, but not RV39, increased lung phosphorylation of Akt. Confocal immunofluorescence showed co-localization of RV1B and phospho-Akt in the airway epithelium. Finally, pre-treatment with the PI 3-kinase inhibitor LY294002 attenuated chemokine production and neutrophil infiltration.
Conclusions: We conclude that RV1B induces airway inflammation in vivo. Evidence is presented that viral replication occurs in vivo and is required for maximal responses. On the other hand, viral replication was not required for a subset of RV-induced responses, including neutrophilic inflammation, airways hyperresponsiveness and Akt phosphorylation. Finally, PI 3-kinase/Akt signaling is required for maximal RV1B-induced airway neutrophilic inflammation, likely via its essential role in virus internalization.