Published ahead of print on February 14, 2008, doi:10.1164/rccm.200708-1243OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200708-1243OC
Human Rhinovirus 1B Exposure Induces Phosphatidylinositol 3-Kinase–dependent Airway Inflammation in Mice1 Department of Molecular and Integrative Physiology, 2 Department of Pediatrics and Communicable Diseases, and 3 Department of Pathology, University of Michigan, Ann Arbor, Michigan; and 4 Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom Correspondence and requests for reprints should be addressed to Marc B. Hershenson, M.D., Medical Sciences Research Building II, 1150 W. Medical Center Drive, Room 3570B, Ann Arbor, MI 48109-0688. E-mail: mhershen{at}umich.edu Rationale: Infection with rhinovirus (RV) triggers exacerbations of asthma and chronic obstructive lung disease. Objectives: We sought to develop a mouse model of RV employing RV1B, a minor group serotype that binds to the low-density lipoprotein receptor. Methods: C57BL/6 mice were inoculated intranasally with RV1B, replication-deficient ultraviolet (UV)-irradiated RV1B, or RV39, a major group virus.
Measurements and Main Results: Viral RNA was present in the lungs of RV1B-treated mice, but not in those exposed to UV-irradiated RV1B or RV39. Lung homogenates of RV-treated mice contained infectious RV 4 days after inoculation. RV1B exposure induced neutrophilic and lymphocytic airway inflammation, as well as increased lung expression of KC, macrophage-inflammatory protein-2, and IFN- 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, airway hyperresponsiveness, and Akt phosphorylation. Finally, phosphatidylinositol 3-kinase/Akt signaling is required for maximal RV1B-induced airway neutrophilic inflammation, likely via its essential role in virus internalization.
Key Words: asthma • chronic obstructive pulmonary disease • Akt • low-density lipoprotein receptor
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and IFN-β. RV1B-exposed mice showed airway hyperresponsiveness 1 and 4 days after inoculation. UV-irradiated RV1B induced modest neutrophilic airway inflammation and hyperresponsiveness 1 day after exposure. Both RV1B and UV-irradiated RV1B, but not RV39, increased lung phosphorylation of Akt. Confocal immunofluorescence showed colocalization of RV1B and phospho-Akt in the airway epithelium. Finally, pretreatment with the phosphatidylinositol 3-kinase inhibitor LY294002 attenuated chemokine production and neutrophil infiltration. 
