This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200708-1243OCv1 177/10/1111    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Newcomb, D. C. Articles by Hershenson, M. B. PubMed PubMed Citation Articles by Newcomb, D. C. Articles by Hershenson, M. B.

Human Rhinovirus 1B Exposure Induces Phosphatidylinositol 3-Kinase–dependent Airway Inflammation in Mice

¹ 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- 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.

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

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Understanding of rhinovirus-induced exacerbations of asthma and chronic obstructive lung disease is incomplete, in part because of the absence of an animal model. What This Study Adds to the Field Rhinovirus-1B exposure induces airway inflammation and hyperresponsiveness in mice. Phosphatidylinositol 3-kinase/Akt signaling is required for maximal rhinovirus-induced airway inflammation.