Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in airway remodeling.
BACKGROUND
Childhood human rhinovirus (HRV) infections are associated with an increased risk of asthma. We reasoned that HRV infections might be important in the pathogenesis of airway remodeling, thereby providing a mechanism by which these children are at risk of asthma.


OBJECTIVE
We sought to determine whether HRV infection of airway epithelial cells regulates production of growth factors associated with airway remodeling and to determine whether vascular endothelial growth factor (VEGF) was upregulated in airways during HRV-induced natural colds.


METHODS
Cultured human airway epithelial cells were infected with HRV. Amphiregulin, activin A, and VEGF protein levels were assayed by means of ELISA, and VEGF mRNA was quantified by using real-time RT-PCR. Pharmacologic inhibitors were used to assess the role of mitogen-activated protein kinase and nuclear factor kappaB pathways. Nasal lavage samples from subjects with confirmed natural HRV infections were assayed for VEGF protein and compared with baseline levels and with control levels.


RESULTS
HRV infection upregulated amphiregulin, activin A, and VEGF protein levels compared with control media (P < .05). VEGF gene expression was maximally induced 3 hours after infection. HRV-induced generation of VEGF was regulated by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 pathways but did not depend on nuclear factor kappaB activation. In subjects with HRV infections, VEGF levels during peak cold symptoms were significantly higher than at baseline (P = .005) or in control subjects (P < .01).


CONCLUSIONS
HRV-16 infection upregulates amphiregulin, activin A, and VEGF in airway epithelial cells, and HRV infections in vivo upregulate airway VEGF production.
Leigh
Richard
R
Airway Inflammation Research Group, Department of Medicine, Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada. rleigh@ucalgary.ca
Oyelusi
Wale
W
Wiehler
Shahina
S
Koetzler
Rommy
R
Zaheer
Raza S
RS
Newton
Robert
R
Proud
David
D
D000328:Adult; D015153:Blotting, Western; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D017817:Nasal Lavage Fluid / Q000737:chemistry; D010850:Picornaviridae Infections / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D020545:Respiratory Mucosa / Q000378:metabolism / Q000821:virology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012229:Rhinovirus; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D012367:RNA, Viral; D042461:Vascular Endothelial Growth Factor A; D048049:Extracellular Signal-Regulated MAP Kinases