Mechanisms of allergy and clinical immunology
Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in airway remodeling

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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 κB 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 κB 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).

Conclusion

HRV-16 infection upregulates amphiregulin, activin A, and VEGF in airway epithelial cells, and HRV infections in vivo upregulate airway VEGF production.

Section snippets

Materials

The following were purchased: Ham's F-12 medium, Eagle's minimal essential medium, Hanks' buffered salt solution, penicillin-streptomycin-amphotericin B, L-glutamine, TRIzol, nonessential amino acids, gentamicin, FBS, deoxyribonucleoside triphosphates, oligo(dT), and Superscript III from Invitrogen Life Technologies (Burlington, Ontario, Canada); bronchial epithelial cell growth medium from BioWhittaker (Walkersville, Md); SB-203580, PD-98059, and SP-600125 from Calbiochem-Novabiochem (San

HRV-16 infection of human airway epithelial cells upregulates production of amphiregulin, activin A, and VEGF

HRV-16 infection of both BEAS-2B and HBE cells resulted in significant upregulation of amphiregulin and activin A production (Fig 1, A and B). In addition, HRV-16 infection resulted in significant upregulation of the proangiogenic factor VEGF in both BEAS-2B and HBE cells (Fig 1, C). Despite significant basal expression of amphiregulin and VEGF in BEAS-2B and HBE cells, HRV-16 infection led to significant increases above these levels in both cell types. There was no basal production of activin

Discussion

Repeated HRV-induced respiratory illnesses during infancy and early childhood are strongly associated with an increased risk of subsequent asthma.8 Our current data support the hypothesis that early childhood HRV infections also might play a role in the development of the airway remodeling that manifests even before the confirmed diagnosis of asthma.3, 4 HRV-16 infection of either the BEAS-2B epithelial cells or primary HBE cells leads to marked upregulation of the profibrotic mediators

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    Supported by an establishment grant from the Alberta Heritage Foundation for Medical Research and by operating grants from the Canadian Institutes of Health Research and the Alberta Lung Association. Richard Leigh is a Canadian Institutes of Health Research Clinician-Scientist (Phase 2) and an Alberta Heritage Foundation for Medical Research Clinician Investigator and holds the GSK-CIHR Professorship in Inflammatory Lung Disease. Robert Newton is an Alberta Heritage Foundation for Medical Research Scholar, and David Proud holds a Canada Research Chair in Inflammatory Airway Diseases.

    Disclosure of potential conflict of interest: R. Leigh has consulting arrangements with AstraZeneca and GlaxoSmithKline and is on the speakers' bureau for AstraZeneca, GlaxoSmithKline, and Novartis. The rest of the authors have declared that they have no conflict of interest.

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