Mechanisms of allergy
Role of nasal nitric oxide in the resolution of experimental rhinovirus infection☆

https://doi.org/10.1016/j.jaci.2004.01.755Get rights and content

Abstract

Background

Human rhinovirus (HRV) infections are associated with exacerbations of asthma, chronic obstructive pulmonary disease, and sinusitis. Nitric oxide (NO) might play an important role in host defense through its potent antiviral properties. Previous studies have shown that HRV infection in human subjects increased nasal epithelial expression of type 2 nitric oxide synthase (NOS2), an isoform of the enzyme that produces NO.

Objective

We sought to investigate whether increases in exhaled NO (eNO) would accompany the increased NOS2 expression and would be associated with clearance of the virus.

Methods

Six human subjects were infected with HRV-16 intranasally. eNO from nasal and lower airways was measured by means of direct measurement at multiple controlled flow rates. eNO was monitored at baseline (day 1) and on days 2 to 5, 8, 14, and 42 after infection. Nasal lavages were performed on days 1 to 5 and 8, and nasal scrapings were performed on days 1 to 4. NOS2 mRNA expression in nasal cells was measured by using quantitative real-time RT-PCR. Viral shedding in nasal lavage fluid was monitored by using real-time RT-PCR and bioassay.

Results

Peak HRV titers and symptom scores were correlated on day 3, and HRV persisted until day 5 (n = 4) or day 8 (n = 2). Infection was associated with transient but significant increases in lymphocytes and monocytes in nasal lavage fluid. Significant increases in both nasal and lower airway eNO concentrations accompanied HRV infection and were positively correlated. Increased nasal eNO concentrations on day 3 were associated with increased expression of NOS2 mRNA in nasal scrapings. Symptom scores on day 4 were inversely correlated with the increases in nasal eNO concentration.

Conclusions

We conclude that increased production of NO occurs as part of the host response to HRV infection and speculate that NO plays a beneficial role in viral clearance.

Section snippets

Subjects

The institutional review board approved the study protocol, and informed consent was obtained from all subjects. Six nonasthmatic healthy adults not allergic to ragweed (5 male and 1 female patients) with no serum-neutralizing antibody to HRV-16 virus or cold symptoms in the previous 6 weeks were recruited.

Rhinovirus inoculum for in vivo studies

A safety-tested HRV-16 inoculum was prepared and subjected to an intensive battery of tests to confirm the absence of any contaminating bacteria, fungi, viruses, or mycoplasmas, according to

HRV-16 infection and cold symptoms

All 6 subjects completed the study and became infected as determined on the basis of self-report and greater than 4-fold increases in serum neutralizing antibody titers. Specifically, serum neutralizing antibody titers were increased by 4-fold (n = 2), 8-fold (n = 1), 16-fold (n = 1), or 32-fold (n = 2) 6 weeks after infection.

Quantitation of HRV-16 in the nasal lavage fluid by means of bioassay and real-time RT-PCR (Table I) were highly correlated (r = 0.88, P = .0001), demonstrating that viral RNA

Discussion

We have previously demonstrated that HRV infection increases epithelial expression of NOS2 mRNA in human subjects.9 We now show that HRV-induced expression of NOS2 mRNA in nasal cells recovered from human subjects after experimental HRV infection is associated with increases in eNO from both the upper and lower airways. More importantly, increases in exhaled nasal NO levels are inversely related to symptom scores, suggesting that NO produced in response to HRV infection might play a role in the

Acknowledgements

We thank Curt Reynolds for technical help with the recruitment and viral challenge of the subjects.

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    ☆

    Supported by grants HL61011 and AI37163 from the National Institutes of Health and by grant 43923 from the Canadian Institutes for Heath Research.

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    Copyright © 2004 American Academy of Allergy, Asthma and Immunology. Published by Mosby, Inc. All rights reserved.