Role of nasal nitric oxide in the resolution of experimental rhinovirus infection

Sanders, Scherer P.; Proud, David; Permutt, Solbert; Siekierski, Edward S.; Yachechko, Robin; Liu, Mark C.

doi:10.1016/j.jaci.2004.01.755

Cited by 92 publications

(77 citation statements)

References 30 publications

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“…To enable the quantification of detected HRV genomic material in nasal lavages, test samples were compared against a standard curve that was analyzed in parallel in each assay, as described previously (6). We also previously established that viral titers quantified using RT-PCR correlate highly with values obtained using standard cell-based viral titer assays (21). Samples were obtained from nine subjects (mean age, 40 yr; range, 21-59 yr; 6 women) with established HRV infections.…”

Section: Clinical Study Design and Methodsmentioning

confidence: 99%

Human Rhinovirus Infection Up-Regulates MMP-9 Production in Airway Epithelial Cells via NF-κB

Tacon¹,

Wiehler²,

Holden³

et al. 2010

Am J Respir Cell Mol Biol

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Human rhinovirus (HRV) infections up-regulate proinflammatory mediators and growth factors that are associated with exacerbations of inflammatory airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Matrix metalloproteinase (MMP)-9 was shown to be increased in the airways of patients with asthma and COPD. We sought to determine whether HRV infection modulated the expression of MMP-9 and its highest-affinity inhibitor, the tissue inhibitor of metalloproteinase (TIMP)-1, and we explored the mechanism by which this modulation occurs. In vitro studies, using RT-PCR, ELISA, zymography, and a fluorescent activity assay, demonstrated that MMP-9 mRNA, protein, and activity were increased upon infection with HRV, whereas TIMP-1 mRNA and protein remained unchanged. These results were verified in vivo, using nasal lavage samples obtained from subjects with confirmed rhinovirus infections. Human rhinovirus infections were shown to up-regulate NF-kB, and NF-kB has also been reported to play a role in the expression of MMP-9. We therefore investigated the role of NF-kB in HRV-induced MMP-9 expression. Using two inhibitors of IkBa kinase b, we observed a concentration-dependent decrease in HRVinduced MMP-9 expression. The role of NF-kB in HRV-induced MMP-9 expression was further confirmed using MMP-9 promoter luciferase constructs, which demonstrated that an NF-kB site at 2620/2607 base pairs was necessary for HRV-induced MMP-9 expression. Electrophoretic mobility shift assays and supershift assays confirmed the nuclear translocation and binding of p50/p65 NF-kB subunits to an MMP-9-specific NF-kB oligonucleotide. This increase in MMP-9 may be a mechanism by which rhinovirus infections contribute to airway inflammation and, potentially, to airway remodeling.Keywords: airway epithelial cell; airway inflammation; airway remodeling; human rhinovirus; matrix metalloproteinase-9Human rhinovirus (HRV) infections are associated with exacerbations of lower airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD) (1). More than 100 serotypes of HRV exist, and they may be grouped according to the cell surface receptor used to gain entry into airway epithelial cells, which are their primary site of infection (2, 3). More than 90% of these HRV serotypes belong to the major group that attaches to the host cell via intercellular adhesion molecule-1, whereas at least 10 serotypes belong to the minor group and use members of the low-density lipoprotein receptor family for attachment (4).Although HRV infections are strongly linked to exacerbations of asthma and COPD, the mechanisms by which such infections cause these exacerbations are not yet fully characterized. It was demonstrated that the HRV infection of airway epithelial cells in vitro induces the production of various cytokines, chemokines, growth factors, and host defense proteins, several of which are also detected in airway secretions during in vivo HRV infections (5, 6). According to the current paradigm, these cellular products s...

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Section: Clinical Study Design and Methodsmentioning

confidence: 99%

Human Rhinovirus Infection Up-Regulates MMP-9 Production in Airway Epithelial Cells via NF-κB

Tacon¹,

Wiehler²,

Holden³

et al. 2010

Am J Respir Cell Mol Biol

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“…Nitric oxide produced in the upper airways may play a protective role for the entire respiratory tract. It has strong bacteriostatic and antiviral activities (1965,1966), in particular on rhinoviruses (1967,1968). It improves oxygenation (1969), exerts bronchodilatory activities (1970) and modulates lower airways responsiveness.…”

Section: Commonalities and Differences In Mechanisms Between Rhinitismentioning

confidence: 99%

Allergic Rhinitis and its Impact on Asthma (ARIA) 2008*

Bousquet¹,

Khaltaev²,

Cruz³

et al. 2008

Allergy

3,859

1,761

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“…One of the plausible mechanisms underlying enhanced viral replication and/or defective viral clearance in injured/regenerating epithelial cell cultures may be a lack of nitric oxide production in these cell cultures. Nitric oxide, which enhances viral clearance and limits RV-stimulated proinflammatory cytokines (39,40), is produced primarily by ciliated cells in the airway epithelium (41), and these cells are absent in injured/regenerating epithelium. Finally, undifferentiated polarized cells also showed higher expression of EGFR than did mucociliary-differentiated cells (37,42).…”

Section: Original Researchmentioning

confidence: 99%

Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium

Faris¹,

Ganesan²,

Chattoraj³

et al. 2016

Am J Respir Cell Mol Biol

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Rhinovirus (RV), which causes exacerbation in patients with chronic airway diseases, readily infects injured airway epithelium and has been reported to delay wound closure. In this study, we examined the effects of RV on cell repolarization and differentiation in a model of injured/regenerating airway epithelium (polarized, undifferentiated cells). RV causes only a transient barrier disruption in a model of normal (mucociliary-differentiated) airway epithelium. However, in the injury/regeneration model, RV prolongs barrier dysfunction and alters the differentiation of cells. The prolonged barrier dysfunction caused by RV was not a result of excessive cell death but was instead associated with epithelial-to-mesenchymal transition (EMT)-like features, such as reduced expression of the apicolateral junction and polarity complex proteins, E-cadherin, occludin, ZO-1, claudins 1 and 4, and Crumbs3 and increased expression of vimentin, a mesenchymal cell marker. The expression of Snail, a transcriptional repressor of tight and adherence junctions, was also up-regulated in RV-infected injured/regenerating airway epithelium, and inhibition of Snail reversed RV-induced EMT-like features. In addition, compared with sham-infected cells, the RV-infected injured/regenerating airway epithelium showed more goblet cells and fewer ciliated cells. Inhibition of epithelial growth factor receptor promoted repolarization of cells by inhibiting Snail and enhancing expression of E-cadherin, occludin, and Crumbs3 proteins, reduced the number of goblet cells, and increased the number of ciliated cells. Together, these results suggest that RV not only disrupts barrier function, but also interferes with normal renewal of injured/regenerating airway epithelium by inducing EMT-like features and subsequent goblet cell hyperplasia.Keywords: barrier function; epithelial-to-mesenchymal transition; Crumbs polarity complex; epithelial growth factor receptor; goblet cell hyperplasia Clinical RelevanceTo the best of our knowledge, this is the first study to demonstrate that rhinovirus delays cell repolarization in a model of injured/regenerating, but not normal, airway epithelium by inducing epithelial-to-mesenchymal transition-like features. Furthermore, rhinovirus reduces ciliated cell differentiation and promotes goblet-cell differentiation and mucin gene expression. These changes depended partially on persistent EGFR activation induced by rhinovirus. Such changes during regeneration can lead to airway epithelium with impaired barrier and mucociliary clearance functions.Airway epithelium that lines the respiratory tract acts as a physical barrier between the external environment and the lung and plays an important role in maintaining tissue homeostasis. Paracellular permeability of airway epithelium is maintained through the co-operation of two functionally distinct structural components: tight and adherence junctions located in the apicolateral membranes. Tight junctions regulate the transport of solutes and ions across airway epithelium...

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Role of nasal nitric oxide in the resolution of experimental rhinovirus infection

Cited by 92 publications

References 30 publications

Human Rhinovirus Infection Up-Regulates MMP-9 Production in Airway Epithelial Cells via NF-κB

Human Rhinovirus Infection Up-Regulates MMP-9 Production in Airway Epithelial Cells via NF-κB

Allergic Rhinitis and its Impact on Asthma (ARIA) 2008*

Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium

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