title: S-nitrosothiols regulate cell-surface pH buffering by airway epithelial cells during the human immune response to rhinovirus.
abstract: Human rhinovirus infection is a common trigger for asthma exacerbations. Asthma exacerbations and rhinovirus infections are both associated with markedly decreased pH and ammonium levels in exhaled breath condensates. This observation is thought to be related, in part, to decreased activity of airway epithelial glutaminase. We studied whether direct rhinovirus infection and/or the host immune response to the infection decreased airway epithelial cell surface pH in vitro. Interferon-gamma and tumor necrosis factor-alpha, but not direct rhinovirus infection, decreased pH, an effect partly associated with decreased ammonium concentrations. This effect was 1) prevented by nitric oxide synthase inhibition; 2) independent of cyclic GMP; 3) associated with an increase in endogenous airway epithelial cell S-nitrosothiol concentration; 4) mimicked by the exogenous S-nitrosothiol, S-nitroso-N-acetyl cysteine; and 5) independent of glutaminase expression and activity. We then confirmed that decreased epithelial pH inhibits human rhinovirus replication in airway epithelial cells. These data suggest that a nitric oxide synthase-dependent host response to viral infection mediated by S-nitrosothiols, rather than direct infection itself, plays a role in decreased airway surface pH during human rhinovirus infection. This host immune response may serve to protect the lower airways from direct infection in the normal host. In patients with asthma, however, this fall in pH could be associated with the increased mucus production, augmented inflammatory cell degranulation, bronchoconstriction, and cough characteristic of an asthma exacerbation.
authors.affiliation: Pediatric Respiratory Medicine, University of Virginia Health System, Box 800386, Charlottesville, VA 22908, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carraro
authors.forename: Joseph
authors.initials: J
authors.lastname: Doherty
authors.forename: Khalequz
authors.initials: K
authors.lastname: Zaman
authors.forename: Iain
authors.initials: I
authors.lastname: Gainov
authors.forename: Ronald
authors.initials: R
authors.lastname: Turner
authors.forename: John
authors.initials: J
authors.lastname: Vaughan
authors.forename: John F
authors.initials: JF
authors.lastname: Hunt
authors.forename: Javier
authors.initials: J
authors.lastname: Márquez
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gaston
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010850:Picornaviridae Infections / Q000276:immunology*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000503:physiopathology* / Q000821:virology; D012229:Rhinovirus; D026403:S-Nitrosothiols / Q000494:pharmacology*; D018417:Th1 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D026403:S-Nitrosothiols; C016276:8-bromocyclic GMP; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester