Purpose of the Study
Although an important association has been established between specific viral respiratory tract infections and acute exacerbations of asthma, the mechanistic basis of this interplay remains to be elucidated. The aim of this investigation was to address the hypothesis that rhinovirus, the most common viral respiratory pathogen implicated in acute exacerbations of asthma, directly affects airway smooth muscle to produce proasthmatic changes in receptor-coupled airway smooth muscle responsiveness.
Adult New Zealand White rabbits were used as the source for airway smooth muscle cells. Human rhinovirus serotype 16 and adenovirus were cultured using standard techniques and inoculated into the prepared cultures of airway smooth muscle cells. The investigators then proceeded to obtain pharmacodynamic measurements of airway smooth muscle responsiveness and determine cyclic adenosine monophosphate (cAMP) accumulation and Gi protein expression. Moreover, the investigators determined ICAM-1 expression in rabbit airway smooth muscle cells by reverse transcriptase polymerase chain reaction and Southern blot analysis, Western blot analysis, and flow cytometry. ICAM-1 expression was also determined in human airway smooth muscle cells by Northern blot analysis.
Isolated rabbit and human airway smooth muscle tissue and cultured airway smooth muscle cells were inoculated with human rhinovirus (serotype 16) or adenovirus, each for 6 or 24 hours. As compared with adenovirus, which had no effect, inoculation of airway smooth muscle tissue with rhinovirus induced heightened airway smooth muscle tissue constrictor responsiveness to acetylcholine and attenuated the dose-dependent relaxation of airway smooth muscle to β-adrenoceptor stimulation with isoproterenol. These changes were largely prevented by pretreating the tissues with pertussis toxin or with a monoclonal blocking antibody to ICAM-1, which is the principal endogenous receptor for most rhinoviruses. The investigators also observed that the rhinovirus-induced changes in airway smooth muscle responsiveness were associated with diminished cAMP accumulation in response to dose-dependent administration of isoproterenol, and this effect was accompanied by upregulated expression of a Gi protein subtype in the airway smooth muscle. Finally, rhinovirus-induced effects on airway smooth muscle responsiveness were accompanied by cell surface expression of ICAM-1.
This investigation provides new evidence that by the binding of rhinovirus to its ICAM-1 receptor in airway smooth muscle directly induces proasthmatic phenotypic changes in airway smooth muscle responsiveness and that this binding results in upregulation of ICAM-1 and the enhanced expression and activation of Gi protein in the rhinovirus-infected tissue.
Over the past decade, we have witnessed an explosion of information regarding the role of certain respiratory viruses, particularly rhinoviruses, in the pathogenesis of asthma and airways hyperresponsiveness. This collective body of evidence supports the concept that the airway hyperresponsiveness observed in asthmatic patients during specific viral respiratory infections results from airway inflammation, cytokine release and, in some cases, specific immunoglobulin E production. This current investigation identifies the important role and molecular mechanism by which airway smooth muscle autologously induces its state of altered responsiveness after infection with rhinovirus. Hopefully, this and related data will “pave the way” for the development of rational, clinically useful therapies to reduce the morbidity and mortality experienced by patients with asthma as a direct consequence of certain viral upper respiratory infections.