Suppression of airway hyperresponsiveness induced by ovalbumin sensitisation and RSV infection with Y-27632, a Rho kinase inhibitor

Abstract

Background: Smooth muscle contraction is one of the hallmarks of asthma. A recently developed pyridine derivative, Y-27632, a selective Rho kinase inhibitor, has been reported to inhibit the smooth muscle contraction of human and animal trachea in ex vivo systems but its effect in animal models of airway hyperresponsiveness (AHR) has not been examined. The purpose of this study was to evaluate the effect of Y-27632 in a murine model of allergic and virally induced AHR. Methods: Baseline lung resistance and methacholine induced AHR were measured in mice sensitised to ovalbumin (OVA) and also in mice infected with respiratory syncytial virus (RSV) following ovalbumin sensitisation (OVA/RSV). Results: Time course and dose ranging experiments indicated that 30 mg/kg Y-27632 given by gavage 2 hours before methacholine challenge significantly reduced baseline lung resistance and prevented AHR in OVA sensitised mice. Y-27632 also suppressed AHR induced by the bronchospastic agent serotonin in OVA sensitised mice and prevented methacholine induced AHR in OVA/RSV mice. Conclusions: These results suggest that the signalling pathway mediated through Rho kinase may have an important role in bronchial smooth muscle tone in allergen induced and virus induced AHR and should be considered as a novel target for asthma treatment.

RhoA-Derived Peptide Dimers Share Mechanistic Properties with Other Polyanionic Inhibitors of Respiratory Syncytial Virus (RSV), Including Disruption of Viral Attachment and Dependence on RSV G

“…RhoA activation appears to be important for the budding of RSV from lipid rafts (36), and cytoskeletal rearrangements mediated by RhoA contribute to, but are not essential for, the growth of RSV in some cell lines (3). RhoA signaling may also contribute to RSV pathogenesis, since interference with RhoA signaling pathways reduces the airway hyperreactivity induced by RSV infection in sensitized mice (23). Thus, RhoA appears to play an important role in RSV infection and disease, although this is likely due to the intrinsic importance of RhoA to cellular physiology (15,20,33), rather than as a specific binding partner for RSV F, as was previously hypothesized (43).…”

Regulation of airway smooth muscle RhoA/ROCK activities by cholinergic and bronchodilator stimuli

“…There has been a great deal of interest recently in the involvement of the Rho/ROCK signalling pathway in excitation-contraction coupling [11][12][13][14][15][16][17] and airway hyperresponsiveness [18][19][20][21][22]. However, the data available are limited in many ways.…”

Challenges and Opportunities for Respiratory Syncytial Virus Vaccines

“…(Hashimoto et al, 2004) While mucus metaplasia and airway mucus obstruction accounts for some of the airways responsiveness witnessed in this model, there is a strong component of smooth muscle constriction as well as evidenced by the inhibition of airways responsiveness with a Rho kinase inhibitor. (Hashimoto et al, 2002) The timing of RSV infection relative to allergic sensitization and challenge is critical to the inflammatory and physiologic phenotypes that result from this combined model. (Hashimoto et al, 2002;Peebles, Jr. et al, 2001a) RSV infection prior to allergen sensitization and challenge reduced airways responsiveness compared to sensitization and challenge alone, while RSV infection either after sensitization and challenge, or during sensitization and challenge increased airways responsiveness.…”

“…(Hashimoto et al, 2002) The timing of RSV infection relative to allergic sensitization and challenge is critical to the inflammatory and physiologic phenotypes that result from this combined model. (Hashimoto et al, 2002;Peebles, Jr. et al, 2001a) RSV infection prior to allergen sensitization and challenge reduced airways responsiveness compared to sensitization and challenge alone, while RSV infection either after sensitization and challenge, or during sensitization and challenge increased airways responsiveness. We are currently in the process of determining the role of IL-17A in RSV-induced airways responsiveness and epithelial cell mucus metaplasia.…”