A rho kinase inhibitor, Y-27632 inhibits pulmonary eosinophilia, bronchoconstriction and airways hyperresponsiveness in allergic mice.
Asthma is a complex inflammatory disorder involving obstruction, constriction, oedema, remodelling and hyperresponsiveness of the airways. These effects are induced by a raft of mediators, many of which exert their actions by stimulating specific G-protein-coupled receptors linked to a signal transduction pathway involving the monomeric GTPase; rho, and a downstream effector; rho kinase. The aim of this study was to determine whether administration of a selective inhibitor of rho kinase, Y-27632, attenuates airway inflammation, bronchoconstriction and hyperresponsiveness in a murine model of acute allergic inflammation. Intranasal administration of Y-27632 caused a dose-dependent inhibition in the number of eosinophils recovered from bronchoalveolar lavage fluid of ovalbumin-sensitised and challenged (allergic) mice. These inhibitory effects of intranasal Y-27632 on pulmonary eosinophilia were accompanied by a significant inhibition of the development of airways hyperresponsiveness in allergic mice. In additional studies, intranasal Y-27632 inhibited methacholine-induced increases in airways resistance in a time-dependent manner. In conclusion, these findings indicate that activation of rho kinase contributes to bronchoconstriction and eosinophil trafficking in murine models of acute allergic airway inflammation and to the development of airway hyperresponsiveness.
Henry
Peter J
PJ
Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Perth 6009, Australia. phenry@receptor.pharm.uwa.edu.au
Mann
Tracy S
TS
Goldie
Roy G
RG
D000281:Administration, Intranasal; D000536:Aluminum Hydroxide / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001315:Australia; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000517:prevention & control*; D018893:Bronchoalveolar Lavage; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006967:Hypersensitivity / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010047:Ovalbumin / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D011657:Pulmonary Eosinophilia / Q000188:drug therapy / Q000517:prevention & control*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D054460:rho-Associated Kinases
D000577:Amides; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D000536:Aluminum Hydroxide; D010047:Ovalbumin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases