The inhaled Rho kinase inhibitor Y-27632 protects against allergen-induced acute bronchoconstriction, airway hyperresponsiveness, and inflammation

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 295; no. 1; p. L214
• Main Authors: Schaafsma, Dedmer, Bos, I Sophie T, Zuidhof, Annet B, Zaagsma, Johan, Meurs, Herman
• Format: Journal Article
• Language: English
• Published: United States 01-07-2008
• Subjects: Acute Disease; Allergens - toxicity; Amides - pharmacology; Animals; Asthma - chemically induced; Asthma - enzymology; Asthma - pathology; Asthma - prevention & control; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Guinea Pigs; Inflammation - chemically induced; Inflammation - enzymology; Inflammation - prevention & control; Male; Neutrophils - enzymology; Neutrophils - pathology; Pyridines - pharmacology; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism; Time Factors
• ISSN: 1040-0605
• DOI: 10.1152/ajplung.00498.2007

Recently, we have shown that allergen-induced airway hyperresponsiveness (AHR) after the early (EAR) and late (LAR) asthmatic reaction in guinea pigs could be reversed acutely by inhalation of the Rho kinase inhibitor Y-27632. The present study addresses the effects of pretreatment with inhaled Y-27632 on the severity of the allergen-induced EAR and LAR, the development of AHR after these reactions, and airway inflammation. Using permanently instrumented and unrestrained ovalbumin (OA)-sensitized guinea pigs, single OA challenge-induced EAR and LAR, expressed as area under the lung function (pleural pressure, P(pl)) time-response curve, were measured, and histamine PC(100) (provocation concentration causing a 100% increase of P(pl)) values were assessed 24 h before, and at 6 and 24 h after, the OA challenge (after the EAR and LAR, respectively). Thirty minutes before and 8 h after OA challenge, saline or Y-27632 (5 mM) was nebulized. After the last PC(100) value, bronchoalveolar lavage (BAL) was performed, and the inflammatory cell profile was determined. It was demonstrated that inhalation of Y-27632 before allergen challenge markedly reduced the immediate allergen-induced peak rise in P(pl), without significantly reducing the overall EAR and LAR. Also, pretreatment with Y-27632 considerably protected against the development of AHR after the EAR and fully prevented AHR after the LAR. These effects could not be explained by a direct effect of Y-27632 on the histamine responsiveness, because of the short duration of the acute bronchoprotection of Y-27632 (<90 min). In addition, Y-27632 reduced the number of total inflammatory cells, eosinophils, macrophages, and neutrophils recovered from the BAL. Altogether, inhaled Y-27632 protects against acute allergen-induced bronchoconstriction, development of AHR after the EAR and LAR, and airway inflammation in an established guinea pig model of allergic asthma.