Effect of inhaled KP-496, a novel dual antagonist of the cysteinyl leukotriene and thromboxane A2 receptors, on a bleomycin-induced pulmonary fibrosis model in mice

• Published in: Pulmonary pharmacology & therapeutics 2010-10, Vol.23 (5), p.425-431
• Main Authors: Kurokawa, Shigeo, Suda, Masahiro, Okuda, Toshiaki, Miyake, Yoshihide, Matsumura, Yuzuru, Ishimura, Masakazu, Saito, Ryota, Nakamura, Tsutomu
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Benzoates - administration & dosage; Benzoates - pharmacology; Bleomycin; Bronchoalveolar Lavage Fluid - cytology; Disease Models, Animal; Inflammation - metabolism; Inflammation - pathology; Inflammation - prevention & control; Leukotriene Antagonists - administration & dosage; Leukotriene Antagonists - pharmacology; Male; Medical Education; Mice; Mice, Inbred ICR; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - prevention & control; Pulmonary/Respiratory; Receptors, Leukotriene - metabolism; Receptors, Thromboxane A2, Prostaglandin H2 - antagonists & inhibitors; Receptors, Thromboxane A2, Prostaglandin H2 - metabolism; Thiazoles - administration & dosage; Thiazoles - pharmacology
• ISSN: 1094-5539; 1522-9629
• DOI: 10.1016/j.pupt.2010.04.008

Abstract Cysteinyl-leukotrienes (cysLTs) and thromboxane A2 (TXA2 ) are important mediators in inflammatory lung diseases such as bronchial asthma and idiopathic pulmonary fibrosis (IPF). We examined the effects of inhaled KP-496, a novel dual antagonist of the cysLTs and TXA2 receptors, on bleomycin-induced IPF in mice. Mice were intravenously injected bleomycin on day 0, and 0.5% of KP-496 was inhaled twice a day (30 min/time) for the entire experimental period. The effects of KP-496 were evaluated by the number of infiltrated cells in bronchoalveolar lavage fluid (BALF), hydroxyl- l -proline content in the lung, and histopathology. Analyses of BALF on days 7 and 21 revealed that inhaled KP-496 significantly decreased total cell numbers, macrophages, neutrophils, and eosinophils on both days. KP-496 significantly decreased hydroxyl- l -proline content in the lung on day 21. Histopathological analyses of lungs on day 21 demonstrated that KP-496 significantly suppressed inflammatory and fibrotic changes. Our results suggested that the suppression of cysLTs and TXA2 pathways by KP-496 could control airway inflammation and pulmonary fibrosis, and that KP-496 could be a new therapeutic agent for lung diseases with inflammation and fibrogenesis such as IPF and chronic obstructive pulmonary disease.