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.

Abstract

Cysteinyl-leukotrienes (cysLTs) and thromboxane A(2) (TXA(2)) 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 TXA(2) 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 TXA(2) 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.

• Authors: Shigeo Kurokawa, Masahiro Suda, Toshiaki Okuda, Yoshihide Miyake, Yuzuru Matsumura, Masakazu Ishimura, Ryota Saito, Tsutomu Nakamura
• Journal: Pulmonary pharmacology & therapeutics (Pulm Pharmacol Ther) Vol. 23 Issue 5 Pg. 425-31 (Oct 2010) ISSN: 1522-9629 [Electronic] England
• PMID: 20457270 (Publication Type: Journal Article)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Benzoates
• KP-496
• Leukotriene Antagonists
• Receptors, Leukotriene
• Receptors, Thromboxane A2, Prostaglandin H2
• Thiazoles
• Bleomycin
• leukotriene D4 receptor

Topics

• Administration, Inhalation
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, pharmacology)
• Benzoates (administration & dosage, pharmacology)
• Bleomycin
• Bronchoalveolar Lavage Fluid (cytology)
• Disease Models, Animal
• Inflammation (metabolism, pathology, prevention & control)
• Leukotriene Antagonists (administration & dosage, pharmacology)
• Male
• Mice
• Mice, Inbred ICR
• Pulmonary Fibrosis (chemically induced, prevention & control)
• Receptors, Leukotriene (metabolism)
• Receptors, Thromboxane A2, Prostaglandin H2 (antagonists & inhibitors, metabolism)
• Thiazoles (administration & dosage, pharmacology)