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.
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.
Kurokawa
Shigeo
S
Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Yamashina-ku, Kyoto, Japan.
Suda
Masahiro
M
Okuda
Toshiaki
T
Miyake
Yoshihide
Y
Matsumura
Yuzuru
Y
Ishimura
Masakazu
M
Saito
Ryota
R
Nakamura
Tsutomu
T
D000280:Administration, Inhalation; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D020024:Leukotriene Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000517:prevention & control*; D018077:Receptors, Leukotriene / Q000378:metabolism*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; C528276:KP-496; D020024:Leukotriene Antagonists; D018077:Receptors, Leukotriene; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013844:Thiazoles; D001761:Bleomycin; C083169:leukotriene D4 receptor