Effect of a cysteinyl leukotriene receptor antagonist on experimental emphysema and asthma combined with emphysema.
The incidence of overlapping bronchial asthma and chronic obstructive pulmonary disease has increased in recent years. Cysteinyl leukotrienes (CysLTs) play an important role in asthma, and the type 1 CysLT receptor (CysLT1R) is expressed by many inflammatory cells. We evaluated the effect of montelukast, a CysLT1R antagonist, on mouse models of asthma, porcine pancreatic elastase (PPE)-induced emphysema, and asthma combined with emphysema. Mice were sensitized with ovalbumin (OVA) on Days 0 and 14 and subsequently challenged with OVA on Days 28, 29, and 30. Pulmonary emphysema was induced by intratracheal instillation of PPE on Day 25. Mice were treated subcutaneously with montelukast or vehicle from Day 25 to Day 31. Airway hyperresponsiveness (AHR), static compliance; the number of inflammatory cells, the levels of cytokines, chemokines, LTs, and perforin in the bronchoalveolar lavage fluid, and the quantitative morphometry of lung sections were analyzed on Day 32. Treatment with montelukast significantly attenuated the AHR and eosinophilic airway inflammation in OVA-sensitized and OVA-challenged mice. Administration of montelukast significantly reduced the AHR, static compliance, and neutrophilic airway inflammation, while attenuating emphysematous lung changes, in PPE-treated mice. In PPE-treated mice subjected to allergen sensitization and challenges, montelukast significantly suppressed the AHR, static compliance, and eosinophilic and neutrophilic airway inflammation in addition to the development of experimentally induced emphysema in the lungs. Our data suggest that CysLT1R antagonists may be effective in ameliorating the consequences of PPE-induced lung damage and the changes that follow allergen sensitization and challenges.
1 Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Genyo
G
Ikeda
Nobuaki
N
Miyahara
Hikari
H
Koga
Yasuko
Y
Fuchimoto
Koichi
K
Waseda
Etsuko
E
Kurimoto
Akihiko
A
Taniguchi
Yasushi
Y
Tanimoto
Mikio
M
Kataoka
Mitsune
M
Tanimoto
Arihiko
A
Kanehiro
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D018925:Chemokines / Q000378:metabolism; D003521:Cyclopropanes; D003545:Cysteine / Q000378:metabolism*; D005260:Female; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D015289:Leukotrienes / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000188:drug therapy / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000188:drug therapy* / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D018077:Receptors, Leukotriene / Q000378:metabolism*; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000085:Acetates; D018925:Chemokines; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha; C112381:cysteinyl-leukotriene; D003545:Cysteine; C083169:leukotriene D4 receptor; C093875:montelukast