Comparison study between the mechanisms of allergic asthma amelioration by a cysteinyl-leukotriene type 1 receptor antagonist montelukast and methylprednisolone.
We investigated the effects of cysteinyl-leukotriene (cysLT) type 1 receptor antagonist montelukast (MK) and compared them with those of methylprednisolone (MP) in an allergic asthma model. Rats sensitized to ovalbumin (OVA) received repeated intratracheal exposure to OVA for up to 3 consecutive days. Pretreatment with MK or MP before OVA exposure inhibited late airway response (LAR) and reduced cellular infiltration into the bronchial submucosa after the triple OVA. The amount of N-acetyl-leukotriene E(4) in the bile was significantly reduced by pretreatment with MK or MP, suggesting that both drugs reduced the production of cysLTs in the lungs. In the in vitro study, when the fragments of lungs that had been repeatedly pretreated with MK or MP and exposed to OVA were removed and incubated with OVA, the coaddition of either drug significantly reduced cysLT production. In contrast, the cysLT production following the addition of OVA to the lung fragments that had not received in vivo pretreatment with either drug was inhibited by MK but not by MP. These results indicate that MK and MP inhibit LAR by suppressing the infiltration of inflammatory cells into the bronchial submucosa, thereby inhibiting the production of cysLTs in the lungs, and that MK but not MP may inhibit cysLT production directly. The different effects on cysLT production between the two drugs may provide a rationale for the use of combination therapy with cysLT(1) receptor antagonists and steroids for the treatment of asthma.
Murai
Akira
A
Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
Abe
Masayoshi
M
Hayashi
Yuri
Y
Sakata
Noriyuki
N
Katsuragi
Takeshi
T
Tanaka
Keiichi
K
D000085:Acetates / Q000494:pharmacology*; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D001646:Bile / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003521:Cyclopropanes; D003545:Cysteine / Q000378:metabolism*; D006967:Hypersensitivity / Q000150:complications; D066298:In Vitro Techniques; D007958:Leukocyte Count; D017572:Leukotriene A4 / Q000037:antagonists & inhibitors; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D015289:Leukotrienes / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008775:Methylprednisolone / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D018077:Receptors, Leukotriene / Q000187:drug effects*; D013440:Sulfides
D000085:Acetates; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D003521:Cyclopropanes; D017572:Leukotriene A4; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; C112381:cysteinyl-leukotriene; D003545:Cysteine; C093875:montelukast; D008775:Methylprednisolone