Neutrophil elastase inhibitor reduces asthmatic responses in allergic sheep.
To determine the role of neutrophil elastase in asthmatic responses, we studied the effect of ONO-5046, a specific neutrophil elastase inhibitor, on antigen-induced asthmatic responses in allergic sheep. Pulmonary resistance (RL) was measured for 8 h after antigen challenge. Measurements of airway responsiveness to methacholine and bronchoalveolar lavage fluid (BALF) were obtained 8 h after challenge. Antigen challenge caused early and late increases in RL, airway hyperresponsiveness (AHR), and recruitment of neutrophils and eosinophils along with increases in TXB2 and LTB4 in BALF. ONO-5046 treatment significantly reduced both early and late bronchoconstriction, neutrophil recruitment, increases in LTB4 in BALF, and AHR. ONO-5046 post-treatment significantly reduced the increase in RL 8 h after antigen challenge. Another neutrophil elastase inhibitor, FR 134043, significantly reduced both early and late bronchoconstriction. ONO-5046 had little effect on calcium ionophore-induced LTB4 release from isolated neutrophils and whole blood obtained from drug-treated sheep. These findings suggest that neutrophil elastase is involved in antigen-induced bronchoconstriction and AHR mediated by neutrophil accumulation and 5-lipoxygenase products in allergic sheep.
Fujimoto
K
K
First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Kubo
K
K
Shinozaki
S
S
Okada
K
K
Matsuzawa
Y
Y
Kobayashi
T
T
Sugane
K
K
D000403:Airway Resistance; D000818:Animals; D000941:Antigens / Q000276:immunology; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D016227:Benzoquinones / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016084:Bronchoconstriction / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D019272:Leukocyte Elastase; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D009637:Masoprocol / Q000494:pharmacology; D016210:Methacholine Chloride; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011083:Polycyclic Compounds / Q000494:pharmacology; D012756:Sheep; D013449:Sulfonamides / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000378:metabolism
D000941:Antigens; D016227:Benzoquinones; C094461:FR 134043; D006571:Heterocyclic Compounds; D011083:Polycyclic Compounds; D013449:Sulfonamides; D016210:Methacholine Chloride; D007975:Leukotriene B4; D000001:Calcimycin; D013929:Thromboxane B2; D009637:Masoprocol; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; C069195:sivelestat; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D005998:Glycine