Inhibition of endotoxin- and antigen-induced airway inflammation by fudosteine, a mucoactive agent.
We evaluated the effect of a mucoactive agent (-)-(R)-2-amino-3-(3-hydroxypropylthio) propionic acid (fudosteine), on airway inflammation using endotoxin- and antigen-induced models. Time courses of growth related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) production, neutrophil migration and goblet cell hyperplasia were examined in endotoxin-induced rat airway inflammation. GRO/CINC-1 in bronchoalveolar lavage fluid (BALF) increased in response to intratracheal instillation of endotoxin and peaked within 4 h. Neutrophils in BALF and goblet cells on trachea peaked 24 and 96 h after endotoxin instillation, respectively. Fudosteine significantly inhibited increases in GRO/CINC-1 at 10-100 mg/kg, and neutrophils and goblet cells at 30 and 100 mg/kg. These results suggest that inflammatory events including neutrophil chemoattractant production and neutrophil migration play important roles for goblet cell hyperplasia in endotoxin-induced airway inflammation, and fudosteine inhibits goblet cell hyperplasia by inhibiting GRO/CINC-1 production and/or neutrophil migration. Furthermore, fudosteine (100 mg/kg) inhibited ovalbumin-induced eosinophil infiltration into BALF, suggesting it attenuates asthmatic inflammation.
Komatsu
H
H
Research Laboratory III, Pharmaceuticals Research Unit, Research and Development Division, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan. komatsu.hirotsugu@mc.m-pharma.co.jp
Yamaguchi
S
S
Komorita
N
N
Goto
K
K
Takagi
S
S
Ochi
H
H
Okumoto
T
T
D000818:Animals; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D003553:Cystine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005100:Expectorants / Q000494:pharmacology*; D020397:Goblet Cells / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009504:Neutrophils / Q000378:metabolism*; D011657:Pulmonary Eosinophilia / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D005100:Expectorants; D036341:Intercellular Signaling Peptides and Proteins; D007975:Leukotriene B4; D003553:Cystine; C113797:fudosteine