In vivo characterization of zymosan-induced mouse peritoneal inflammation.
Intraperitoneal administration of zymosan to mice resulted in marked biosynthesis of eicosanoids and influx of neutrophils with distinct time course profiles. 6-Keto-prostaglandin-F1 alpha (6-KPA) increased between 30 and 60 min and rapidly decreased thereafter. Leukotriene (LT)C4 levels showed similar patterns, but were sustained for several hours. LTB4 increased in a biphasic manner with peak increases between 2 to 3 hr. Repeated injections with zymosan suggested that incoming neutrophils generate most of the LTB4. Myeloperoxidase (MPO), an enzyme marker for neutrophils, continued to increase throughout the time course. Mast cells regulate LTB4 biosynthesis and neutrophil trafficking, whereas resident macrophages contribute to 6-KPA and LTC4 biosynthesis. The complement fragment C5a has a minimal role in zymosan-induced inflammation. Selective 5-lipoxygenase (5-LO) inhibitors, zileuton [N-(1-benzo[b]thienyl-2yl-ethyl)-N-hydroxyurea], TZI-41127 [2-(4-hydroxy-3,5-dimethylphenyl)-5-methoxy-3-methylindole] and cyclooxygenase (CO) inhibitors selectively modulated eicosanoid biosynthesis. Both 5-LO and CO inhibitors attenuated influx of neutrophils to varying degrees. A LTB4 receptor antagonist, SC-41930 [7-(3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8- propyl-2H-1-benzopyran-2-carboxylic acid) and an LTD4 receptor antagonist, LY-171883 [1-(2-hydroxy-3-propyl-4-(4-1H-tetrazol-5-yl)butoxy-phenyl) ethanone)] (i.v.) attenuated influx of neutrophils and associated LTB4 biosynthesis. These results suggest that both 5-LO and CO metabolites regulate neutrophil influx in this model. Marked eicosanoid biosynthesis and cellular influx in response to zymosan provides an attractive experimental paradigm to evaluate anti-inflammatory effects of inhibitors of arachidonate CO or 5-LO pathways.
Searle Research & Development, St. Louis, Missouri.
T S
TS
Rao
J L
JL
Currie
A F
AF
Shaffer
P C
PC
Isakson
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology; D001578:Benzopyrans / Q000494:pharmacology; D015936:Complement C5a / Q000502:physiology; D007975:Leukotriene B4 / Q000096:biosynthesis; D008297:Male; D008407:Mast Cells / Q000502:physiology; D051379:Mice; D010538:Peritonitis / Q000139:chemically induced* / Q000378:metabolism; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology*
D000098:Acetophenones; D001578:Benzopyrans; D013777:Tetrazoles; C059950:SC 41930; D007975:Leukotriene B4; D015936:Complement C5a; C044660:LY 171883; D015054:Zymosan; D009195:Peroxidase; D001094:Arachidonate 5-Lipoxygenase