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.[1]References
- In vivo characterization of zymosan-induced mouse peritoneal inflammation. Rao, T.S., Currie, J.L., Shaffer, A.F., Isakson, P.C. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
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