Abstract
Injection of monosodium urate (MSU) crystals, the etiological cause of gouty arthritis, into murine peritoneal cavities produced an intense recruitment of polymorphonuclear leukocytes (PMN). After 3 mg MSU crystal injection, cell influx was maximal (∼ 10 × 106 cells per mouse) at 6 hr postinjection and sustained up to the 24 hr time-point. In mice depleted of mast cells by administration of compound 48/80 72 hr before challenge with MSU crystals a lower PMN influx was measured (58% reduction). The occurrence of endogenous mast cell activation, in the MSU response, was validated by the observation that MSU challenge reduced by more than 90% the number of intact mast cells recovered in the peritoneal washes. Pretreatment of mice with a histamine H1 antagonist (tripolidine; 0.5 mg/kg) or a platelet-activating factor receptor antagonist (WEB2086; 10 mg/kg) significantly reduced by 50 to 60% the number of PMN recovered from the peritoneal cavities. The molecular determinants of this process of leukocyte recruitment were also investigated. Treatment of mice with an anti-CD62P or anti-CD62E monoclonal antibody (mAb; 100 μg i.v.) produced a distinct inhibition of PMN recruitment measured at 6 hr, whereas only a combined administration of both monoclonal antibodies was effective in reducing by 60% the influx of PMN caused by the MSU crystals within 24 hr. In conclusion, these data highlight a role for endogenous mast cells and for endothelial-derived selectins in MSU crystal-induced PMN recruitment into the peritoneal cavity, and may be useful to dissect molecular mechanism(s) which may be operating in gouty arthritis.
Footnotes
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Send reprint requests to: Dr. Mauro Perretti, Department of Biochemical Pharmacology, The William Harvey Research Institute, Charterhouse Square, London EC1 M 6BQ, United Kingdom.
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↵1 This work was supported by an endowment to the William Harvey Research Institute by the Ono Pharmaceutical Co. (Osaka, Japan). R.J.F. is a Principal Research Fellow of the Wellcome Trust. L.P. is supported by grants from Consiglio Nazionale delle Ricerche nos. 95.02383.CT04 and 96.03339.CT04. M.A.M. is recipient of a CNPq fellowship (Brasil).
- Abbreviations:
- CPPD
- calcium pyrophosphate dihydrate
- EDTA
- ethylenediaminetetraacetic sodium salt
- mAb
- monoclonal antibody
- MSU
- monosodium urate
- peptide Ac2–26
- lipocortin 1-derived N-terminus peptide
- PBS
- phosphate-buffered saline
- PAF
- platelet-activating factor
- PMN
- polymorphonuclear leukocyte
- Received February 24, 1997.
- Accepted June 2, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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