Platelet contribution to leukotriene production in inflammation: In vivo evidence in the rabbit

The contribution of platelets to arachidonic acid transcellular metabolism may represent an important pathway of leukotriene (LT) production. The aim of this study was to investigate the role of platelets on LT production in an acute inflammatory model in the rabbit. preliminary experiments showed t hat rabbit whole blood (5 mi) stimulated in vitro with the calcium ionophor e A23187 produced LTB4 (52.7 +/- 13.9 ng) and the mixed 5,12-DiHETE (7.25 /- 075 ng). In A23187-stimulated thrombocytopenic blood, LTB4 was significa ntly reduced to 19.5 +/- 8.6 ng and 5,12-DiHETE was undetectable. Peptido-L Ts were undetectable in both conditions. In experiments using washed cells, addition of thrombin-activated platelets to fMLP-activated PMN resulted in the appearance of 5,12-DiHETE and in more than twofold increase of LTB4 sy nthesis. When H-3-arachidonic acid-labelled platelets were mixed with unlab elled PMN and challenged with fMLP and thrombin, radioactive LTB4 and 5,12- DiHETE were produced, indicating that platelet-derived arachidonic acid was utilized by PMN 5-lipoxygenase. Intravenous infusion of fMLP (2.5 nmol/kg/ min) in the rabbit induced marked granulocytopenia, thrombocytopenia and in creased TxB(2) plasma concentrations within 3 min. Electron microscopy of l ungs showed morphologically activated and aggregated platelets occluding th e capillary lumen. Activation and recruitment of circulating cells was acco mpanied by the production of LTB4 (peak levels at 1 min: 30.0 +/- 9.5 ng/ml ) and LTE4 (peak levels at 10 minutes: 77.8 +/- 11.6 ng/ml). The areas unde r the blood concentration-time curve (AUC, ng min/mi) corresponded to 812 /- 182 and 3692 +/- 658 for LTB4 and LTE4, respectively. In immunologically thrombocytopenic rabbits, the AUC for LTB4 (86.0 +/- 23.0) and LTE4 (1165 +/- 542) were both significantly different from controls while in rabbits t reated with an anti-leukoyte antiserum, both LTB4 and LTE4 were similar to controls. This experimental model provides in vivo evidence that platelets, involved in an acute inflammatory event contribute to the transcellular pr oduction of LTs.