Pharmacological modulation of Paf-induced rat pleurisy and its role in inflammation by zymosan.

1. The intrapleural injection of Paf-acether into rats caused, at 30 min, a marked exudation accompanied by a reduction in the pleural leucocyte count. At 6 h, the exudate volume had decreased and a significant increase in the total leucocyte count, particularly eosinophils was noted. 2. Two Paf-acether antagonists, WEB 2086 and 48740 RP abrogated the pleural leucopenia observed 30 min after Paf-acether administration, whereas the exudation was inhibited only by the former. Pleurisy was also reduced by about 60% with dexamethasone, by about 45% with BW 755C or LY 171883, a mixed cyclo-oxygenase/lipoxygenase inhibitor and a peptido-leukotriene antagonist respectively, and by about 30% with indomethacin, flurbiprofen or piroxicam. 3. Repeated daily intrapleural injections of Paf-acether led to a state of progressive desensitization to Paf-acether itself, whereas responsiveness to 5-hydroxytryptamine was maintained. In addition, the Paf-induced auto-desensitization was largely inhibited by WEB 2086. 4. Pleurisy induced by zymosan, but not by carrageenin, was significantly reduced in Paf-acether-desensitized animals. These results were consistent with those obtained with WEB 2086 which suppressed zymosan-induced but not carrageenin-induced pleurisy. 5. This study suggests that Paf-acether-induced pleurisy in the rat may be mediated by lipoxygenase arachidonic acid metabolites and that pleurisy induced by zymosan, but not by carrageenin, is largely dependent upon Paf-acether.