PRO-INFLAMMATORY AND ANTIINFLAMMATORY EFFECTS OF THE STABLE PROSTAGLANDIN-D-2 ANALOG, ZK-118.182

This study examined the pro- and anti-inflammatory effects of the stab le prostaglandin (PG) D-2 analogue, ZK 118.182 and the mechanism by wh ich prostaglandins may exert their anti-inflammatory activity. Co-inje cted locally, ZK 118.182, like PGE(2) and PGD(2), dose-dependently inc reased plasma leakage induced by intradermal injection of bradykinin i n rabbit skin. Infused i.v., ZK 118.182 (0.45 mu g/kg/min), a dose whi ch did not affect systemic blood pressure, inhibited oedema formation in rabbit skin induced by the neutrophil-dependent agonists, formyl-me thionyl-leucyl-phenylalanine (FMLP) and leukotriene B-4 (LTB(4)). Howe ver, it did not modify plasma leakage induced by the neutrophil-indepe ndent mediators, bradykinin and platelet-activating factor (PAF). In c ontrast, neutrophil accumulation in response to LTB(4) and FMLP was no t affected in animals infused with ZK 118.182. In vitro, ZK 118.182, l ike PGE(2) and PGD(2) inhibited FMLP-induced superoxide anion (O-2(-)) production by rabbit neutrophils. The compound, however, had minimal effects on O-2(-) production induced by phorbol myristate acetate (PMA ). ZK 118.182 inhibited to a small extent FMLP but not PMA-induced neu trophil adherence. These results show that depending on the route of a dministration, the PGD(2) analogue, ZK 118.182, exhibits either pro- o r anti-inflammatory effects. The anti-inflammatory effect may be relat ed to the ability of the compound to inhibit increased microvascular p ermeability induced by neutrophil activation without interfering with neutrophil accumulation. This latter effect may be due to the analogue 's capacity to suppress neutrophil secretion to a greater extent than neutrophil adherence.