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 stable prostaglandin (PG) D-2 analogue, ZK 118.182 and the mechanism by which prostaglandins may exert their anti-inflammatory activity. Co-injected locally, ZK 118.182, like PGE(2) and PGD(2), dose-dependently increased plasma leakage induced by intradermal injection of bradykinin in rabbit skin. Infused i.v., ZK 118.182 (0.45 mu g/kg/min), a dose which did not affect systemic blood pressure, inhibited oedema formation in rabbit skin induced by the neutrophil-dependent agonists, formyl-methionyl-leucyl-phenylalanine (FMLP) and leukotriene B-4 (LTB(4)). However, it did not modify plasma leakage induced by the neutrophil-independent mediators, bradykinin and platelet-activating factor (PAF). In contrast, neutrophil accumulation in response to LTB(4) and FMLP was not affected in animals infused with ZK 118.182. In vitro, ZK 118.182, like 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 neutrophil adherence. These results show that depending on the route of administration, the PGD(2) analogue, ZK 118.182, exhibits either pro- or anti-inflammatory effects. The anti-inflammatory effect may be related to the ability of the compound to inhibit increased microvascular permeability 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.