Pro-inflammatory and anti-inflammatory effects of the stable prostaglandin D2 analogue, ZK 118.182.
This study examined the pro- and anti-inflammatory effects of the stable prostaglandin (PG) D2 analogue, ZK 118.182 and the mechanism by which prostaglandins may exert their anti-inflammatory activity. Co-injected locally, ZK 118.182, like PGE2 and PGD2, dose-dependently increased plasma leakage induced by intradermal injection of bradykinin in rabbit skin. Infused i.v., ZK 118.182 (0.45 microgram/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 B4 (LTB4). 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 LTB4 and FMLP was not affected in animals infused with ZK 118.182. In vitro, ZK 118.182, like PGE2 and PGD2 inhibited FMLP-induced superoxide anion (O2-) production by rabbit neutrophils. The compound, however, had minimal effects on O2- 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 PGD2 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.
Pons
F
F
Department of Applied Pharmacology, National Heart and Lung Institute, London, UK.
Williams
T J
TJ
Kirk
S A
SA
McDonald
F
F
Rossi
A G
AG
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D066298:In Vitro Techniques; D007205:Indium Radioisotopes; D018836:Inflammation Mediators / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D012867:Skin / Q000473:pathology; D013481:Superoxides / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007205:Indium Radioisotopes; D018836:Inflammation Mediators; D010975:Platelet Aggregation Inhibitors; D013481:Superoxides; C067426:ZK 118182; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015237:Dinoprost; D015230:Prostaglandin D2