Drug modulation of antigen-induced paw oedema in guinea-pigs: effects of lipopolysaccharide, tumour necrosis factor and leucocyte depletion.

1. In guinea-pigs previously sensitized with ovalbumin, the intra-plantar administration of the antigen induced dose-dependent and sustained oedema. An intense infiltrate of neutrophils and eosinophils was observed at the peak of the oedema (4 h). 2. Oedema induced by ovalbumin at the doses of 50 or 200 micrograms/paw was not inhibited by antihistamines (meclizine and cetirizine), a PAF antagonist (BN 50730), a cyclo-oxygenase inhibitor (indomethacin), a lipoxygenase inhibitor (MK-886), a dual type lipo- and cyclo-oxygenase inhibitor (NDGA), a bradykinin antagonist (Hoe 140) or the combination of cetirizine, MK-886, indomethacin and BN 50730. These drugs did inhibit paw oedema induced by their specific agonists or by carrageenin. These results suggest that histamine, PAF, prostaglandins, leukotrienes or bradykinin are not important in the development of immune paw oedema in guinea-pigs. 3. Dexamethasone (10 mg kg-1) inhibited oedema induced by ovalbumin (50 or 200 micrograms/paw, P < 0.05). This effect apparently does not result from inhibition of arachidonate metabolism, since indomethacin, MK-886 and NDGA were without effect. 4. Oedema induced by ovalbumin (50 or 200 micrograms/paw) was also inhibited by azelastine. This effect was not due to the anti-histaminic property of azelastine since two other potent-antihistamines, meclizine and cetirizine, were ineffective. 5. Intravenous injection of lipopolysaccharide (LPS) dose-dependently inhibited the oedema induced by ovalbumin (200 micrograms/paw). This effect could not be attributed to hypotension or leucopenia since the maximal dose applied (81 micrograms kg-1) did not induce significant changes in the blood pressure or in the white blood cell levels of the animals. It is suggested that the effect of LPS is mediated by the endogenous release of cytokines, including tumour necrosis factor (TNF alpha). Murine TNF alpha dose dependently(9-81 microg kg-1) inhibited the paw oedema induced by ovalbumin.7. The anti-oedematogenic effects of LPS and/or TNF alpha are possibly associated with their capacity to inhibit leucocyte emigration. Accordingly, guinea-pigs rendered leucopenic with vinblastine exhibited less intense oedema after ovalbumin. Vinblastine did not affect oedema induced by PAF or bradykinin,indicating that vascular responsiveness was not involved.