Edema and cell infiltration in the phorbol ester-treated mouse ear are temporally separate and can be differentially modulated by pharmacologic agents.

The temporal patterns of edema and accumulation of the PMN marker enzyme, myeloperoxidase (MPO), were examined following application of tetradecanoylphorbol acetate (TPA) to mouse ears. After application of 2.5 micrograms TPA, edema peaked at 6 hr, while MPO activity peaked at 24 hr. Pharmacological agents with defined mechanisms of action, delivered orally or topically, were assessed for effects on these responses. For oral administration, compounds were delivered 1 hr before and 6 hr after TPA and for topical administration compounds were delivered at 15 min and 6 hr after TPA. Topical and oral corticosteroids inhibited both edema and MPO accumulation. Cyclooxygenase and lipoxygenase inhibitors were very effective against MPO accumulation but were either inactive or moderately active vs edema. Anti-histamine/anti-serotonin agents had little effect on edema, but could inhibit or exacerbate MPO accumulation depending on dose and route of administration. Topically applied histamine itself did not effect TPA-induced edema, but markedly suppressed MPO accumulation. Acetone, the vehicle, when topically applied between 0.5 and 2 hr after TPA inhibited MPO accumulation by 60-80%, but had little effect on edema. Acetone applied before 0.5 hr or after 2 hr had no effect on either parameter. These results indicate that in the TPA-induced ear inflammation model the MPO response at 24 hr may be a useful additional indicator of drug activity.

Biology and pharmacology of recombinant human interleukin-1 beta-induced rat ear inflammation.

A single, 10 ng intradermal injection of human recombinant interleukin-1 beta (rIL-1 beta) into rat ears produced acute inflammation. Tissue wet weight (edema) and total myeloperoxidase activity (PMN accumulation), peaked at 3 hours and returned to base line at 3 days. Given orally, 1 hour prior to rIL-1 beta injection, cyproheptadine, dexamethasone, conventional NSAID's, or mixed cyclooxygenase/lipoxygenase inhibitors were potent antagonists of edema and moderate antagonists of PMN accumulation. In addition, the putative DMARD's, auranofin, dapsone, and levamisole were effective inhibitors of rIL-1 beta induced inflammation.

The effects of histamine and serotonin on polymorphonuclear leukocyte accumulation in the rat.

Histamine and serotonin were evaluated for their effects on rat polymorphonuclear leukocyte (PMN) accumulation in vivo and PMN migration in vitro. Both of the mediators inhibited the accumulation of PMNs when injected into the pleural cavity in a saline vehicle, and reduced the PMN content of the peripheral blood. Histamine also reduced the cellular influx when administered in combination with an intrapleural injection of carrageenan. Peripheral blood leukocytes removed from rats injected intrapleurally with histamine and carrageenan had a lesser chemotactic responsiveness compared with those removed from rats injected only with carrageenan. The effects of histamine in reducing PMN accumulation was abolished by treatment with cimetidine, an H2 antagonist, but not by treatment with chlorpheniramine, an H1 antagonist. These results suggest that a local release of histamine may play a role in reducing cellular infiltration into an inflammatory site.

Three day pleural inflammation: a new model to detect drug effects on macrophage accumulation.

Mononuclear cell accumulation is of major importance in maintaining chronic inflammatory conditions. In an effort to model this phenomenon, 0.3 ml of a 1% carrageenan solution was injected into the pleural cavity of rats; at various times thereafter peripheral blood and pleural exudate samples were collected. Seventy-two hours after carrageenan injection, 82.3 +/- 3.7 x 10(6) cells (N = 6; mean +/- S.E.) were present in the pleural cavity; over 80% of these cells were macrophages as determined by morphologic and histochemical criteria. Animals treated with dexamethasone had a significantly reduced number of pleural macrophages. Animals treated with the nonsteroidal anti-inflammatory agents, naproxen and indomethacin, had an elevated intrapleural macrophage content. The number of intrapleural cells was not affected by the antirheumatic agents levamisole, d- and dl-penicillamine or gold sodium thiomalate. Animals treated with tilorone, dapsone, hydroxychloroquine, phenylmethane-sulfonyl fluoride and 1,10 phenanthroline had a reduced pleural cell count.