Analysis of tumor-promoter-induced inflammation in rats: participation of histamine and prostaglandin E₂

Inflammatory reactions induced by TPA (12-O-tetradecanoylphorbol 13-acetate)-type tumor promoters, including TPA, teleocidin and aplysiatoxin, and chemical mediators responsible for such inflammatory reactions were analyzed. The tumor promoter dissolved in a 0.8% sodium carboxymethyl cellulose solution was injected into a subcutaneous air pouch preformed on the dorsum of rats. Within 30 min after the injection, vascular permeability as measured by the leakage of labeled albumin into the pouch fluid was increased, with a concomitant increase in histamine level. This increase in vascular permeability was inhibited by a histamine antagonist, pyrilamine, and a serotonin antagonist, methysergide. Vascular permeability at 4 h was not inhibited by pyrilamine or methysergide but was inhibited by a cyclooxygenase inhibitor, indomethacin, with a parallel decrease in the prostaglandin E₂ level in the pouch fluid. These results suggest that the TPA-type tumor promoters induce inflammation by the mechanism of mast cell degranulation within a short period, this being followed by the stimulation of arachidonic acid metabolism. The mechanism of the in vivo effect of the TPA-type tumor promoters is discussed and compared with in vitro effects that we have previously reported.