Tachyphylaxis in 12-0-tetradecanoylphorbol acetate- and arachidonic acid-induced ear edema

Abstract

12-0-Tetradecanoylphorbol acetate (TPA) applied to mouse ears rapidly induces an edema which is maximal by 6 hr but has substantially waned by 24 hr. (This is in contrast to many inflammatory agents that cause a prolonged edema lasting many days.) Reapplication of TPA at 16-24 hr will not provoke a second edematous response although increased erythema is evident. Arachidonic acid (AA) applied to mouse ears (4 mg) provokes an even more rapid edema which is maximal at 1 hr and has substantially waned by 6 hr. Reapplication of AA at 3-24 hr also will not provoke a second edematous response although, again, increased erythema does result. Pretreatment of ears with AA results in inhibition of the edema response to subsequent application of TPA, and TPA pretreatment moderately inhibits a subsequent response to AA. TPA-induced edema can be delayed by agents such as naproxen, an inhibitor of AA cyclooxygenase. In contrast, AA-induced edema is inhibited only by agents, such as phenidone, that inhibit both cyclooxygenase and lipoxygenase. The data suggest that the edemas result from interaction of the products of the cyclooxygenase and lipoxygenase pathways of AA metabolism. The lack of secondary edema response appears to be related to the inability of TPA or AA to reinduce vascular permeability. The effect is specific to AA and TPA; responses to xylene or anthralin are unaffected by TPA or AA pretreatment. It is postulated that the tachyphylactic effects observed involve lipoxygenase metabolites of AA.