Pharmacological modification of 12-O-tetradecanoylphorbol-13-acetate induced inflammation and epidermal cell proliferation in mouse skin

Abstract

Topical application of TPA to mouse skin causes oedema (2-6 h) neutrophil influx (3-24 h) and epidermal cell proliferation (24-48 h). Topical application of a cyclooxygenase inhibitor (indomethacin) dual cyclooxygenase and lipoxygenase inhibitors (phenidone and BW755C) a selective lipoxygenase inhibitor (AA861), protein synthesis inhibitors (cycloheximide and actinomycin D) or a glucocorticosteroid (prednisolone) inhibited oedema and neutrophil influx. Systemic administration of an inhibitor of microtubule assembly (colchicine) also prevented neutrophil influx and oedema. These results suggest that the inflammatory response to TPA depends on an interaction between a protein and products of arachidonic acid metabolism to produce a neutrophil dependent oedema. Epidermal cell proliferation was inhibited by topical administration of prednisolone, indomethacin, BW755C and cycloheximide but not systemically administered methotrexate. This suggests that inhibition of the early inflammatory response to TPA prevents the subsequent epidermal proliferation.

Topical Anti-Inflammatory Activity of Human Recombinant Epidermal Growth Factor

“…This experimental model has been suggested for the evaluation of new therapeutic agents for the treatment of inflammatory dermatoses [13].…”

Effects of Ciclosporin and Protein Synthesis Inhibitors on Cutaneous Inflammation in Mouse Skin

“…The inability of ciclosporin to in hibit this response distinguishes it from anti-inflammatory steroids which inhibit all the inflammatory reactions described in this paper [8,11,13], Ciclosporin is therefore a potent inhibitor of cutaneous inflammatory responses which are dependent on protein synthesis and in the mouse it can exert its effect after systemic absorption through the skin.…”

“…Myeloperoxidase (MPO) activity, as an index of PMN infiltration, and epidermal proliferation were determined as previously described [8]. Briefly, MPO activity was determined in ear homogenates using Odianisidine hydrochloride and hydrogen peroxide as substrates.…”

“…However, there are concerns about the possible toxicity of ciclosporin after oral administration and therefore attempts have been made to use the drug topically to limit toxicity [4], It has recently been reported that ciclo sporin inhibits a variety of responses to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin [7] suggest ing that the drug may have additional activ ities. We have recently reported that protein synthesis inhibitors are also potent inhibi tors of TPA-induced inflammation in mouse skin [8], We have therefore compared the effects of ciclosporin with protein synthesis inhibitors on a variety of cutaneous inflam matory responses in the mouse and at tempted to determine if the effect of Ciclo sporin is limited to the site of application to the skin.…”

Anti-Inflammatory Properties of Docosahexaenoic and Eicosapentaenoic Acids in Phorbol-Ester-lnduced Mouse Ear Inflammation

“…Edema formation has been estimated as the increase in wet weight of TPA-challenged ears as compared to unchallenged ears. The time course curves done during the development of this model showed that ede ma fonnation reached its maximum at approximately 6.5 h while MPO activity as a parameter of neutrophil influx peaked around 24 h [24]. Therefore, the inflammatory re sponse was measured 6.5 and 24 h after TPA challenge.…”