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Mouse skin inflammation induced by multiple topical applications of 12-O-tetradecanoylphorbol-13-acetate
P L Stanley1, S Steiner, M Havens
1Bristol-Myers Squibb Pharmaceutical Research Institute, Buffalo, N.Y.
Abstract:
It is well known that applications of a single dose of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse ears induces an acute inflammatory reaction consisting of erythema, edema and polymorphonuclear leukocyte (PMN) infiltration. We report here that multiple topical applications of TPA to mouse ears produce a prolonged inflammatory reaction characterized by increases in ear weight, inflammatory cell infiltration and epidermal hyperplasia. TPA was applied 5 times over 10 days to mouse ears. Epidermal thickness and PMN infiltration (myeloperoxidase content) increased 3- and 160-fold, respectively, by day 3 and remained elevated over control values throughout the test period. Ear weight was elevated from day 1 and remained high. Hydrocortisone 17-valerate and betamethasone dipropionate significantly reduced all three parameters of inflammation. Indomethacin and two other cyclo-oxygenase inhibitors, and an antihistamine had little or no effect on any of the parameters. This chronic skin inflammation model may be more relevant for evaluating anti-inflammatory compounds than the acute TPA model because the test compounds are applied after the inflammatory lesion is established, which mirrors the use of clinical anti-inflammatory drugs. Also this model may be more selective than the acute TPA model for compounds which affect leukotriene production since other pharmacological agents which are active in the acute model are not active in the multiple-application model.
Insights
Multiple topical applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse ears induce a chronic skin inflammation model. This model is more relevant for evaluating anti-inflammatory drugs than the acute TPA model.
Area of Science:
- Dermatology
- Pharmacology
- Immunology
Background:
- Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) induces acute mouse ear inflammation.
- Acute models may not accurately reflect chronic inflammatory conditions or drug efficacy.
Purpose of the Study:
- To develop and characterize a chronic skin inflammation model using multiple TPA applications.
- To compare the efficacy of anti-inflammatory agents in acute versus chronic TPA models.
Main Methods:
- Multiple topical applications of TPA (5 times over 10 days) to mouse ears.
- Quantification of ear weight, epidermal thickness, and polymorphonuclear leukocyte (PMN) infiltration (myeloperoxidase content).
- Evaluation of anti-inflammatory compounds, including hydrocortisone, betamethasone, indomethacin, and an antihistamine.
Main Results:
- Multiple TPA applications resulted in prolonged increases in ear weight, epidermal thickness, and PMN infiltration.
- Hydrocortisone and betamethasone significantly reduced inflammation parameters.
- Indomethacin and antihistamines showed minimal effects in the chronic model.
Conclusions:
- The chronic TPA mouse ear model provides a more relevant platform for evaluating anti-inflammatory compounds compared to the acute model.
- This model may be more selective for identifying compounds targeting leukotriene pathways.