The goals of this investigation are the elucidation of the roles of arachidonic acid (AA) metabolism in the tumor promotion stage of mouse skin carcinogenesis. Since inhibition of this metabolism reduces papilloma incidence, it is proposed that at least some of these AA metabolites have a direct or indirect role in the processes needed for tumor development. These functions will be determined by addressing the following questions: (1) Do specific AA metabolites play a role in the normal and TPA induced growth and differentiation processes of the epidermis? The effect of the principal prostaglandins (PGE/2, PGF/2 alpha and PGD/2) and the predominant lipoxygenase products (5-, 12- and 5-HETE) on proliferation and maturation parameters will be determined using primary cultures of murine epidermis in defined media, in the presence and absence of TPA and cyclooxygenase of lipoxygenase inhibitors. (2) Are the TPA-induced AA metabolites responsible for the inflammation observed in SENCAR mice and is this metabolism or inflammation important for the final carcinoma incidence? Inflammation will be quantitated by measuring vascular permeability, edema and the cellular infiltrate component in inbred SENCAR and C57B1/6 treated once or repeatedly with tumor promoters, with and without cyclooxygenase or lipoxgenase inhibitors. It will be determined if inhibitors of AA metabolism inhibit principally papilloma formation or whether inhibition of conversion to carcinomas also occurs. (3) Does TPA alter immune responsiveness, are these changes mediated in part by excessive arachidonate metabolism and are the differences in response to TPA between C57B1/6 and inbred SENCAR with regard to promotion due to differences in immune response? Selected parameters of the immune system with emphasis on the skin will be measured in nomal and TPA- treated (once or multiply) inbred SENCAR and C57B1/6 mice: Langerhans cells, T-helper and T-suppressor populations and responses.
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