The long term objective is to understand the mechanisms by which lung tumor growth is enhanced by non-genotoxic compounds and to identify the genes which regulate susceptibility to this process. The food additive, butylated hydroxytoluene (BHT), encourages the development of tumors from previously initiated cells. The quinone methide, QM-OH, is derived from a hydroxylated metabolite of BHT, BHTOH, and is the probable reactive species that promotes tumors. These metabolic reactions occur in the bronchiolar nonciliated Clara cells, one of the cell types from which these tumors arise. Inbred strains vary in their susceptibility to BHT-induced lung tumor promotion. Chronic administration of BHT to promotion sensitive (B+ phenotype) mice causes a chronic inflammation not observed in promotion resistant (B-phenotype) mice. Hypothesis 1: We will test whether this inflammation is necessary for promotion using genetic tests, pharmacologic interventions, and directly adding BAL (bronchoalveolar lavage) fluid to Clara cell isolates and to tumorigenic and non-tumorigenic cultured lung epithelial lines. Hypothesis 2: Inflammatory mediators and the BHT metabolites prevent normal lung cells from inhibiting the clonal expansion of neighboring initiated (Kras mutated) cells. Two important mechanisms for doing this are disrupting heterologous gap junctional intercellular communication (GJIC) between normal and initiated cells and causing selective apoptosis of the normal cells. This will be tested by examining GJIC and apoptosis in vivo in B+ and B- strains after BHT treatment. We will also test whether the Gja1 gene encoding the gap junction protein, Cx43, regulates susceptibility to promotion.
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