RESUMO
Two outbred mouse lines, phenotypically selected for differential subcutaneous (s.c.) acute inflammatory response (AIR), were analysed for urethane-induced lung inflammatory response and susceptibility to lung tumorigenesis. AIR(min) mice, which show a low response to s.c. acute inflammation, developed a persistent subacute lung inflammatory response and a 40-fold higher lung tumor multiplicity than did AIR(max) mice, which are selected for high response to s.c. acute inflammation and showed a transient lung inflammatory response. A highly significant linkage disequilibrium pattern was observed in AIR(max) and AIR(min) mice at marker alleles located within a 452-kb pulmonary adenoma susceptibility 1 (Pas1) locus region, thus defining the location of gene candidacy for inflammatory response and for the biological effects of Pas1 in this region. AIR(min) and AIR(max) mice segregated by descent the Pas1(s) and Pas1(r) alleles, respectively, providing evidence for the involvement of the Pas1 locus in the inflammatory response. The 452-kb region contains Kras2 and four additional genes, including the lymphoid-restricted membrane protein (Lrmp) gene, whose Pro-->Leu nonconservative variation was linked with inflammatory response and Pas1 allelotype. These results provide a model to explore the mechanism underlying inherited predisposition to lung cancer in the context of a link to inflammation.
Assuntos
Adenoma/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Pneumonia/genética , Animais , Animais não Endogâmicos , Marcadores Genéticos , Desequilíbrio de Ligação , Proteínas de Membrana/genética , Camundongos , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Locos de Características Quantitativas , Proteínas rasRESUMO
Two outbred mouse lines, phenotypically selected for differential subcutaneous (s.c.) acute inflammatory response (AIR), were analysed for urethane-induced lung inflammatory response and susceptibility to lung tumorigenesis. AIRmin mice, which show a low response to s.c. acute inflammation, developed a persistent subacute lung inflammatory response and a 40-fold higher lung tumor multiplicity than did AIRmax mice, which are selected for high response to s.c. acute inflammation and showed a transient lung inflammatory response. A highly significant linkage disequilibrium pattern was observed in AIRmax and AIRmin mice at marker alleles located within a 452-kb pulmonary adenoma susceptibility 1 (Pas1) locus region, thus defining the location of gene candidacy for inflammatory response and for the biological effects of Pas1 in this region. AIRmin and AIRmax mice segregated by descent the Pas1s and Pas1r alleles, respectively, providing evidence for the involvement of the Pas1 locus in the inflammatory response. The 452-kb region contains Kras2 and four additional genes, including the lymphoid-restricted membrane protein (Lrmp) gene, whose Pro¨ Leu nonconservative variation was linked with inflammatory response and Pas1 allelotype. These results provide a model to explore the mechanism underlying inherited predisposition to lung cancer in the context of a link to inflammation.
