Cigarette smoking is a major cause of lung cancer; however,it has been difficult to reproduce the tumorigenicity of cigarette smoke in preclinical animal models.Increased lung tumorigenicity has previously only been observed in A/J mice exposed for 5 months to cigarette mainstream smoke (MS) followed by 4 months without further exposure.Here we report on long-term (18-month) whole-body exposure (6 h/day,5 d/wk) of male A/J mice to MS at total particulate matter concentrations of 150 and 300 mg/m3 or to fresh air (sham).Classical histopathological evaluation of step-serial sections identified nodular alveolar hyperplasia,bronchiolo-alveolar adenoma,and carcinoma in all groups.Lung tumor multiplicity calculated from the histopathological evaluation indicated increases of up to 5-fold for adenomas and 2-fold for carcinomas in the MS-exposed groups.Tumor nodules and surrounding normal lung tissue were microdissected from all groups.RNA array analysis of the normal lung tissue revealed the expression of several MS-exposure-related genes,such as those involved in oxidative stress,sustained inflammatory effects,and xenobiotic metabolizing pathways.MS exposure did not significantly change the K-ras mutation pattern in the three "hot spot" codons (12,13,and 61) in the tumor nodules.Our data show that long-term inhalation of MS in the A/J mouse is a promising model for cigarette-smoke-related lung cancer.Further investigations are warranted to qualify the biological relevance of the model.