In an effort to develop cigarette smoke-induced COPD animal models, we investigated the inflammatory and histological changes in lungs from A/J mice with known susceptibility to cigarette smoke-induced emphysema. Female A/J mice were exposed to either fresh air or mainstream smoke (MS) from the reference cigarette 2R4F for 2, 3, or 4 x 1 hour per day, 5 days/week at 750 µg total particulate matter/l for 3 or 5 months (10 to 16 mice/group). Bronchoalveolar lavage (BAL) was performed; inflammatory mediators and cells were quantified in BAL fluid (BALF). Lymphocyte subpopulations were quantified in bronchial lymph nodes by flow cytometry; lungs were evaluated histopathologically. Inflammatory mediators such as IL1α, TNFα, MCP-1, KC, MIP-2, as well as matrix metalloproteinase-9 showed a 4- to 134-fold increase in BALF following MS-exposure. BAL cells increased significantly in smoke-exposed mice resulting from an influx of both lymphocytes (8e4 ± 0.8e4 vs.1e4 ± 0.4e4) and neutrophils (3e5 ± 0.3e5 vs. 8e3 ± 7e3, MS high dose vs sham, mean ± se, 5 months). Alveolar macrophages were activated, as shown by increased MAC1 and CD86 expression. Lymph node lymphocytes were unaffected by MS exposure. Histopathological analysis of lung tissue revealed epithelial hyperplasia and thickened and inflamed perivascular and peribronchial interstitium as well as indications of emphysema. This needs to be further confirmed by morphometric analysis. Thus, following MS-exposure A/J mice showed pronounced pulmonary inflammation accompanied by histopathologically detectable signs of emphysema. Therefore, the A/J mouse should be further investigated as a potential model for cigarette smoke-induced COPD.