Airflow limitation due to small airway diseases and emphysema is a defining feature of COPD. We investigated lung function in female A/J mice exposed to fresh air or MS from the reference cigarette 2R4F for 2, 3, or 4 x 1 hour/day, 5 days/week at 750 µg total particulate matter (TPM)/L for 3 and 5 months. Respiratory mechanics were determined in anesthetized mice (10/group) using a computer-controlled small animal ventilator (Flexivent). At 3 months, no significant increase in tissue elastance (HTIS) was found, while at 5 months HTIS was significantly increased at all smoke doses (14.6±1.2, 19.1±5.9, 18.9±2.0 and 19.4±1.8 for 0, 1500, 2250, and 3000 µg TPM/(L x day), respectively. For all MS-exposed mice at 3 and 5 months, maximal lung volume (at 30 cm H2O) was significantly increased (30.3±3.2 vs 58.5±4.2 ml/Kg, Sham vs 3000 µg TPM/(L x day) group at 5 months) and the maximal airway pressure at total lung capacity was significantly decreased (40.4.±4.4 vs 24.9±4.1 cm H2O, sham vs 3000 µg TPM/(L x day) group at 5 months). Subchronic MS exposure in A/J mice resulted in time- and dose-dependent changes in lung function parameters, similar to changes observed in bleomycin (fibrosis)- and elastase (emphysema)-treated mice.