Tetomilast was originally identified as a potent inhibitor of superoxide production in human neutrophils, and is of interest because it may relieve oxidative stress related to chronic obstructive pulmonary disease (COPD). Our objective was to determine whether tetomilast effectively protects against the development of porcine pancreatic elastase (PPE)-induced emphysema in rabbits. Rabbits were divided into three groups (sham n 19, PPE n 19, PPE/Tetomilast n 18). The rabbits were once daily orally administered vehicle solution or tetomilast 5 d/week for 4 weeks before the PPE instillation. We compared pulmonary function, inflammatory cell infiltration, oxidative stress, and the incidences of apoptosis among the three groups. Tetomilast suppressed PPE-induced increases in the incidence of apoptosis and the production of 8-hydroxydeoxyguanosine (8-OHdG) in lung tissues. PPE-instilled rabbits treated with tetomilast showed significantly less mean linear intercept and significantly better pulmonary function than rabbits administered PPE alone. Tetomilast may inhibit the development of emphysema by attenuating pulmonary inflammation and apoptosis caused by PPE-induced oxidative stress.Key words chronic obstructive pulmonary disease; tetomilast; oxidative stress; 8-hydroxy-deoxyguanosine Pulmonary emphysema is a chronic, progressive obstructive pulmonary disease pathologically defined as "dilation of the alveolar space without desmoplasia by breakdown of alveolar walls and degradation of gas exchange." 1-6) Among the numerous factors known to play key roles in the pathogenesis of the disease are inflammation, reactive oxygen species (ROS), smoking, α 1 -antitrypsin defects and disequilibrium between elastase and anti-elastase, as well as between matrix metalloproteases (MMPs) and tissue MMP inhibitor.7-9) Airflow limitation in chronic obstructive pulmonary disease (COPD) patients results from mucosal inflammation and edema, bronchoconstriction, increased secretions in the airways and loss of elastic recoil. Phosphodiesterase 4 (PDE4) is expressed in almost all inflammatory cell types. While PDE4 inhibitors are very efficacious at inhibiting pro-inflammatory mediator release from certain cell types (e.g. neutrophils, eosinophils), 10,11) there is evidence to suggest that dual inhibition of PDE4 is additive or synergistic at suppressing the activation/ functions of other cell types, which are thought to play a role in COPD (e.g. macrophages, dendritic cells, epithelial cells, lymphocytes, airway smooth muscle cells and endothelial cells).12-15) Tetomilast (6-[2-(3,4-diethoxyphenyl)thiazol-4-yl]-pyridine-2-carboxylic acid), a PDE4 inhibitor was initially isolated in vitro as the lead compound in a series of thiazole derivatives with inhibitory effects on superoxide production by human neutrophils. Tetomilast exerts both vasoprotectant and anti-inflammatory effects, mediated by inhibition of PDE4 and superoxide production.16) Tetomilast also attenuates acute lung injury, 17,18) and its anti-inflammatory effects have been n...