Tetomilast Attenuates Elastase-Induced Pulmonary Emphysema through Inhibition of Oxidative Stress in Rabbits

Abstract

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...

Protective effect of Galectin-9 in murine model of lung emphysema: Involvement of neutrophil migration and MMP-9 production

“…One of the current accepted hypotheses regarding the pathogenesis of cigarette-smoke-induced emphysema is the involvement of a protease–antiprotease imbalance. Based on this hypothesis, experimental emphysema mice models were designed by the administration of elastolytic enzymes, such as PPE, either by intratracheal instillation or aerosol inhalation [34, 35]. The PPE-induced emphysema models have been used in studies for more than 40 years [36] to reproduce some of the characteristics of cigarette-smoke-induced disease in humans, such as enlargement of air spaces, inflammatory cell influx into the lung, and systemic inflammation [37].…”

Therapeutic effects of LASSBio-596 in an elastase-induced mouse model of emphysema

“…Several studies have developed new pharmacologic strategies to mitigate the inflammation or remodeling processes (Churg et al, 2007 ; Baila et al, 2012 ). Despite the results obtained in animal models, application of these therapies in patients was associated with only mild improvement and did not prevent disease progression (Loza et al, 2012 ; Zuo et al, 2014 ).…”

Oxidative Stress and Inflammation in Acute and Chronic Lung Injuries

“…The use of animal models for emphysema and COPD allows for the investigation of specific pathological features, such as bronchoconstriction and alveolar destruction, and the identification of contributing mechanisms, which ultimately facilitates the development of novel therapeutic strategies. The large majority of these models have been designed in mice and rats, although guinea pigs [ 163 ], hamsters [ 164 ], rabbits [ 165 ], and dogs [ 166 ] have been used as well.…”