Overexpression of tumor necrosis factor-alpha produces an increase in lungvolumes and pulmonary hypertension

Tumor necrosis factor (TNF)-alpha is a key proinflammatory cytokine that is thought to be important in the development of pulmonary fibrosis, whereas its role in pulmonary emphysema has not been as thoroughly documented. In t he present study, TNF-alpha was overexpressed in alveolar type II cells und er the control of the human surfactant protein C promoter. In this report, we further characterized the pulmonary abnormalities and provided a physiol ogical assessment of these mice. Histopathology of the lungs revealed chron ic inflammation, severe alveolar air space enlargement and septal destructi on, and bronchiolitis. However, pulmonary fibrosis was very limited and onl y seen in the subpleural, peribronchiolar, and perivascular regions. Physio logical assessment showed an increase in lung volumes and a decrease in ela stic recoil characteristic of emphysema; there was no evidence of restricti ve lung disease characteristic of pulmonary fibrosis. In addition, the mice raised in ambient conditions in Denver developed pulmonary hypertension. G elatinase activity was increased in the lavage fluid from these lungs. Thes e results suggest that in these mice TNF-alpha contributed to the developme nt of pulmonary emphysema through chronic lung inflammation and activation of the elastolytic enzymes but by itself was unable to produce significant pulmonary fibrosis.