ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA IN THE SPONTANEOUS DEVELOPMENT OFPULMONARY FIBROSIS IN VIABLE MOTH-EATEN MUTANT MICE

The viable motheaten mutant mouse is severely immunodeficient and dies from a naturally occurring progressive pulmonary inflammation at appr oximately 10 weeks of age. The pulmonary disease is characterized by e xcessive macrophage accumulation in the lung and fibrosis. We correlat ed the development of lung injury in viable motheaten mice with tumor necrosis factor-alpha (TNF-alpha) levels in serum and lung. Significan tly increased serum TNF-alpha levels were observed by enzyme-linked im munosorbent assay in viable motheaten mice at 4, 6, and 10 weeks of ag e as compared with normal control littermate mice. These ages correlat ed well with observed changes in lung wet weights, lung collagen conte nt, and histological evidence of pulmonary inflammation and fibrosis. Qualitative assessment of lung tissue TNF-alpha levels was performed b y immunohistochemical staining using immunoperoxidase techniques. Thes e studies revealed increased levels of TNF-alpha in macrophage-like ce lls in viable motheaten mice from 5 to 10 weeks of age as compared wit h littermate control animals. Alveolar macrophages isolated from viabl e motheaten mice produced significantly greater amounts of TNF-alpha w hen stimulated with lipopolysaccharide compared with alveolar macropha ges from control animals. In addition, administration of anti-TNF-alph a antibody to motheaten bone marrow recipient mice decreased the sever ity of acute lung injury. The results demonstrate a close correlation between the development of pulmonary injury and TNF-alpha levels in th is model of spontaneously developing fibrotic lung disease.