TRANSFER OF TUMOR-NECROSIS-FACTOR-ALPHA TO RAT LUNG INDUCES SEVERE PULMONARY INFLAMMATION AND PATCHY INTERSTITIAL FIBROGENESIS WITH INDUCTION OF TRANSFORMING GROWTH-FACTOR-BETA-1 AND MYOFIBROBLASTS

Tumor necrosis factor-alpha is up-regulated in a variety of different human immune-inflammatory and fibrotic pulmonary pathologies, However, its precise role in these pathologies and, in particular, the mechani sm(s) by which it may induce fibrogenesis are not yet elucidated. Usin g a replication-deficient adenovirus to transfer the cDNA of tumor nec rosis factor-alpha to rat lung, we have been able to study the effect of transient but prolonged (7 to 10 days) overexpression of tumor necr osis factor-alpha in normal adult pulmonary tissue. We have demonstrat ed that local overexpression resulted in severe pulmonary inflammation with significant increases in neutrophils, macrophages, and lymphocyt es and, to a lesser extent, eosinophils, with a peak at day 7. By day 14, the inflammatory cell accumulation had declined, and fibrogenesis became evident, with fibroblast accumulation and deposition of extrace llular matrix proteins. Fibrotic changes were patchy but persisted to beyond day 64. To elucidate the mechanism underlying this fibrogenesis , we examined bronchoalveolar fluids for the presence of the fibrogeni c cytokine transforming growth factor-beta 1 and tissues for induction of alpha-smooth muscle actin-rich myofibroblasts. Transforming growth factor-beta 1 was transiently elevated from day 7 (peak at day 14) im mediately preceding the onset of fibrogenesis, Furthermore, there was a striking accumulation of myofibroblasts from day 7, with the most ex tensive and intense immunostaining at day 14, ie, coincident with the up-regulation of transforming growth factor-beta 1 and onset of fibrog enesis. Thus, we have provided a model of tumor necrosis factor-alpha- mediated pulmonary inflammation and fibrosis in normal adult lung, and we suggest that the fibrogenesis maybe mediated by the secondary up-r egulation of transforming growth factor-beta 1 and induction of pulmon ary myofibroblasts.