Transfer of tumor necrosis factor-alpha to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-beta1 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 mechanism(s) by which it may induce fibrogenesis are not yet elucidated. Using a replication-deficient adenovirus to transfer the cDNA of tumor necrosis factor-alpha to rat lung, we have been able to study the effect of transient but prolonged (7 to 10 days) overexpression of tumor necrosis factor-alpha in normal adult pulmonary tissue. We have demonstrated that local overexpression resulted in severe pulmonary inflammation with significant increases in neutrophils, macrophages, and lymphocytes 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 extracellular 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 fibrogenic cytokine transforming growth factor-beta1 and tissues for induction of alpha-smooth muscle actin-rich myofibroblasts. Transforming growth factor-beta1 was transiently elevated from day 7 (peak at day 14) immediately preceding the onset of fibrogenesis. Furthermore, there was a striking accumulation of myofibroblasts from day 7, with the most extensive and intense immunostaining at day 14, ie, coincident with the up-regulation of transforming growth factor-beta1 and onset of fibrogenesis. 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 may be mediated by the secondary up-regulation of transforming growth factor-beta1 and induction of pulmonary myofibroblasts.
Sime
P J
PJ
Rayne Laboratory, Respiratory Medicine Unit, University of Edinburgh, Scotland.
Marr
R A
RA
Gauldie
D
D
Xing
Z
Z
Hewlett
B R
BR
Graham
F L
FL
Gauldie
J
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007124:Immunoenzyme Techniques; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D011014:Pneumonia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha