Transfer of tumor necrosis factor-α to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-β1 and myofibroblasts

被引:231
作者
Sime, PJ
Marr, RA
Gauldie, D
Xing, Z
Hewlett, BR
Graham, FL
Gauldie, J
机构
[1] McMaster Univ, Hlth Sci Ctr, Dept Pathol, Hamilton, ON L8N 3Z5, Canada
[2] McMaster Univ, Dept Biol, Hamilton, ON L8N 3Z5, Canada
[3] Univ Edinburgh, Rayne Lab, Resp Med Unit, Edinburgh, Midlothian, Scotland
基金
英国医学研究理事会;
关键词
D O I
10.1016/S0002-9440(10)65624-6
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
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-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) 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-beta 1 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 maybe mediated by the secondary up-regulation of transforming growth factor-beta 1 and induction of pulmonary myofibroblasts.
引用
收藏
页码:825 / 832
页数:8
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