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

Abstract

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.

Paclitaxel Interrupts TGF-β1 Signaling Between Gallbladder Epithelial Cells and Myofibroblasts

“…After 48 h of co-culture, however, LPS prominently increased the release of TGF-β1 protein into the basolateral media. Since GBEC released TNF-α soon after being treated with LPS (5-24 h), it is possible that the basolaterally secreted TNF-α might have stimulated the release of TGF-β1 from the underlying GBMF that was observed after 48 h. This is compatible with reports on pulmonary inflammation and intestinal fibrogenesis, which show that TNF-α contributes to the induction of TGF-β1 in myofibroblasts [37].…”

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

“…[42][43][44] Overexpression of TNF-a in the rat lungs led to severe pulmonary inflammation followed by accumulation of ECM, which was mediated by secondary upregulation of TGF-b. 45 TNF-a acts as a mediator of inflammation and cellular immune responses produced mainly by activated macrophages. 46 Macrophages represent the predominant cell type, contributing to elevated CB levels, but other cell types also participate.…”

Pulmonary inflammation and bronchopulmonary dysplasia

“…This is typically associated with increased levels of TGF-b and its receptors, and overexpression of TGF-b has been shown to result in severe pulmonary fibrosis. 76 In preterm infants with BPD, increased levels of TGF-b have been detected in the airway secretions. [77][78][79] Using the data of the inhibitory effects of TGF-b levels on normal lung development, it can be speculated that interference of this cytokine with lung growth and suboptimal levels of different growth factors may also add to the pathogenesis of 'new BPD' and its possible long-term consequences.…”