Reduction of bleomycin induced lung fibrosis by transforming growth factor beta soluble receptor in hamsters

Department of Molecular Biosciences, University of California, Davis, California 95616, USA Biogen Inc, Cambridge, Massachusetts 02142, USA.
Thorax (Impact Factor: 8.56). 10/1999; 54(9):805-12.
Source: PubMed

ABSTRACT Transforming growth factor beta (TGF-beta) is a key mediator of collagen synthesis in the development of lung fibrosis. It has previously been shown that the administration of TGF-beta antibody and TGF-beta binding proteoglycan, decorin, reduced bleomycin (BL) induced lung fibrosis in animals. The present study was carried out to investigate whether intratracheal instillation of TGF-beta soluble receptor (TR) would minimise the BL induced lung fibrosis in hamsters.
The effect of a recombinant TR (TGFbetaRII) on the lung collagen accumulation was evaluated in a BL hamster model of pulmonary fibrosis. Animals were divided into four groups and intratracheally injected with saline or BL at 6.5 U/4 ml/kg followed by intratracheal instillation of phosphate buffered saline (PBS) or 4 nmol TR in 0.3 ml twice a week. Twenty days after the first intratracheal instillation the hamsters were killed for bronchoalveolar lavage (BAL) fluid, biochemical, and histopathological analyses.
Treatment of hamsters with TR after intratracheal instillation of BL significantly reduced BL induced lung fibrosis as shown by decreases in the lung hydroxyproline level and prolyl hydroxylase activity, although they were still significantly higher than those of the saline control. Histopathological examination showed a considerable decrease in BL induced fibrotic lesions by TR treatment. However, TR did not prevent the BL induced increases in total cells and protein in the BAL fluid.
These results suggest that TR has antifibrotic potential in vivo and may be useful in the treatment of fibrotic diseases where increased TGF-beta is associated with excess collagen accumulation.

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Available from: Shri N Giri, Jan 14, 2014
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    • "Transforming growth factor-b (TGF-b) is a key cytokine that has been implicated in both epithelial repair and matrix deposition and there is considerable evidence that it plays a central role the pathogenesis of fibrotic diseases. Increased levels of TGF-b have been found in fibroblastic foci of IPF patients (Broekelmann et al. 1991), overexpression of active TGF-b induces fibrosis (Sime et al. 1997), whereas inhibition has prevented fibrosis (Wang et al. 1999) in animal models of disease. Despite the considerable evidence implicating TGF-b in pulmonary fibrosis, no specific inhibitors of TGF-b have emerged as therapies for IPF. "
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    ABSTRACT: Transforming growth factor-β (TGF-β) plays an important role in the development of tissue fibrosis, and molecules inhibiting this pathway are attractive therapeutic targets for fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). Activation of TGF-β is the rate-limiting step in TGF-β bioavailability, and activation by the αVβ6 integrin is important in fibrosis of the lung, liver, and kidney. Activation of TGF-β by αVβ6 requires direct cell–cell contact and measurable release of active TGF-β in extracellular fluid compartments does not reflect tissue specific activation. The aim of this study was to determine the effect of antifibrotic compounds on both total, and specific αVβ6 integrin-mediated TGF-β activity. Using a transformed mink lung cell (TMLC) TGF-β reporter, the effects of potential antifibrotic therapies including an activin-like kinase (Alk5) inhibitor, Dexamethasone, Pirfenidone, N-acetylcysteine (NAC), and BIBF1120 were assessed. Effects due to αVβ6 integrin-mediated TGF-β activity were measured using reporter cells cocultured with cells expressing αVβ6 integrins. These high-throughput studies were validated using a phosphorylated Smad2 Enzyme-Linked Immunosorbent Assay. Alk5 inhibitors are potent inhibitors of TGF-β activity, whereas the novel antifibrotics, Pirfenidone, BIBF1120, and NAC are only moderate inhibitors, and Dexamethasone does not specifically affect TGF-βactivity, but inhibits TGF-β-induced gene expression. None of the current small molecular inhibitors inhibit αVβ6-mediated TGF-β activity. These results demonstrate the potential of this high-throughput assay of αVβ6-specific TGF-β activity and illustrate that currently available antifibrotics have limited effects on αVβ6 integrin-mediated TGF-β activity.
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    • "This suggests that TGF-b inhibition would enhance the efficacy of currently used therapies [4]. Indeed, a protective effect on the development of lung fibrosis has been described in different animal models when using anti-TGF-b antibodies, decorin or TGF-b soluble receptors [5] [6] [7] [8]. "
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    • "For example, it has been demonstrated that IFN-g can inhibit the in vitro production of collagen by fibroblasts and chondrocytes and can decrease type I and III procollagen mRNA steady-state levels in these two types of cells (Sakaida et al., 1999). TGF-b is a well-known inducer of collagen synthesis, and agents antagonizing TGF-b-induced fibrosis have been shown to block or attenuate experimentally induced fibrosis (Wang et al., 1999; Yamamoto et al., 1999). Therefore, strategies focused at neutralizing the most fibrogenic cytokine, TGF-b, may provide a promising approach to preventing excessive accumulation of collagen in fibrosis. "
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