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

Abstract

Background-Transforming growth factor (TGF-) is a key mediator of collagen synthesis in the development of lung fibrosis. It has previously been shown that the administration of TGF-antibody and TGF-binding proteoglycan, decorin, reduced bleomycin (BL) induced lung fibrosis in animals. The present study was carried out to investigate whether intratracheal instillation of TGF-soluble receptor (TR) would minimise the BL induced lung fibrosis in hamsters. Methods-The eVect of a recombinant TR (TGF RII) 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 buVered 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. Results-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. Conclusions-These results suggest that TR has antifibrotic potential in vivo and may be useful in the treatment of fibrotic diseases where increased TGF-is associated with excess collagen accumulation. (Thorax 1999;54:805-812)

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

“…[22][23][24] Moreover, TGF-β antagonism with neutralizing antibodies, soluble TGF-β receptors, and over expression decorin or dominant negative TGF-β receptors has resulted in attenuation of tissue fibrosis can be attenuated in a variety of different tissues including the heart. [25][26][27] Further, expression of Smad7, an endogenous inhibitor of TGF-β induced signaling, attenuates experimentally induced lung and kidney fibrosis. 28,29 Taken together, these observations suggest that sustained activation of TGF-β can lead to pathological tissue fibrosis and/or tissue dysfunction in a variety of organs, including the heart.…”

α‐melanocyte–stimulating hormone suppresses bleomycin‐induced collagen synthesis and reduces tissue fibrosis in a mouse model of scleroderma: Melanocortin peptides as a novel treatment strategy for scleroderma?

“…A key feature in all of these diseases is excessive collagen deposition due to increased expression of profibrotic cytokines, in particular, transforming growth factor ␤1 (TGF␤1) (1). Strategies that neutralize the action of TGF␤ (2,3) or its downstream events, e.g., the Smad signal transduction pathway, have been shown to suppress experimentally induced fibrosis (4,5).…”

Prevention of radiation-induced pneumonitis by recombinant adenovirus-mediated transferring of soluble TGF-β type II receptor gene

“…Using soluble TGF-b type II receptor protein has been reported to reduce the bleomycininduced lung fibrosis in hamsters and to ameliorate radiation enteropathy in mice. 34,35 However, these strategies all require the long-term administration of the recombinant protein.…”

“…[30][31][32][33] Furthermore, the use of soluble TGF-b type II receptor protein has been demonstrated to reduce bleomycin-induced lung fibrosis in hamsters and to ameliorate radiation enteropathy in mice. 34,35 It is therefore logical to hypothesize that the intervention of TGF-b and its receptor may be a promising prophylactic target to prevent radiation-induced pneumonitis.…”