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


METHODS
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.


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-beta is associated with excess collagen accumulation.
Wang
Q
Q
Department of Molecular Biosciences, University of California, Davis, California 95616, USA Biogen Inc, Cambridge, Massachusetts 02142, USA.
Wang
Y
Y
Hyde
D M
DM
Gotwals
P J
PJ
Koteliansky
V E
VE
Ryan
S T
ST
Giri
S N
SN
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D001761:Bleomycin / Q000009:adverse effects*; D001992:Bronchoalveolar Lavage Fluid; D002455:Cell Division / Q000187:drug effects; D003094:Collagen; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D006909:Hydroxyproline / Q000494:pharmacology; D008297:Male; D008647:Mesocricetus; D006899:Mixed Function Oxygenases / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000517:prevention & control*; D018125:Receptors, Transforming Growth Factor beta / Q000008:administration & dosage / Q000627:therapeutic use*
D000903:Antibiotics, Antineoplastic; D018125:Receptors, Transforming Growth Factor beta; D001761:Bleomycin; D003094:Collagen; D006899:Mixed Function Oxygenases; D006909:Hydroxyproline