Effects of delayed treatment with transforming growth factor-p soluble receptor in a three-dose bleomycin model of lung fibrosis in hamsters

Transforming growth factor-beta (TGF-beta) plays a pivotal role in an exaggerated synthesis and accumulation of collagen in fibrotic disorders of many organs. We have previously demonstrated that repeated intratracheal (IT) instillation of TGF-beta soluble receptor (TR) in hamsters markedly decreased the bleomycin (BL)-induced lung fibrosis in response to a single dose. The present study was carried out in a 3-dose BL-hamster model of lung fibrosis to better evaluate the therapeutic potential of TR. Three doses of BL (2.5, 2.0, and 1.5 U/4 mL/kg) or an equivalent volume of isotonic saline was administered IT consecutively at weekly intervals, and phosphate-buffered saline (PBS) or TR (4 nmol/0.3 mL/hamster) by the same route twice a week, starting after the 2nd BL or 3rd BL dose. Twenty-one days after the 3rd dose of BL instillation, the hamsters were killed for bronchoalveolar lavage (BAL) and biochemical and histopathological analyses. The results showed that treatment with TR starting after either the 2nd or 3rd dose of BL caused significant reduction in BL-induced lung fibrosis, as demonstrated by marked decreases in the hydroxyproline level and prolyl hydroxylase activity of the lungs. Histopathological evaluation of the lungs also revealed that the hamsters in both BL + TR groups had markedly fewer fibrotic lesions than hamsters in BL + PBS group. These results demonstrate the beneficial effects of delayed treatment with TR in attenuating the progression of ongoing fibrotic process and suggest its potential therapeutic uses in the management of lung fibrosis in humans.