ANTIFIBROTIC EFFECT OF DECORIN IN A BLEOMYCIN HAMSTER MODEL OF LUNG FIBROSIS

We reported previously that treatment with antibody to transforming gr owth factor-beta (TGF-beta) caused a marked attenuation of bleomycin ( BL)-induced lung fibrosis (LF) in mice. Decorin (DC), a proteoglycan, binds TGF-beta and thereby down regulates all of its biological activi ties. In the present study, we evaluated the antifibrotic potential of DC in a three-dose BL-hamster model of lung fibrosis. Hamsters were p laced in the following groups: (1) saline (SA) + phosphate-buffered sa line (PBS) (SA + PBS); (2) SA + DC; (3) BL + PBS; and (4) BL + DC. Und er pentobarbital anesthesia, SA (4 mL/kg) or BL was instilled intratra cheally in three consecutive doses (2.5, 2.0, 1.5 units/kg/4 mt) at we ekly intervals. DC (1 mg/mL) or PBS was instilled intratracheally in 0 .4 mL/hamster on days 3 and 5 following instillation of each dose of S A or BL. In week 4, hamsters received three doses of either DC or PBS every other day. The hamsters were killed at 30 days following the fir st instillation, and their lungs were appropriately processed. Lung hy droxyproline levels in SA + PBS, SA + DC, BL + PBS, and BL + DC groups were 965, 829, 1854, and 1387 mu g/lung, respectively. Prolyl hydroxy lase activities were 103, 289, and 193% of SA + PBS control in SA + DC , BL + PBS, and BL; DC groups, respectively. The myeloperoxidase activ ities in the corresponding groups were 222, 890, and 274% of control ( 0.525 units/lung). Intratracheal instillation of BL caused significant increases in these biochemical markers, and instillation of DC dimini shed these increases in the BL + DC group. DC treatment also caused a significant reduction in the infiltration;of neutrophils in the bronch oalveolar lavage fluid (BALF) of hamsters in the BL + DC group. Howeve r, DC treatment had little effect on BL-induced increases in lung supe roxide dismutase activity and lipid peroxidation and leakage of plasma proteins in the BALF of the BL + DC group. Hamsters in the BL + PBS g roup showed severe multifocal fibrosis and accumulation of mononuclear inflammatory cells and granulocytes. In contrast, hamsters in the BL + DC group showed mild multifocal septal thickening with aggregations of mononuclear inflammatory cells. Hamsters in both control groups (SA + PBS and SA + DC) showed normal lung structure. Frozen lung sections following immunohistochemical staining revealed an intense staining f or EDA fibronectin and collagen type I in the BL + PBS group as compar ed with all other groups. It was concluded that DC potentially offers a novel pharmacological intervention that may be useful in tl-eating p ulmonary fibrosis. (C) 1997 Elsevier Science Inc.