DOSE-RELATED EFFECTS OF AMPLIGEN (POLY(I)CENTER-DOT-POLY(C12U)), A MISMATCHED DOUBLE-STRANDED-RNA, IN A BLEOMYCIN-MOUSE MODEL OF PULMONARY FIBROSIS

The antifibrotic effect of the mismatched double-stranded RNA, Amplige n (poly(I). poly(C12U)), was evaluated in a bleomycin-mouse model of p ulmonary fibrosis. Mice received a single intratracheal dose of bleomy cin (0.125 U/mouse) or saline (50 mu L) at the beginning of the experi ment, followed by 5 or 6 intraperitoneal injections of Ampligen (1.0, 5.0, 10.0, 15.0, or 25.0 mg/kg) or saline at regular intervals for 2 w eeks. Ampligen did not produce increased mortality or weight loss by i tself. However, it produced varying degrees of mortality in combinatio n with bleomycin. Five injections of 10 mg/kg Ampligen or three inject ions of 25 mg/kg Ampligen plus three injections of 10 mg/kg Ampligen i n combination with bleomycin produced significant reductions in lung c ollagen accumulation as indicated by lung hydroxyproline content compa red to the bleomycin control group. Animals receiving bleomycin plus A mpligen at all dosages had significantly reduced prolyl hydroxylase ac tivity compared to the bleomycin control group. Lipid peroxidation and bronchoalveolar lavage fluid (BALF) - supernatant protein content for the groups receiving bleomycin plus Ampligen were not reduced compare d to the bleomycin control group. In the BALF - supernatant, the activ ity of acid phosphatase, a lysosomal enzyme produced by neutrophils, m onocytes, and macrophages, was significantly decreased in the group re ceiving bleomycin plus 10 mg/kg Ampligen. Also, selected BALF differen tial immune cell counts were reduced in some of the groups receiving b leomycin plus Ampligen, but not in a consistent or dose-dependent mann er. The results of this study indicate that Ampligen can significantly reduce the bleomycin-induced increased collagen accumulation and may be therapeutically useful in the management of lung fibrosis in humans .