Dose-related effects of Ampligen (poly(I).poly(C12U)), a mismatched double-stranded RNA, in a bleomycin-mouse model of pulmonary fibrosis.
The antifibrotic effect of the mismatched double-stranded RNA, Ampligen (poly(I).poly(C12U)), was evaluated in a bleomycin-mouse model of pulmonary fibrosis. Mice received a single intratracheal dose of bleomycin (0.125 U/mouse) or saline (50 microL) at the beginning of the experiment, 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 weeks. Ampligen did not produce increased mortality or weight loss by itself. However, it produced varying degrees of mortality in combination with bleomycin. Five injections of 10 mg/kg Ampligen or three injections of 25 mg/kg Ampligen plus three injections of 10 mg/kg Ampligen in combination with bleomycin .produced significant reductions in lung collagen accumulation as indicated by lung hydroxyproline content compared to the bleomycin control group. Animals receiving bleomycin plus Ampligen at all dosages had significantly reduced prolyl hydroxylase activity 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 compared to the bleomycin control group. In the BALF-supernatant, the activity of acid phosphatase, a lysosomal enzyme produced by neutrophils, monocytes, and macrophages, was significantly decreased in the group receiving bleomycin plus 10 mg/kg Ampligen. Also, selected BALF differential immune cell counts were reduced in some of the groups receiving bleomycin plus Ampligen, but not in a consistent or dose-dependent manner. 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.
Wild
J S
JS
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis 95616, USA.
Hyde
D M
DM
Hubbell
H R
HR
Giri
S N
SN
D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001761:Bleomycin; D001835:Body Weight / Q000502:physiology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006909:Hydroxyproline / Q000032:analysis; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology*; D011072:Poly U / Q000494:pharmacology*; D011393:Procollagen-Proline Dioxygenase / Q000032:analysis; D011506:Proteins / Q000032:analysis; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000188:drug therapy* / Q000401:mortality; D012330:RNA, Double-Stranded / Q000494:pharmacology
D000998:Antiviral Agents; D011506:Proteins; D012330:RNA, Double-Stranded; D001761:Bleomycin; D011072:Poly U; C047490:poly(I).poly(c12,U); D011393:Procollagen-Proline Dioxygenase; D000135:Acid Phosphatase; D011070:Poly I-C; D006909:Hydroxyproline