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Dose-related effects of Ampligen (poly(I).poly(C12U)), a mismatched double-stranded RNA, in a bleomycin-mouse model
J S Wild1, D M Hyde, H R Hubbell
1Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis 95616, USA.
Abstract:
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.
Insights
Ampligen (poly(I).poly(C12U)) significantly reduced lung collagen in a bleomycin-induced pulmonary fibrosis mouse model. This double-stranded RNA may offer therapeutic benefits for human lung fibrosis management.
Area of Science:
- Immunology
- Pharmacology
- Pulmonary Medicine
Background:
- Pulmonary fibrosis is a progressive lung disease characterized by excessive collagen deposition.
- Current treatments for pulmonary fibrosis have limited efficacy and significant side effects.
- Investigating novel antifibrotic agents is crucial for managing this condition.
Purpose of the Study:
- To evaluate the antifibrotic effects of Ampligen (poly(I).poly(C12U)) in a bleomycin-induced mouse model of pulmonary fibrosis.
- To assess the impact of Ampligen on collagen accumulation, prolyl hydroxylase activity, and inflammatory markers in lung tissue.
- To determine the safety and efficacy of Ampligen as a potential therapeutic agent for lung fibrosis.
Main Methods:
- A bleomycin-induced mouse model of pulmonary fibrosis was established.
- Mice were treated with varying doses of Ampligen via intraperitoneal injections.
- Lung collagen content (hydroxyproline), prolyl hydroxylase activity, lipid peroxidation, protein content, and bronchoalveolar lavage fluid (BALF) immune cell counts were analyzed.
Main Results:
- Ampligen treatment significantly reduced lung collagen accumulation and prolyl hydroxylase activity in bleomycin-treated mice.
- Ampligen did not increase mortality or weight loss when administered alone.
- Specific dosages of Ampligen demonstrated a reduction in acid phosphatase activity and certain immune cell counts in BALF.
Conclusions:
- Ampligen exhibits significant antifibrotic effects in a preclinical model of pulmonary fibrosis.
- Ampligen demonstrates potential as a therapeutic agent for managing lung fibrosis in humans.
- Further research is warranted to explore the precise mechanisms of action and clinical applicability of Ampligen.