Abstract
BackgroundFibrosing diseases are a leading cause of morbidity and mortality worldwide and, therefore, there is a need for safe and effective antifibrotic therapies. Adenosine, generated extracellularly by the dephosphorylation of adenine nucleotides, ligates specific receptors which play a critical role in development of hepatic and dermal fibrosis. Results of recent clinical trials indicate that tenofovir, a widely used antiviral agent, reverses hepatic fibrosis/cirrhosis in patients with chronic hepatitis B infection. Belonging to the class of acyclic nucleoside phosphonates, tenofovir is an analogue of AMP. We tested the hypothesis that tenofovir has direct antifibrotic effects in vivo by interfering with adenosine pathways of fibrosis using two distinct models of adenosine and A2AR-mediated fibrosis.MethodsThioacetamide (100mg/kg IP)-treated mice were treated with vehicle, or tenofovir (75mg/kg, SubQ) (n = 5–10). Bleomycin (0.25U, SubQ)-treated mice were treated with vehicle or tenofovir (75mg/kg, IP) (n = 5–10). Adenosine levels were determined by HPLC, and ATP release was quantitated as luciferase-dependent bioluminescence. Skin breaking strength was analysed and H&E and picrosirus red-stained slides were imaged. Pannexin-1expression was knocked down following retroviral-mediated expression of of Pannexin-1-specific or scrambled siRNA.ResultsTreatment of mice with tenofovir diminished adenosine release from the skin of bleomycin-treated mice and the liver of thioacetamide-treated mice, models of diffuse skin fibrosis and hepatic cirrhosis, respectively. More importantly, tenofovir treatment diminished skin and liver fibrosis in these models. Tenofovir diminished extracellular adenosine concentrations by inhibiting, in a dose-dependent fashion, cellular ATP release but not in cells lacking Pannexin-1.ConclusionsThese studies suggest that tenofovir, a widely used antiviral agent, could be useful in the treatment of fibrosing diseases.
Highlights
Fibrosing diseases are a leading cause of morbidity and mortality worldwide [1]
Tenofovir diminished extracellular adenosine concentrations by inhibiting, in a dose-dependent fashion, cellular ATP release but not in cells lacking Pannexin-1. These studies suggest that tenofovir, a widely used antiviral agent, could be useful in the treatment of fibrosing diseases
To confirm that tenofovir had direct antifibrotic effects independent of its effects on viral infection we tested the effect of the drug in mice with bleomycin-induced dermal fibrosis, an established murine model of scleroderma
Summary
The excess accumulation of extracellular matrix (ECM), affects a variety of organs including, among others, the liver, lung, and skin. The specific etiology of fibrosis in most organs is only incompletely understood an antifibrotic agent, pirfenidone was recently approved for the therapy of interstitial pulmonary fibrosis. No such agents have entered the clinic for the treatment of hepatic cirrhosis or skin fibrosis. Mice lacking adenosine deaminase have a marked increase in extracellular adenosine and suffer from excess fibrosis in lung, skin and other organs and blockade or deletion of A2AR and A2BR prevents this fibrosis [13, 14]. We tested the hypothesis that tenofovir has direct antifibrotic effects in vivo by interfering with adenosine pathways of fibrosis using two distinct models of adenosine and A2AR-mediated fibrosis
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