Abstract
BackgroundInflammation and fibrogenesis are directly related to chronic liver disease progression, including hepatocellular carcinoma (HCC) development. Currently there are few therapeutic options available to inhibit liver fibrosis. We have evaluated the hepatoprotective and anti-fibrotic potential of orally-administered 5′-methylthioadenosine (MTA) in Mdr2−/− mice, a clinically relevant model of sclerosing cholangitis and spontaneous biliary fibrosis, followed at later stages by HCC development.MethodologyMTA was administered daily by gavage to wild type and Mdr2−/− mice for three weeks. MTA anti-inflammatory and anti-fibrotic effects and potential mechanisms of action were examined in the liver of Mdr2−/− mice with ongoing fibrogenesis and in cultured liver fibrogenic cells (myofibroblasts).Principal FindingsMTA treatment reduced hepatomegaly and liver injury. α-Smooth muscle actin immunoreactivity and collagen deposition were also significantly decreased. Inflammatory infiltrate, the expression of the cytokines IL6 and Mcp-1, pro-fibrogenic factors like TGFβ2 and tenascin-C, as well as pro-fibrogenic intracellular signalling pathways were reduced by MTA in vivo. MTA inhibited the activation and proliferation of isolated myofibroblasts and down-regulated cyclin D1 gene expression at the transcriptional level. The expression of JunD, a key transcription factor in liver fibrogenesis, was also reduced by MTA in activated myofibroblasts.Conclusions/SignificanceOral MTA administration was well tolerated and proved its efficacy in reducing liver inflammation and fibrosis. MTA may have multiple molecular and cellular targets. These include the inhibition of inflammatory and pro-fibrogenic cytokines, as well as the attenuation of myofibroblast activation and proliferation. Downregulation of JunD and cyclin D1 expression in myofibroblasts may be important regarding the mechanism of action of MTA. This compound could be a good candidate to be tested for the treatment of (biliary) liver fibrosis.
Highlights
Liver diseases are currently the fifth cause of mortality in the Western world, and as opposed to other major causes of mortality their incidence is increasing [1,2]
Regardless of the etiology, chronic tissue injury and inflammation are increasingly recognized as driver mechanisms in liver disease progression from fibrosis, characterized by the excessive accumulation of extracellular matrix (ECM), to hepatocellular carcinoma (HCC) [1,2,3]
These links include a variety of intracellular pathways triggered by extracellular mediators like the cytokines interleukin 1 (IL1), IL6 and tumour necrosis factor alpha (TNFa), platelet-derived growth factors and transforming growth factor beta (TGFb), among others [3,4,5]
Summary
Liver diseases are currently the fifth cause of mortality in the Western world, and as opposed to other major causes of mortality their incidence is increasing [1,2]. The molecular links in the so-called inflammation-fibrosiscancer axis in the liver are currently being elucidated in experimental models of acute and chronic injury These links include a variety of intracellular pathways triggered by extracellular mediators like the cytokines interleukin 1 (IL1), IL6 and tumour necrosis factor alpha (TNFa), platelet-derived growth factors and transforming growth factor beta (TGFb), among others [3,4,5]. The absence of phosphatidylcholine from bile occurring in these mice leads to bile regurgitation into the portal tracts, causing periportal inflammation and injury early in life (2–3 weeks), periportal fibrosis (4 weeks), and the appearance of preneoplastic lesions (at 4–6 months) [10,11,12] These pathogenic characteristics resemble what occurs in human primary sclerosing cholangitis and biliary fibrosis, making these mice an excellent model to study disease mechanisms, and a test ground for hepatoprotective and antifibrotic therapies [10,11,12,13]. We have evaluated the hepatoprotective and anti-fibrotic potential of orally-administered 59-methylthioadenosine (MTA) in Mdr22/2 mice, a clinically relevant model of sclerosing cholangitis and spontaneous biliary fibrosis, followed at later stages by HCC development
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