Repeated Administration of Kupffer Cells-Targeting Nanoantioxidant Ameliorates Liver Fibrosis in an Experimental Mouse Model

• Published in: Biological & pharmaceutical bulletin 2020/01/01, Vol.43(1), pp.93-101
• Main Authors: Maeda, Hitoshi, Minayoshi, Yuki, Ichimizu, Shota, Mizuta, Yuki, Nagasaki, Taisei, Matsusaka, Kotaro, Oshiro, Shun, Oniki, Kentaro, Saruwatari, Junji, Ishima, Yu, Watanabe, Hiroshi, Otagiri, Masaki, Maruyama, Toru
• Format: Article
• Language: English
• Subjects: Acetylcysteine; Actin; Albumin; antioxidant; Antioxidants; Apoptosis; Ashes; Chemokines; chronic hepatitis; Collagen; Epidermal growth factor; Extracellular matrix; Fibrosis; Gelatinase B; Growth factors; Hepatitis; Hepatocytes; Human serum albumin; Inflammation; Interleukin 6; Kupffer cells; Liver; liver fibrosis; Mannose; Matrix metalloproteinase; Metalloproteinase; Mucin; Muscles; Oxidative stress; Reactive oxygen species; Smooth muscle; Tissue inhibitor of metalloproteinase 1; Toll-like receptors; Transforming growth factor-b; Tumor necrosis factor-TNF
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b19-00599

Kupffer cells are a major producer of reactive oxygen species and have been implicated in the development of liver fibrosis during chronic hepatitis in non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH). We recently reported on the development of a polythiolated and mannosylated human serum albumin (SH-Man-HSA) that functions as a Kupffer cell-targeting nanoantioxidant. In this material, the albumin is mannosylated, which permits it to be taken up by mannose receptor C type 1 expressed on Kupffer cells, and is also polythiolated to have antioxidant activity. To clarify the anti-fibrotic property of this nanoantioxidant, we repeatedly administered SH-Man-HSA to a liver fibrosis mouse model that was induced by the repeated treatment of the concanavalin-A, which mimics the liver fibrosis observed in NASH and ASH. SH-Man-HSA dramatically improved the survival rate and suppressed liver fibrosis in the experimental model. In addition, SH-Man-HSA suppressed hepatic oxidative stress levels, thereby decreasing the numbers of apoptotic cells. In contrast, N-acetylcysteine, which contains the same thiol content as the SH-Man-HSA, failed to show a substantial therapeutic effect in these mice. The expression levels of inflammatory genes including epidermal growth factor module-containing mucin-like receptor (Emr-1/F4/80), Toll-like receptor-4 (TLR-4), high mobility group box-1 (HMGB-1), CC chemokine ligand-5 (CCL-5), tumor necrosis factor-α (TNF-α), CCL-2, interleukin-6 (IL-6), and IL-1β, as well as fibrotic (α-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-β), and Snail) and extracellular matrix genes (collagen, type Iα2 (Col1α2), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase 1 (TIMP-1)), showed some decreasing trends by the SH-Man-HSA administration. These findings suggest that the repeated administration of the Kupffer cell-targeting nanoantioxidant, SH-Man-HSA, ameliorates liver fibrosis in mice by suppressing the level of oxidative stress and a portion of the inflammation, and has a potential therapeutic effect against NASH and ASH.