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Hepatic stellate cell‐targeted delivery of M6P‐HSA‐glycyrrhetinic acid attenuates hepatic fibrogenesis in a bile duct ligation rat model
Author(s) -
Luk John M.,
Zhang QiSheng,
Lee Nikki P.,
Wo Jana Y.,
Leung Pauline P.,
Liu LingXiao,
Hu MeiYu,
Cheung KwokFan,
Hui CheeKin,
Lau George K.,
Fan SheungTat
Publication year - 2007
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2007.01452.x
Subject(s) - hepatic stellate cell , immunostaining , kupffer cell , pathology , sirius red , procollagen peptidase , microbiology and biotechnology , biology , immunocytochemistry , bile duct , liver cytology , staining , chemistry , immunohistochemistry , medicine , endocrinology , liver metabolism
Background/Aims: Hepatic stellate cells (HSCs) play a key role in fibrogenesis. Here, we used mannose‐6‐phosphate‐modified human serum albumin (M6P 26 ‐HSA) as a selective carrier to deliver antifibrotic drug 18β‐glycyrrhetinic acid (18β‐GA) in experimental fibrosis animals, and tested its effect in injured liver tissues. Methods: Bile duct ligation (BDL) was performed to induce liver damage in rats. Masson's stain and immunocytochemistry were used to assess hepatic collagen deposits and uptakes of M6P 26 ‐HSA‐GA in HSCs in rat livers. Gene expression profiles of procollagen type I α2, smooth muscle actin (SMA), and transforming growth factor‐β1 (TGF‐β1) were analysed by TaqMan and quantitative polymerase chain reaction assays. The depositions of M6P 26 ‐HSA‐GA in the HSC‐T6 cell line and primary HSCs were assessed by immunofluorescent staining. Results: Treatment with M6P 26 ‐HSA‐GA at 10 mg/kg (three times/week for 2 weeks), but not the equivalent doses of free 18β‐GA and M6P 26 ‐HSA carrier alone, could significantly attenuate collagen deposits in BDL rat liver. Masson's stain and TaqMan assay revealed significant modulation of procollagen type I α2 in the BDL‐injured liver. The depositions of M6P 26 ‐HSA‐GA in HSCs were revealed by immunostaining with HSA and SMA markers. M6P 26 ‐HSA bound activated HSCs in vitro and the immunoreactivity of M6P 26 ‐HSA‐GA was detected in the cytoplasm and cell surface of HSCs and HSC‐T6 cells. The gene transcript levels of SMA and TGF‐β1 were modulated in HSC‐T6 cells treated with M6P 26 ‐HSA‐GA. Conclusions: The M6P 26 ‐HSA holds promise as a targeting carrier for the liver or HSCs, which may be used to deliver 18β‐GA as a therapeutic agent to treat liver fibrosis.