Effective Prevention of Liver Fibrosis by Liver-targeted Hydrodynamic Gene Delivery of Matrix Metalloproteinase-13 in a Rat Liver Fibrosis Model

被引：27

作者：

Abe, Hiroyuki ^{[1
]}

Kamimura, Kenya ^{[1
]}

Kobayashi, Yuji ^{[1
]}

Ohtsuka, Masato ^{[2
]}

Miura, Hiromi ^{[2
]}

Ohashi, Riuko ^{[3
]}

Yokoo, Takeshi ^{[1
]}

Kanefuji, Tsutomu ^{[1
]}

Suda, Takeshi ^{[1
]}

Tsuchida, Masanori ^{[4
]}

Aoyagi, Yutaka ^{[1
]}

Zhang, Guisheng ^{[5
]}

Liu, Dexi ^{[5
]}

Terai, Shuji ^{[1
]}

机构：

[1] Niigata Univ, Grad Sch Med & Dent Sci, Div Gastroenterol & Hepatol, Niigata 9518510, Japan

[2] Tokai Univ, Sch Med, Div Basic Med Sci & Mol Med, Dept Mol Life Sci, Isehara, Kanagawa 25911, Japan

[3] Niigata Univ, Med & Dent Hosp, Dept Pathol, Niigata 9518510, Japan

[4] Niigata Univ, Grad Sch Med & Dent Sci, Div Thorac & Cardiovasc Surg, Niigata 9518510, Japan

[5] Univ Georgia, Coll Pharm, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA

来源：

MOLECULAR THERAPY-NUCLEIC ACIDS | 2016年 / 5卷

关键词：

gene therapy; hydrodynamic gene delivery; liver cirrhosis; MMP13; nucleic acids delivery; HEPATIC STELLATE CELLS; NAKED PLASMID DNA; SWINE LIVER; CIRRHOSIS; EXPRESSION; MICE; HEPATOCYTES; COLLAGENASE; ACTIVATION; RESOLUTION;

D O I：

10.1038/mtna.2015.49

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

Liver fibrosis is the final stage of liver diseases that lead to liver failure and cancer. While various diagnostic methods, including the use of serum marker, have been established, no standard therapy has been developed. The objective of this study was to assess the approach of overexpressing matrix metalloproteinase-13 gene (MMP13) in rat liver to prevent liver fibrosis progression. A rat liver fibrosis model was established by ligating the bile duct, followed by liver-targeted hydrodynamic gene delivery of a MMP13 expression vector, containing a CAG promoter-MMP13-IRES-tdTomato-polyA cassette. After 14 days, the serum level of MMP13 peaked at 71.7 pg/ml in MMP13-treated group, whereas the nontreated group only showed a level of similar to 5 pg/ml (P < 0.001). These levels were sustained for the next 60 days. The statistically lower level of the hyaluronic acids in treated group versus the nontreated group (P < 0.05) reveals the therapeutic effect of MMP13 overexpression. Quantitative analysis of tissue stained with sirius red showed a statistically larger volume of fibrotic tissue in the nontreated group compared to that of MMP13-treated rats (P < 0.05). These results suggest that the liver-targeted hydrodynamic delivery of MMP13 gene could be effective in the prevention of liver fibrosis.

引用

页数：8

共 37 条

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