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Adenovirus‐mediated inhibition of SPARC attenuates liver fibrosis in rats
Author(s) -
Camino Alejandra M.,
Atorrasagasti Catalina,
Maccio Daniela,
Prada Federico,
Salvatierra Edgardo,
Rizzo Miguel,
Alaniz Laura,
Aquino Jorge B.,
Podhajcer Osvaldo. L.,
Silva Marcelo,
Mazzolini Guillermo
Publication year - 2008
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1228
Subject(s) - hepatic stellate cell , thioacetamide , osteonectin , hepatic fibrosis , fibrosis , transdifferentiation , in vivo , extracellular matrix , timp1 , myofibroblast , pathology , transforming growth factor , hepatotoxin , chemistry , biology , endocrinology , medicine , cell , gene expression , microbiology and biotechnology , biochemistry , alkaline phosphatase , toxicity , gene , osteocalcin , enzyme
Background The interaction between fibrogenic cells and extracellular matrix plays a role in liver fibrosis, yet the mechanisms are largely unknown. Secreted protein, acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that is expressed by hepatic stellate cells and is overexpressed in fibrotic livers. We investigated the in vivo role of SPARC in experimentally induced liver fibrosis in rats. Methods A recombinant adenovirus carrying antisense SPARC was constructed (AdasSPARC). Advanced liver fibrosis was induced in Sprague‐Dawley rats by prolonged intraperitoneal administration of thioacetamide. Animals received injections of AdasSPARC or Adβgal (control adenovirus) via the tail vein and directly into the liver 1 week after the first dose. The pathological changes in liver tissues and indices of fibrosis were assessed at eight weeks. Expression of SPARC, transforming growth factor (TGF)‐β and α‐smooth muscle actin were evaluated by quantitative real‐time polymerase chain reaction, western blotting, enzyme‐linked immunosorbent assay and immunohistochemistry. Results Hepatic SPARC expression significantly increased during the development of liver fibrosis. AdasSPARC markedly attenuated the development of hepatic fibrosis in rats treated with thiocetamide, as assessed by decreased collagen deposition, lower hepatic content of hydroxyproline and less advanced morphometric stage of fibrosis. AdasSPARC treatment reduced inflammatory activity (Knodell score) and suppressed transdifferentiation of hepatic stellate cell to the myofibroblasts like phenotype in vivo . Furthermore, in vitro inhibition of SPARC on hepatic stellate cells decreases the production of TGF‐β. Conclusions This is the first study to demonstrate that knockdown of hepatic SPARC expression ameliorates thioacetamide‐induced liver fibrosis in rats with chronic liver injury. SPARC is a potential target for gene therapy in liver fibrosis. Copyright © 2008 John Wiley & Sons, Ltd.