title: Adenovirus-mediated inhibition of SPARC attenuates liver fibrosis in rats.
abstract: 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 Ad beta gal (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)-beta and alpha-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-beta.
  
  
  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.
authors.affiliation: Gene Therapy Laboratory, Liver Unit, School of Medicine, Austral University, Buenos Aires, Argentina.
authors.forename: Alejandra M
authors.initials: AM
authors.lastname: Camino
authors.forename: Catalina
authors.initials: C
authors.lastname: Atorrasagasti
authors.forename: Daniela
authors.initials: D
authors.lastname: Maccio
authors.forename: Federico
authors.initials: F
authors.lastname: Prada
authors.forename: Edgardo
authors.initials: E
authors.lastname: Salvatierra
authors.forename: Miguel
authors.initials: M
authors.lastname: Rizzo
authors.forename: Laura
authors.initials: L
authors.lastname: Alaniz
authors.forename: Jorge B
authors.initials: JB
authors.lastname: Aquino
authors.forename: Osvaldo L
authors.initials: OL
authors.lastname: Podhajcer
authors.forename: Marcelo
authors.initials: M
authors.lastname: Silva
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mazzolini
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D009379:Neoplasms, Muscle Tissue / Q000378:metabolism; D015676:Osteonectin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide / Q000633:toxicity; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D015676:Osteonectin; D012333:RNA, Messenger; D013853:Thioacetamide; D016212:Transforming Growth Factor beta; C498862:Acta2 protein, rat