Non-viral Smad7 gene delivery and attenuation of postoperative peritoneal adhesion in an experimental model.
BACKGROUND
Postoperative intra-abdominal adhesion is associated with high morbidity and mortality. Smad7, a protein that occupies a strategic position in fibrogenesis, inhibits the transforming growth factor (TGF) beta/Smad signalling pathway. In this study the therapeutic potential of exogenous Smad7 in preventing fibrogenesis in postoperative intra-abdominal adhesion was investigated.


METHODS
Intra-abdominal adhesion was induced in a rodent model by peritoneal abrasion. Smad7 was delivered into the peritoneal cavity by a non-viral ultrasound-microbubble-mediated naked gene transfection system. The effect of Smad7 transgene on adhesion formation was studied by measuring changes in TGF-beta, fibrogenic factors, alpha-SMA and Smad2/3 activation in the anterior abdominal wall.


RESULTS
Four weeks after surgical abrasion, all rats developed significant peritoneal adhesion with enhanced TGF-beta expression, increased levels of extracellular matrix components and activated myofibroblasts, accompanied by decreased Smad7 expression and increased Smad2/3 activation. In rats treated with the Smad7 transgene, the incidence and severity of peritoneal adhesion were significantly reduced, with biochemical downregulation of fibrogenic factors and inhibition of Smad2/3 activation. Serial quantitation using magnetic resonance imaging revealed a significant reduction in adhesion areas from day 14 onwards.


CONCLUSIONS
Ultrasound-microbubble-mediated gene transfection provides timely targeted gene delivery for the treatment of postoperative peritoneal adhesions.
Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong.
H
H
Guo
J C K
JC
Leung
J S
JS
Cheung
L Y Y
LY
Chan
E X
EX
Wu
K N
KN
Lai
D034861:Abdominal Wall; D000818:Animals; D005109:Extracellular Matrix / Q000473:pathology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D045423:Microbubbles; D010532:Peritoneal Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000008:administration & dosage* / Q000235:genetics; D000267:Tissue Adhesions / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D019076:Transgenes / Q000502:physiology*; D015854:Up-Regulation
D051899:Smad2 Protein; D051900:Smad3 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta