The gene transfer of soluble VEGF type I receptor (Flt-1) attenuates peritoneal fibrosis formation in mice but not soluble TGF-beta type II receptor gene transfer.
Peritoneal fibrosis formation is a consequence of inflammation/injury and a significant medical problem to be solved. The effects of soluble VEGF receptor type I (sFlt-1) gene transfer on experimental peritoneal fibrosis were examined and compared with soluble transforming growth factor-beta (TGF-beta) receptor type II (sTGF beta RII) gene transfer. Male C57BL/6 mice were injected with 1.5 x 10(8) plaque-forming unit of adenovirus encoding active TGF-beta (AdTGF beta) intraperitoneally. Some mice had been treated with sTGF betaRII or sFlt-1 plasmid injection into skeletal muscle with electroporation 4 days before virus administration. Mice were euthanized at day 14 after virus administration. AdTGF beta induced significant elevation of serum active TGF-beta, caused significant inflammatory response [weight loss, elevation of serum amyloid-P (SAP) and IL-12, increased expression of monocyte chemoattractant protein-1 (MCP-1) mRNA], and induced marked thickening of the peritoneum and collagen deposition. Gene transfer of sFlt-1 reduced the collagen deposition approximately 81% in mesenteric tissue. Treatment with sFlt-1 decreased ICAM-1 and MCP-1 mRNA expression significantly. Significant negative correlation between serum sFlt-1 and placental growth factor level was observed, whereas there was no significant negative correlation between sFlt-1 and VEGF. On the other hand, sTGF beta RII treatment enhanced the AdTGF beta-induced inflammation (significant elevation of SAP, TNF-alpha, and IL-12 levels and upregulation of ICAM-1 and MCP-1 mRNA expressions) and failed to prevent collagen deposition. These observations indicate that sFlt-1 gene transfer might be of therapeutic benefit in peritoneal fibrosis.
Intestinal Disease Research Programme, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
Y
Y
Motomura
H
H
Kanbayashi
W I
WI
Khan
Y
Y
Deng
P A
PA
Blennerhassett
P J
PJ
Margetts
J
J
Gauldie
K
K
Egashira
S M
SM
Collins
D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis; D005355:Fibrosis; D018014:Gene Transfer Techniques; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D010537:Peritoneum / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D016212:Transforming Growth Factor beta; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000502:physiology*
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D040281:Vascular Endothelial Growth Factor Receptor-1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II