科研之友
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摘要
BackgroundSoluble TGF-1 type II receptor (sTRII) via TGF-1 inhibition could inhibit hepatic fibrosis, but over-dosage triggers autoimmune responses.AimTo test whether the use of a TGF-1-responsive collagen I promoter COL1A1, via generating a feedback loop to TGF-1 level, could offer accurate control on sTRII expression.MethodsRecombinant adenoviruses with COL1A1 (Ad-COL-sTRII/Luc) or CMV promoter (Ad-CMV-sTRII/Luc) were constructed and characterized. Inhibition of TGF- activity was determined both in vitro and in vivo. Total and bioactive TGF-, hepatic fibrosis scale, -SMA, collagen levels, and liver function were determined.ResultsCOL1A1, but not CMV, responded to TGF-1 in vitro. Both in vitro and in vivo, Ad-COL-sTRII could significantly, but not completely inhibit TGF-1 activity while Ad-CMV-sTRII almost completely inhibited TGF-1 activity. As evidenced by fibrosis scale, -SMA, and collagen levels in liver tissue, Ad-COL-sTRII and Ad-CMV-sTRII had comparable efficacies in treating hepatic fibrosis. Ad-COL-sTRII was better than Ad-CMV-sTRII in liver function restore. Ad-CMV-sTRII, but not Ad-COL-sTRII, induced high level of anti-dsDNA and anti-Sm antibodies in rats.ConclusionsCOL1A1 can precisely control sTRII expression to inhibit excessive bioactive TGF- level and thus inhibit hepatic fibrosis but without inducing autoimmune responses.
