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TGF-beta in the Pathogenesis of Experimental Biliary Atresia

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Key Personnel

  • Evan Nadler, M.D.
  • Tatiana Iordanskaia, Ph.D.

We have previously shown that pre-treatment with our novel cyclophilin (Cyp) inhibitor, MM284, could prevent disease in the animal model of biliary atresia (BA) by decreasing SMAD phosphorylation and TIMP-4 and MMP-7 expression. We hypothesized that MM284 treatment after viral infection would be similarly effective, and in vitro MM284 could prevent Cyp stimulation of hepatic stellate cells (HSCs). Newborn Balb/c mice were randomized to receive an intraperitoneal injection with saline control or rhesus rotavirus (RRV) within 24 hours of birth. Animals receiving RRV were further randomized to receive either 20mg/kg i.p. of MM284 or control vehicle starting day of life 2, and then thrice weekly. Mice treated with MM284 were normal weight, had an approximately five-fold decrease in TIMP-4 and a tenfold decrease in MMP7 mRNA expression when compared to RRV mice. SMAD2/3 phosphorylation in the HSC lysates revealed a significant 1.5-fold increase after CypA treatment relative to untreated cells which was completed abrogated by MM284. These findings suggest that Cyp blockade may be a novel treatment strategy in not only BA, but other liver diseases that are putatively mediated by HSC activation.