Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension in a murine model of common bile-duct ligation

Development of portal hypertension (pht) is a central prognostic factor in patients with cirrhosis. circulating microparticles (mps) are released by hepatocytes in a caspase-dependent manner, are increased in circulation of patients with cirrhosis, and contribute to pht via induction of impaired vasoconstrictor responses. here, we tested the hypothesis that emricasan, a pan-caspase inhibitor, ameliorates pht and reduction in release of mps. we used a short-term and long-term protocol following common bile-duct ligation (bdl) in c57bl/6 mice (10 and 20 days, respectively). mice were treated daily via intraperitoneal injection with 10 mg/kg/day of emricasan or placebo. circulating mp levels were analyzed using flow cytometry and function via ex vivo angiogenesis assays. in contrast to bdl-placebo group, nearly all bdl-emricasan-treated mice survived after long-term bdl. assessment of portal pressure showed a significant increase in bdl-placebo mice compared to sham-placebo mice. in contrast, bdl-emricasan mice had significantly lower levels of portal pressure compared to bdl-placebo mice. although emricasan treatment resulted in a decrease in fibrosis, the changes did not reach statistical significance, suggesting that the effects on pht are at least in part independent of the anti-fibrotic effects of the drug. following short-term bdl, hepatocellular cell death as well as liver fibrosis had improved and circulating mps were significantly reduced in bdl-emricasan mice compared to bdl-placebo. circulating mps from bdl-placebo mice induced endothelial cell activation, and this was significantly reduced in mps from bdl-emricasan mice. our results indicate that emricasan treatment improves survival and pht in a murine model of long-term bdl. emricasan is a promising agent for the treatment of pht.