Therapeutic targets for cholestatic liver injury.

INTRODUCTION: Cholestasis is a reduction in bile flow that occurs during numerous pathologies. Blockage of the biliary tracts results in hepatic accumulation of bile acids or their conjugate bile salts. The molecular mechanisms behind liver injury associated with cholestasis are extensively studied, but not well understood. Multiple models of obstructive cholestasis result in a significant inflammatory infiltrate at the sites of necrosis that characterize the injury. AREAS COVERED: This review will focus on direct bile acid toxicity during cholestasis, bile acid signaling processes and on the development and continuation of inflammation during cholestasis, with a focus on novel proposed molecular mediators of neutrophil recruitment. While significant progress has been made on these molecular mechanisms, a continued focus on how cholestasis and the innate immune system interact is necessary to discover targetable therapeutics that might protect the liver while leaving global immunity intact. EXPERT OPINION: While bile acid toxicity likely occurs in humans and other mammals when toxic bile acids accumulate, persistent inflammation is likely responsible for continued liver injury during obstructive cholestasis. Targeting molecular mediators of inflammation may help prevent liver injury during acute cholestasis both in murine models and human patients.