Abstract
Background and AimsAcute liver failure (ALF) is a rapidly progressive heterogeneous illness with high mortality rate and no widely accessible cure. A promising drug candidate according to previous preclinical studies is the Reg3α (or HIP/PAP) lectin, which alleviates ALF through its free-radical scavenging activity. Here we study the therapeutic targets of Reg3α in order to gain information on the nature of the oxidative stress associated with ALF.MethodsPrimary hepatocytes stressed with the reactive oxygen species (ROS) inducers TNFα and H2O2 were incubated with a recombinant Reg3α protein. ALF was induced in C57BL/6J mice by an anti-CD95 antibody. Livers and primary hepatocytes were harvested for deoxycholate separation of cellular and extracellular fractions, immunostaining, immunoprecipitation and malondialdehyde assays. Fibrin deposition was studied by immunofluorescence in frozen liver explants from patients with ALF.ResultsFibrin deposition occurs during experimental and clinical acute liver injuries. Reg3α bound the resulting transient fibrin network, accumulated in the inflammatory extracellular matrix (ECM), greatly reduced extracellular ROS levels, and improved cell viability. Hepatocyte treatment with ligands of death receptors, e.g. TNFα and Fas, resulted in a twofold increase of malondialdehyde (MDA) level in the deoxycholate-insoluble fractions. Reg3α treatment maintained MDA at a level similar to control cells and thereby increased hepatocyte survival by 35%. No antioxidant effect of Reg3α was noted in the deoxycholate-soluble fractions. Preventing fibrin network formation with heparin suppressed the prosurvival effect of Reg3α.ConclusionsReg3α is an ECM-targeted ROS scavenger that binds the fibrin scaffold resulting from hepatocyte death during ALF. ECM alteration is an important pathogenic factor of ALF and a relevant target for pharmacotherapy.
Highlights
IntroductionAcute liver failure (ALF) is a rapidly progressive illness of diverse etiologies characterized by a massive cell death and a suppression of the regenerative capacity of the liver, often leading to multi-organ failure [1,2,3]
Reg3α is an extracellular matrix (ECM)-targeted reactive oxygen species (ROS) scavenger that binds the fibrin scaffold resulting from hepatocyte death during Acute liver failure (ALF)
Acute liver failure (ALF) is a rapidly progressive illness of diverse etiologies characterized by a massive cell death and a suppression of the regenerative capacity of the liver, often leading to multi-organ failure [1,2,3]
Summary
Acute liver failure (ALF) is a rapidly progressive illness of diverse etiologies characterized by a massive cell death and a suppression of the regenerative capacity of the liver, often leading to multi-organ failure [1,2,3]. The mechanisms of liver cell injury in ALF are etiology-dependent and involve multiple interconnected death pathways, making it difficult to identify pertinent therapeutic targets. Hepatocellular oxidative cell death, which is a shared process among different ALFs, is not well understood, except, to some extent, in the case of acetaminophen-induced hepatotoxicity [6]. There is indirect evidence that ALF, like other acute tissue injuries, activates a specific fibrogenesis, different from the common fibrosis of chronic liver diseases [7,8,9,10].
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