Inhibition of endogenous hedgehog signaling protects against acute liver injury after ischemia reperfusion

Pharm Res. 2010 Nov;27(11):2492-504. doi: 10.1007/s11095-010-0246-z. Epub 2010 Aug 25.

Abstract

Purpose: Although Hedgehog (Hh) signaling is required for endodermal commitment and hepatogenesis, the possibility that it regulates liver injury after ischemia reperfusion (I/R) has not been considered. Therefore, we determined the expression pattern of Hh signaling and its role in liver injury following I/R using Hh antagonist cyclopamine (CYA).

Methods: Sprague-Dawley rats were randomly divided into three groups. Sham group underwent a sham operation with no liver I/R. Vehicle or CYA preconditioned I/R groups underwent liver ischemia for 90 min followed by reperfusion for 1 h. Liver tissue and blood were analyzed for gene expression, histological and biochemical evaluation.

Results: Hedgehog ligands were upregulated after reperfusion injury. Serum levels of aspartate transaminase and alanine transaminase, inflammatory cytokines, neutrophil infiltration, and tissue damage were significantly less in CYA-pretreated rats compared with vehicle-pretreated rats. CYA also decreased the phosphorylated form of JNK and ERK.

Conclusions: This study provides evidence that endogenous Hh signaling is an early mediator of liver injury and inflammation after I/R. CYA abrogates normothermic I/R injury in rats by inhibiting the MAPK pathway and decreasing the acute inflammatory response. This novel strategy of preconditioning livers with Hh antagonist may have effective therapeutic potential in preventing acute liver injury.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Base Sequence
  • Cytokines / metabolism
  • DNA Primers
  • Enzyme-Linked Immunosorbent Assay
  • Fluorescent Antibody Technique
  • Hedgehog Proteins / metabolism*
  • Inflammation Mediators / metabolism
  • Liver Diseases / prevention & control*
  • Mitogen-Activated Protein Kinases / metabolism
  • Polymerase Chain Reaction
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / prevention & control*
  • Signal Transduction*
  • Veratrum Alkaloids / therapeutic use

Substances

  • Cytokines
  • DNA Primers
  • Hedgehog Proteins
  • Inflammation Mediators
  • Veratrum Alkaloids
  • Mitogen-Activated Protein Kinases
  • cyclopamine