The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis

Apoptosis. 2005 Oct;10(5):927-39. doi: 10.1007/s10495-005-1055-4.

Abstract

Liver fibrosis and its end-stage disease cirrhosis are major world health problems arising from chronic injury of the liver by a variety of etiological factors including viruses, alcohol and drug abuse, the metabolic syndrome, autoimmune disease and hereditary disorders of metabolism. Fibrosis is a progressive pathological process in which wound-healing myofibroblasts of the liver respond to injury by promoting replacement of the normal hepatic tissue with a scar-like matrix composed of cross-linked collagen. Until recently it was believed that this process was irreversible. However emerging experimental and clinical evidence is starting to show that even cirrhosis is potentially reversible. Key to this is the discovery that reversion of fibrosis is accompanied by clearance of hepatic stellate cells (HSC) by apoptosis. Furthermore, proof-of-concept studies in rodents have demonstrated that experimental augmentation of HSC apoptosis will promote the resolution of fibrosis. Consequently there is now considerable interest in determining the molecular events that regulate HSC apoptosis and the discovery of drugs that will stimulate HSC apoptosis in a selective manner. This review will consider the regulatory role played by growth factors (e.g. NGF, IGF-1, TGFbeta), death receptor ligands (TRAIL, FAS), components and regulators of extracellular matrix (integrins, collagen, matrix metalloproteinases and their tissue inhibitors) and signal transduction proteins and transcription factors (Rho/Rho kinase, Jun N-terminal Kinase (JNK), IkappaKinase (IKK), NF-kappa B). The potential for known pharmacological agents such as gliotoxin, sulfasalazine, benzodiazepine ligands, curcumin and tanshinone I to induce HSC apoptosis and therefore to be used therapeutically will be explored.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Curcumin / pharmacology
  • Extracellular Matrix / physiology
  • Gliotoxin / pharmacology
  • Growth Substances / physiology
  • Humans
  • Liver / cytology*
  • Liver / physiopathology
  • Liver Cirrhosis / pathology*
  • Liver Cirrhosis / therapy
  • MAP Kinase Signaling System / physiology
  • Macrophages / physiology
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology
  • NF-kappa B / physiology
  • Sirolimus / pharmacology

Substances

  • Growth Substances
  • NF-kappa B
  • Gliotoxin
  • Mitogen-Activated Protein Kinase 3
  • Curcumin
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Sirolimus