Molecular mechanisms in the pathogenesis of N-nitrosodimethylamine induced hepatic fibrosis

Cell Death Dis. 2019 Jan 8;10(1):18. doi: 10.1038/s41419-018-1272-8.

Abstract

Hepatic fibrosis is marked by excessive synthesis and deposition of connective tissue proteins, especially interstitial collagens in the extracellular matrix of the liver. It is a result of an abnormal wound healing in response to chronic liver injury from various causes such as ethanol, viruses, toxins, drugs, or cholestasis. The chronic stimuli involved in the initiation of fibrosis leads to oxidative stress and generation of reactive oxygen species that serve as mediators of molecular events involved in the pathogenesis of hepatic fibrosis. These processes lead to cellular injury and initiate inflammatory responses releasing a variety of cytokines and growth factors that trigger activation and transformation of resting hepatic stellate cells into myofibroblast like cells, which in turn start excessive synthesis of connective tissue proteins, especially collagens. Uncontrolled and extensive fibrosis results in distortion of lobular architecture of the liver leading to nodular formation and cirrhosis. The perpetual injury and regeneration process could also results in genomic aberrations and mutations that lead to the development of hepatocellular carcinoma. This review covers most aspects of the molecular mechanisms involved in the pathogenesis of hepatic fibrosis with special emphasize on N-Nitrosodimethylamine (NDMA; Dimethylnitorsmaine, DMN) as the inducing agent.

Publication types

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

MeSH terms

  • Actins / metabolism
  • Animals
  • Antioxidants / metabolism
  • Collagen / metabolism
  • Cytokines / metabolism
  • Dimethylnitrosamine / chemistry
  • Dimethylnitrosamine / metabolism
  • Dimethylnitrosamine / pharmacology*
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Hepatic Stellate Cells / metabolism
  • Humans
  • Liver Cirrhosis / chemically induced*
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology*
  • Oxidative Stress / drug effects
  • Reactive Oxygen Species / metabolism
  • Wound Healing

Substances

  • ACTA2 protein, human
  • Actins
  • Antioxidants
  • Cytokines
  • Reactive Oxygen Species
  • Collagen
  • Dimethylnitrosamine