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

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.

Fig. 1. Metabolic activation and degradation of N-nitrosodimethylamine (NDMA) in liver.

The metabolic degradation of NDMA produces formaldehyde and methanol, and the alkylating intermediate reacts with nucleic acids and proteins to form methylated macromolecules

Fig. 2. Schematic representation of the sequence of events involved in the pathogenesis of N-nitrosodimethylamine (NDMA) induced hepatic fibrosis, cirrhosis, and hepatocellular carcinoma.

The metabolic activation and detoxification of NDMA cause hepatocyte injury, inflammation, neutrophilic infiltration, and massive hepatic necrosis, which results in oxidative stress and production of reactive oxygen species. These processes induce activation of hepatic stellate cells and increased synthesis of connective tissue components, especially collagens that end up in hepatic fibrosis. The chronic liver injury and perpetual fibrosis lead to liver cirrhosis, which could develop into hepatocellular carcinoma

Fig. 3. Schematic representation of the cellular interactions and molecular mechanisms involved in the pathogenesis of N-nitrosodimethylamine induced hepatic fibrosis.

Hepatocyte injury leads to inflammation and generation of reactive oxygen species that in turn activate Kupffer cells. The activated Kupffer cells produce the most potent fibrogenic factor TGF-β1, which activate the quiescent hepatic stellate cells into myofibroblast like cells with the expression of α-smooth muscle actin filaments. Alternatively, metabolism of NDMA cause activation of lymphocytes and injury to sinusoidal endothelial cells which produce potent fibrogenic factors like TGF-β1, CTGF, and FGF-1 and cytokines and growth factors such as NF-κB, IL-1β, IL-6, IL-13, IL-22, and CXCL4 which altogether contribute the activation of resting hepatic stellate cells. The activated and transformed stellate cells express and upregulate hundreds of genes, especially for collagens and other connective tissue proteins. The excessive synthesis and deposition of these proteins, specifically fibril forming collagens in the extracellular matrix of the liver leads to fibrosis and cirrhosis and ultimately to HCC