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