Mast cell, myofibroblast and nerve terminal complexes in carbon tetrachloride-induced cirrhotic rat livers

Background/Aims: Extracellular matrices in liver fibrosis are known to be produced by myofibroblasts that are transformed from fat-storing cells. The development of the fibrotic process is thought to be mediated by various fibrogenic mediators. Recently, the involvement of mast cells and cholinergic neurotransmitters in fibrogenesis has been suggested. We have studied the distribution of these cells and cholinergic nerve fibers in normal rat livers and 6-week carbon tetrachloride-induced rat cirrhotic livers. Methods: Mast cells and myofibroblasts were identified by immunohistochemistry for mast cell tryptase (AA1) and α-smooth muscle actin. Cholinergic nerve fibers and terminals were localized using the acetyl-cholinesterase neurohistochemistry method for light and transmission electron microscopy. Results: In normal rat livers, a few nerve terminals were connected with fibroblasts near the vascular walls in the portal tracts. In contrast, in cirrhotic rat livers, numerous acetylcholinesterase-positive nerve fibers were observed in the fibrous septa, forming a network. Ultrastructurally, the nerve terminals were observed in close contact with mast cells and myofibroblasts in fibrous septa, forming characteristics mast cell/myofibroblast/nerve terminal complexes. In cirrhotic nodules, nerve terminals were situated in close contact with myofibroblasts in the periseptal sinusoids. These axon terminals contained numerous small clear vesicles, and acetylcholinesterase-positive products were noted in the space of the synaptic membranes. Conclusion: Our findings demonstrate that mast cell/myofibroblast/cholinergic nerve terminal complexes may play a role in the development of liver fibrosis, probably because of the production of extracellular matrix components by myofibroblasts.