Abstract
Background and aimsDuctular reaction is a standard component of fibrotic liver tissue but its function is largely unknown. It is supposed to interact with the matrix producing myofibroblasts and compensate the declining regenerative capacity of hepatocytes. The relationship between the extent of fibrosis—ductular reaction, proliferative activity of hepatocytes and ductular reaction were studied sequentially in experimental hepatic fibrosis models.MethodsLiver fibrosis/cirrhosis was induced in wild type and TGFβ overproducing transgenic mice by carbon tetrachloride and thioacetamide administration. The effect of thioacetamide was modulated by treatment with imatinib and erlotinib. The extent of ductular reaction and fibrosis was measured by morphometry following cytokeratin 19 immunofluorescent labeling and Picro Sirius staining respectively. The proliferative activity of hepatocytes and ductular reaction was evaluated by BrdU incorporation. The temporal distribution of the parameters was followed and compared within and between different experimental groups.ResultsThere was a strong significant correlation between the extent of fibrosis and ductular reaction in each experimental group. Although imatinib and erlotinib temporarily decreased fibrosis this effect later disappeared. We could not observe negative correlation between the proliferation of hepatocytes and ductular reaction in any of the investigated models.ConclusionsThe stringent connection between ductular reaction and fibrosis, which cannot be influenced by any of our treatment regimens, suggests that there is a close mutual interaction between them instead of a unidirectional causal relationship. Our results confirm a close connection between DR and fibrogenesis. However, since the two parameters changed together we could not establish a causal relationship and were unable to reveal which was the primary event. The lack of inverse correlation between the proliferation of hepatocytes and ductular reaction questions that ductular reaction can compensate for the failing regenerative activity of hepatocytes. No evidences support the persistent antifibrotic property of imatinib or erlotinib.
Highlights
Chronic damage of liver tissue causes gradual accumulation of extracellular matrix (ECM), fibrosis, which can eventually progress to complete architectural reconstruction termed cirrhosis
Liver fibrosis/cirrhosis was induced in wild type and transforming growth factor beta (TGFβ) overproducing transgenic mice by carbon tetrachloride and thioacetamide administration
Falkowski et al [7] proposed that the ductular reaction may be an alternative regenerative pathway, which is activated when the replicative capacity of the senescent hepatocytes is compromised
Summary
Chronic damage of liver tissue causes gradual accumulation of extracellular matrix (ECM), fibrosis, which can eventually progress to complete architectural reconstruction termed cirrhosis. Small epithelial tubules called “bile duct proliferation” were observed along the fibrotic septa of cirrhotic livers a long time ago but no special attention was paid to them These tubules are referred to as ductular reaction and they are thought to represent hepatic progenitor cells [1]. Falkowski et al [7] proposed that the ductular reaction may be an alternative regenerative pathway, which is activated when the replicative capacity of the senescent hepatocytes is compromised This view was later supported by the description of hepatocytic differentiation of ductular progenitor cells [8, 9]. The relationship between the extent of fibrosis—ductular reaction, proliferative activity of hepatocytes and ductular reaction were studied sequentially in experimental hepatic fibrosis models.
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