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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.

BackgroundIt remains unclear if the vascular and connective tissue structures of primary and metastatic tumors are intrinsically determined or whether these characteristics are defined by the host tissue. Therefore we examined the microanatomical steps of vasculature and connective tissue development of C38 colon carcinoma in different tissues.MethodsTumors produced in mice at five different locations (the cecal wall, skin, liver, lung, and brain) were analyzed using fluorescent immunohistochemistry, electron microscopy and quantitative real-time polymerase chain reaction.ResultsWe found that in the cecal wall, skin, liver, and lung, resident fibroblasts differentiate into collagenous matrix-producing myofibroblasts at the tumor periphery. These activated fibroblasts together with the produced matrix were incorporated by the tumor. The connective tissue development culminated in the appearance of intratumoral tissue columns (centrally located single microvessels embedded in connective tissue and smooth muscle actin-expressing myofibroblasts surrounded by basement membrane). Conversely, in the brain (which lacks fibroblasts), C38 metastases only induced the development of vascularized desmoplastic tissue columns when the growing tumor reached the fibroblast-containing meninges.ConclusionsOur data suggest that the desmoplastic host tissue response is induced by tumor-derived fibrogenic molecules acting on host tissue fibroblasts. We concluded that not only the host tissue characteristics but also the tumor-derived fibrogenic signals determine the vascular and connective tissue structure of tumors.

Unbiased morphological characterization of cirrhotic livers can provide valuable, clinically relevant information. Similar evaluation of routine core biopsies may increase the significance of this 'Gold Standard' examination.

IntroductionThe liver is well known for its enormous regenerative capacity. If the hepatocytes are compromised the reserve stem cells can regrow the lost tissue by means of oval cells differentiating into hepatocytes. We were curious whether this standby system was able to compensate for ontogenic liver growth arrested by 2-acetylaminofluorene (AAF) treatment or if it can be influenced by cholic acid, known to promote liver growth in several reactions. Methods(i) Four weeks-old (60-70g) male F344 rats were kept on standard chow and treated with solvent only, (ii) others were kept on 0,2% cholic acid (CA) enriched diet, (iii) treated with AAF, or (iiii) given a combination of CA diet and AAF treatment (AAF/CA).The proliferative response of epithelial cells was characterized by pulse bromodeoxyuridine labelling. The relative gene expression levels of senescence-related factors and bile acid receptors were determined by quantitative real-time polymerase chain reaction analysis. ResultsAAF administration efficiently inhibited the physiological proliferation of hepatocytes in young, male F344 rats after weaning. The activation of stem cells was indicated by the increased proliferation of periportal biliary/oval cells (B/OC). If the rats were fed additionally by cholic acid enriched diet, typical oval cell reaction emerged, subsequently the oval cells differentiated into hepatocytes restituting liver growth. This reaction was mediated by increased production of HGF, IL-6 and SCF by the damaged liver. Moreover, upregulation of FXR expression on B/OC made them competent for bile acids. Our results indicate that endogenous, autocrine mechanisms involved in liver ontogeny are also able to activate the backup regenerative machinery of stem cells.