The liver is a vital organ, playing numerous critical roles in the body. The liver's ability to perform essential functions is disturbed by injuries that are often associated with many complications such as calcification. Although many reports in the literature document observations of liver calcification, the mechanisms regulating this phenomenon remain unclear. Herein, we aim to investigate the cellular and molecular events that occur during pathological calcification of the liver. / To study the mechanisms of calcification, assessments included histological-staining, immunolabeling, and biochemical and electron microscopy analyses. The findings suggest that calcification may result from hydroxyapatite precipitation in necrotic or apoptotic hepatocytes. Similarly, calcification may be associated with differentiated myofibroblasts expressing bone matrix proteins downstream of TGFbeta signalling. / To identify specific protein regulators linked to the various stages in calcification, and to assess the protein composition of the tissue, a proteomic analysis was used. This analysis identified IQGAP1, an effector of the Rho-GTPases and a master regulator of cell adhesion and migration. IQGAP1 is strongly expressed in myofibroblasts, suggesting that IQGAP1 may be implicated in myofibroblasts migrating towards calcification. Studies on IQGAP1 interactions with its binding partners reveal that it is part of a protein complex that includes beta-catenin, an adhesion protein, and Rac1, a cytoskeletal regulator. These results suggest that IQGAP1 may play an important role in myofibroblast migration upon liver injury. / Having identified that activin and TGFbeta signalling are activated in myofibroblasts, we hypothesised that they may stimulate myofibroblast differentiation and proliferation. Studies using a C3H/10T1/2 cell model reveal that both activin and TGFbeta stimulate differentiation, but only activin induces cell proliferation in a Smad-independent fashion, which requires activation of the ERK/MAPK pathway. / In summary, this work provides new mechanistic insights on the global regulation of liver calcification. The various phases of this work collectively cover the central role of myofibroblasts in liver injury: association with calcification, rapid proliferation, differentiation to an activated form, and migration toward the injured area. The findings allow us to better understand the mechanisms by which liver myofibroblasts are regulated in a specific pathological context.

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A evolução da recorrência da hepatie C pós-transplante hepático pode ter um curso bastante variável. Raramente a doença pode progredir para uma forma conhecida como hepatite recorrente colestática grave, cuja patogenia ainda não é bem conhecida. Nós estudamos nesse trabalho alguns aspectos virológicos, histológicos e imunohistoquímicos de seis pacientes com essa forma rara de recorrência da doença, tendo como comparação um grupo pareado de seis pacientes transplantados com a forma leve de hepatite C recorrente, e como controle imunocompetente, cinco pacientes não transplantados com hepatite crônica pelo vírus C. Foram avaliados como possíveis fatores preditivos de gravidade da progressão da recorrência: viremia do VHC, evolução de quasispécies, parâmetros histopatológicos, e imunoreatividade para o antígeno core do VHC. / Following liver transplantation (OLT) HCV-related disease severity is highly variable, with a minority of cases progressing to an extremely severe form of cholestatic hepatitis, in which the pathogenesis is not yet understood. We aim to compare virological, histological and immunohistological changes in patients developing mild and severe post-OLT HCV recurrence. Twelve patients with recurrent HCV infection were studied (6 with severe and 6 with mild disease). Five HCV-infected immunocompetent patients were used as controls. We looked at viral load, quasispecies evolution of HCV, several histological parameters and immuno-reactivity of core antigens at three time-points (pre-OLT, early post-OLT and late post-OLT) as predictors of severity of recurrence post-OLT.

A evolução da recorrência da hepatie C pós-transplante hepático pode ter um curso bastante variável. Raramente a doença pode progredir para uma forma conhecida como hepatite recorrente colestática grave, cuja patogenia ainda não é bem conhecida. Nós estudamos nesse trabalho alguns aspectos virológicos, histológicos e imunohistoquímicos de seis pacientes com essa forma rara de recorrência da doença, tendo como comparação um grupo pareado de seis pacientes transplantados com a forma leve de hepatite C recorrente, e como controle imunocompetente, cinco pacientes não transplantados com hepatite crônica pelo vírus C. Foram avaliados como possíveis fatores preditivos de gravidade da progressão da recorrência: viremia do VHC, evolução de quasispécies, parâmetros histopatológicos, e imunoreatividade para o antígeno core do VHC. / Following liver transplantation (OLT) HCV-related disease severity is highly variable, with a minority of cases progressing to an extremely severe form of cholestatic hepatitis, in which the pathogenesis is not yet understood. We aim to compare virological, histological and immunohistological changes in patients developing mild and severe post-OLT HCV recurrence. Twelve patients with recurrent HCV infection were studied (6 with severe and 6 with mild disease). Five HCV-infected immunocompetent patients were used as controls. We looked at viral load, quasispecies evolution of HCV, several histological parameters and immuno-reactivity of core antigens at three time-points (pre-OLT, early post-OLT and late post-OLT) as predictors of severity of recurrence post-OLT.