RESUMO
The mechanism of damage of the biliary epithelium remains partially unexplored. However, recently many works have offered new evidence regarding the cholangiocytes' damage process, which is the main target in a broad spectrum of pathologies ranging from acute cholestasis, cholangiopathies to cholangiocarcinoma. This is encouraging since some works addressed this epithelium's relevance in health and disease until a few years ago. The biliary tree in the liver, comprised of cholangiocytes, is a pipeline for bile flow and regulates key hepatic processes such as proliferation, regeneration, immune response, and signaling. This review aimed to compile the most recent advances on the mechanisms of cholangiocellular damage during cholestasis, which, although it is present in many cholangiopathies, is not necessarily a common or conserved process in all of them, having a relevant role cAMP and PKA during obstructive cholestasis, as well as Ca2+-dependent PKC in functional cholestasis. Cholangiocellular damage could vary according to the type of cholestasis, the aggressor, or the bile ducts' location where it develops and what kind of damage can favor cholangiocellular carcinoma development.
Assuntos
Procedimentos Cirúrgicos do Sistema Biliar/efeitos adversos , Sistema Biliar/patologia , Colestase/patologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Animais , Sistema Biliar/metabolismo , Proliferação de Células , Colestase/metabolismo , Colestase/cirurgia , Humanos , Ligadura , Transdução de SinaisRESUMO
Among hepatic diseases, cholestatic ductopenic cholangiopathies are poorly studied, and they are rarely given the importance they deserve, especially considering their high incidence in clinical practice. Although cholestatic ductopenic cholangiopathies have different etiologies and pathogenesis, all have the same target (the cholangiocyte) and similar mechanistic basis of cell death. Cholestatic cholangiopathies are characterized, predominantly, by obstructive or functional damage in the biliary epithelium, resulting in an imbalance between proliferation and cholangiocellular death; this leads to the progressive disappearance of bile ducts, as has been shown to occur in primary sclerosing cholangitis, primary biliary cholangitis, low-phospholipid-associated cholelithiasis syndrome, cystic fibrosis-related liver disease, and drug-induced ductopenia, among other biliary disorders. This review summarizes the features of the more common ductopenic syndromes and the cellular mechanisms involved in cholengiocellular death, with focus on the main forms of cholangiocyte death described so far, namely apoptosis, autophagy, necrosis, and necroptosis. It also emphasizes the importance to study in depth the molecular mechanisms of cholengiocyte death to make possible to counteract them with therapeutic purposes. These therapeutic strategies are limited in number and efficacy at present, and this is why it is important to find complementary, safe strategies to stimulate cholangiocellular proliferation in order favor bile duct replenishment as well. Successful in finding appropriate treatments would prevent the patient from having liver transplantation as the only therapeutic alternative.
Assuntos
Apoptose , Doenças dos Ductos Biliares/tratamento farmacológico , Doenças dos Ductos Biliares/patologia , Colagogos e Coleréticos/uso terapêutico , Animais , HumanosRESUMO
Resumen Encontrar a un representante celular que reúna la estructura y las funciones que se revisan en los cursos de biología celular no es tarea fácil, pero el hepatocito reúne esas características. Además de él, en el hígado hay otras células de interés que vale la pena revisar como un complemento para contar con una visión más general de las múltiples funciones que ocurren en esta glándula. Incluimos algunas imágenes y revisamos algunas funciones de esa maravillosa célula conocida como hepatocito, que además integra a la biología celular y a la bioquímica.
Abstract To find a cell that gathers the functions and the structure that are most commonly reviewed in the cellular biology texts is a difficult task, but the hepatocyte meet these attributes. In addition it, there are other interesting cells in the liver that are important to review as a complement in order to have a general view of the multiple functions that occur in the liver. We included images and reviewed some of the functions of the hepatocyte that integrate cellular biology and biochemistry.
RESUMO
Schistosomiasis is a major cause of portal hypertension worldwide. It associates with portal fibrosis that develops during chronic infection. The mechanisms by which the pathogen evokes these host responses remain unclear. We evaluated the hypothesis that schistosome eggs release factors that directly stimulate liver cells to produce osteopontin (OPN), a pro-fibrogenic protein that stimulates hepatic stellate cells to become myofibroblasts. We also investigated the utility of OPN as a biomarker of fibrosis and/or severity of portal hypertension. Cultured cholangiocytes, Kupffer cells and hepatic stellate cells were treated with soluble egg antigen (SEA); OPN production was quantified by quantitative reverse transcriptase polymerase chain reaction (qRTPCR) and ELISA; cell proliferation was assessed by BrdU (5-bromo-2'-deoxyuridine). Mice were infected with Schistosoma mansoni for 6 or 16 weeks to cause early or advanced fibrosis. Liver OPN was evaluated by qRTPCR and immunohistochemistry (IHC) and correlated with liver fibrosis and serum OPN. Livers from patients with schistosomiasis mansoni (early fibrosis n=15; advanced fibrosis n=72) or healthy adults (n=22) were immunostained for OPN and fibrosis markers. Results were correlated with plasma OPN levels and splenic vein pressures. SEA-induced cholangiocyte proliferation and OPN secretion (P<0.001 compared with controls). Cholangiocytes were OPN (+) in Schistosoma-infected mice and humans. Liver and serum OPN levels correlated with fibrosis stage (mice: r=0.861; human r=0.672, P=0.0001) and myofibroblast accumulation (mice: r=0.800; human: r=0.761, P=0.0001). Numbers of OPN (+) bile ductules strongly correlated with splenic vein pressure (r=0.778; P=0.001). S. mansoni egg antigens stimulate cholangiocyte proliferation and OPN secretion. OPN levels in liver and blood correlate with fibrosis stage and portal hypertension severity.