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1.
Gut ; 52(7): 1060-7, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12801967

RESUMO

BACKGROUND AND AIM: Liver regeneration after severe liver damage depends in part on proliferation and differentiation of hepatic progenitor cells (HPCs). Under these conditions they must be able to withstand the toxic milieu of the damaged liver. ATP binding cassette (ABC) transporters are cytoprotective efflux pumps that may contribute to the preservation of these cells. The aim of this study was to determine the ABC transporter phenotype of HPCs. METHODS: HPC activation was studied in rats treated with 2- acetylaminofluorene (2-AAF) followed by partial hepatectomy (PHx). ABC transporter gene expression was determined by real time detection reverse transcription-polymerase chain reaction in isolated HPCs, hepatocytes, cholangiocytes, and cultured progenitor cell-like RLF phi 13 cells and by immunohistochemistry of total liver samples. ABC transporter efflux activity was studied in RLF phi 13 cells by flow cytometry. RESULTS: 2-AAF/PHx treated animals showed increased hepatic mRNA levels of the genes encoding multidrug resistance proteins Mdr1b, Mrp1, and Mrp3. Immunohistochemistry demonstrated expression of Mrp1 and Mrp3 proteins in periportal progenitor cells and of the Mdr1b protein in periportal hepatocytes. Freshly isolated Thy-1 positive cells and cultured RLF phi 13 progenitor cells highly expressed Mrp1 and Mrp3 mRNA while the hepatocyte specific transporters Mdr2, Bsep, Mrp2, and Mrp6 were only minimally expressed. Blocking Mrp activity by MK-571 resulted in accumulation of the Mrp specific substrate carboxyfluorescein in RLF phi 13 cells. CONCLUSION: HPCs express high levels of active Mrp1 and Mrp3. These may have a cytoprotective role in conditions of severe hepatotoxicity.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Fígado/citologia , Células-Tronco/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/análise , Transportadores de Cassetes de Ligação de ATP/análise , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Divisão Celular/fisiologia , Linhagem Celular , Citometria de Fluxo/métodos , Expressão Gênica , Genes MDR/genética , Imuno-Histoquímica/métodos , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Organismos Livres de Patógenos Específicos
2.
Gastroenterology ; 120(7): 1774-83, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11375958

RESUMO

BACKGROUND & AIMS: Our previous studies have shown that Cryptosporidium parvum induces biliary epithelial cell apoptosis in vivo and causes apoptosis in bystander uninfected biliary epithelia in vitro. We analyzed C. parvum-induced nuclear factor kappa B (NF-kappaB) activation in human biliary epithelial cells and assessed its relevance to epithelial cell apoptosis. METHODS: In vitro models of cryptosporidial infection using a human biliary epithelial cell line were used to assay C. parvum- induced NF-kappaB activation and associated apoptosis. RESULTS: Degradation of I(kappa)B and nuclear translocation of the NF-kappaB family of proteins (p65 and p50) were observed in the biliary epithelial cell cultures directly exposed to the parasite. Activation of NF-kappaB was found only in directly infected cells (but not in bystander uninfected cells). A time-dependent secretion of a known NF-kappaB gene product, interleukin 8, from infected cell cultures was detected. C. parvum-induced biliary epithelial cell apoptosis was limited to bystander uninfected cells. In contrast, inhibition of NF-kappaB activation resulted in apoptosis in directly infected cells and significantly enhanced C. parvum-induced apoptosis in bystander uninfected cells. CONCLUSIONS: These observations support the concept that, while C. parvum triggers host cell apoptosis in bystander uninfected biliary epithelial cells, which may limit spread of the infection, it directly activates the NF-kappaB/I(kappa)B system in infected biliary epithelia thus protecting infected cells from death and facilitating parasite survival and propagation.


Assuntos
Apoptose , Ductos Biliares/parasitologia , Cryptosporidium parvum/fisiologia , NF-kappa B/metabolismo , Animais , Ductos Biliares/metabolismo , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/parasitologia , Humanos , Interleucina-8/biossíntese , Microscopia Imunoeletrônica
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