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J Crohns Colitis ; 12(10): 1200-1209, 2018 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-29659773

RESUMO

Background and Aims: The aetiology of Crohn's disease is poorly understood. By investigating twin pairs discordant for Crohn's disease, we aimed to assess whether the dysregulated barrier represents a cause or a consequence of inflammation and to evaluate the impact of genetic predisposition on barrier function. Methods: Ileal biopsies from 15 twin pairs discordant for Crohn's disease [monozygotic n = 9, dizygotic n = 6] and 10 external controls were mounted in Ussing chambers to assess paracellular permeability to 51Chromium [Cr]-EDTA and trancellular passage to non-pathogenic E. coli K-12. Experiments were performed with and without provocation with acetylsalicylic acid. Immunofluorescence and ELISA were used to quantify the expression level of tight junction proteins. Results: Healthy co-twins and affected twins displayed increased 51Cr-EDTA permeability at 120 min, both with acetylsalicylic acid [p < 0.001] and without [p < 0.001] when compared with controls. A significant increase in 51Cr-EDTA flux was already seen at 20 min in healthy monozygotic co-twins compared with controls [p≤0.05] when stratified by zygosity, but not in healthy dizygotic co-twins. No difference in E. coli passage was observed between groups. Immunofluorescence of the tight junction proteins claudin-5 and tricellulin showed lower levels in healthy co-twins [p < 0.05] and affected twins [p < 0.05] compared with external controls, while ELISA only showed lower tricellulin in Crohn's disease twins [p < 0.05]. Conclusion: Our results suggest that barrier dysfunction is a primary defect in Crohn's disease, since changes were predominantly seen in healthy monozygotic co-twins. Passage of E. coli seems to be a consequence of inflammation, rather than representing a primary defect.


Assuntos
Aspirina/farmacocinética , Radioisótopos de Cromo/farmacocinética , Claudina-5/genética , Doença de Crohn , Ácido Edético/farmacocinética , Escherichia coli K12/metabolismo , Íleo , Proteína 2 com Domínio MARVEL/genética , Adulto , Quelantes/farmacologia , Doença de Crohn/genética , Doença de Crohn/patologia , Técnicas de Diagnóstico por Radioisótopos , Feminino , Predisposição Genética para Doença , Humanos , Íleo/metabolismo , Íleo/patologia , Masculino , Pessoa de Meia-Idade , Permeabilidade , Junções Íntimas/genética , Junções Íntimas/metabolismo , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
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