Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases
| Autor: | Marco Marzioni, Raul Jimenez-Agüero, Maite Merino-Azpitarte, Maite G. Fernandez-Barrena, Elizabeth Hijona, Jose J.G. Marin, Oihane Erice, Ander Arbelaiz, Maria J. Perugorria, Jesus M. Banales, Aura D. Urribarri, Jesús Prieto, Luis Bujanda, Nicholas F. LaRusso, Elisa Lozano, Tatyana V. Masyuk, Patricia Munoz-Garrido, J.P. Jimeno |
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| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Blotting Western Cell Culture Techniques Fluorescent Antibody Technique Enzyme-Linked Immunosorbent Assay Matrix metalloproteinase Biology Hydroxamic Acids Real-Time Polymerase Chain Reaction Article Cholangiocyte Paracrine signalling Fibrosis Internal medicine medicine Animals Humans Enzyme Inhibitors Autocrine signalling Cysts Liver Diseases Hepatobiliary disease Gastroenterology Metalloendopeptidases Interleukin medicine.disease Immunohistochemistry Rats Endocrinology Liver Cytokines Bile Ducts Cytophotometry Marimastat medicine.drug |
| Zdroj: | Gut. 63:1658-1667 |
| ISSN: | 1468-3288 0017-5749 |
| DOI: | 10.1136/gutjnl-2013-305281 |
| Popis: | Objective Polycystic liver diseases (PCLDs) are genetic disorders characterised by progressive bile duct dilatation and/or cyst development. Their pathogenesis is a consequence of hyperproliferation, hypersecretion and microRNA alterations in cholangiocytes. Here we evaluate the role of matrix metalloproteases (MMPs) in the hepatic cystogenesis of PCLDs. Design Metalloprotease activity was measured by microfluorimetric assays in normal and polycystic cholangiocyte cultures from humans and rats, and gene expression by real time quantitative PCR. The role of cytokines, oestrogens and growth factors present in the cystic fluid of PCLD patients was evaluated for MMP activity. The MMP inhibitor marimastat was examined for cystic expansion in vitro and in polycystic kidney (PCK) rats. Results Polycystic human and rat cholangiocytes displayed increased MMP activity, which was associated with increased mRNA levels of different MMPs. Interleukin (IL)-6 and IL-8, and 17β-oestradiol, all stimulated MMP activity in human cholangiocytes. The presence of antibodies against IL-6 and/or IL-8 receptor/s inhibited baseline MMP hyperactivity of polycystic human cholangiocytes but had no effect on normal human cholangiocytes. MMP-3 was overexpressed in cystic cholangiocytes from PCLD human and PCK rat livers by immunohistochemistry. Marimastat reduced MMP hyperactivity of polycystic human and rat cholangiocytes and blocked the cystic expansion of PCK cholangiocytes cultured in three-dimensions. Chronic treatment of 8-week-old PCK rats with marimastat inhibited hepatic cystogenesis and fibrosis. Conclusions PCLDs are associated with cholangiocyte MMP hyperactivity resulting from autocrine/paracrine stimulation by IL-6 and IL-8. Inhibition of this MMP hyperactivity with marimastat decreased hepatic cystogenesis in vitro and in an animal model of PCLD, offering a potential therapeutic tool. |
| Databáze: | OpenAIRE |
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