The biological response modifier AM3 attenuates the inflammatory cell response and hepatic fibrosis in rats with biliary cirrhosis
Authors
Albillos Martínez, Agustín; Álvarez De Mon Soto, Melchor; Nieto González, Mónica; Úbeda Cantera, María Del Pilar; Muñoz Zamarrón, Leticia; [et al.]Identifiers
Permanent link (URI): http://hdl.handle.net/10017/61144DOI: 10.1136/gut.2008.168831
ISSN: 0017-5749
Date
2010-07Affiliation
Universidad de Alcalá. Departamento de Biología Celular y Genética; Universidad de Alcalá. Departamento de Medicina; Universidad de Alcalá. Departamento de Microbiología y ParasitologíaFunders
Ministerio de Educación
Junta de Comunidades de Castilla-La Mancha
Ministerio de Sanidad
Instituto de Salud Carlos III
Fundación Mutua Madrileña
Comunidad de Madrid
Bibliographic citation
Gut, 2010, v. 59, n. 7, p. 943-952
Keywords
Inflamación
Cirrosis Hepatica
Liver Cirrhosis
Inflammation
Description / Notes
10 p.
Project
info:eu-repo/grantAgreement/MEC//BES-2004-5534/ES//
info:eu-repo/grantAgreement/MEC//BFU 2006-09280%BFI/ES//
info:eu-repo/grantAgreement/ISCIII// EC08%00122/ES//
info:eu-repo/grantAgreement/ISCIII/Ciberehd/ PI051871/ES//
info:eu-repo/grantAgreement/CM//MITIC-CM S-BIO-0189%2006/ES//
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/acceptedVersion
Rights
© 2010 The Authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Access rights
info:eu-repo/semantics/openAccess
Abstract
Background: An inflammatory immune system response ensues in the liver and in the systemic circulation in cirrhosis, where it contributes to hepatic fibrosis and peripheral vasodilation. Modulation of the inflammatory response without increasing susceptibility to infection is a therapeutic target in cirrhosis. AM3 is a low-toxicity biological response modifier with regulatory effects on innate and adaptative immunity, and the ability to normalise the production of tumour necrosis factor alpha (TNFalpha). Aims: This was an experimental study to investigate the effects of oral AM3 on the systemic and hepatic inflammatory response, liver fibrosis and on the haemodynamic abnormalities of portal hypertension in rats with biliary cirrhosis. Design: Bile-duct ligated rats received a 3-week oral course of AM3 or placebo. Results: In cirrhotic rats, AM3 blunted the inflammatory switch of circulating and intrahepatic monocytes and T-cells to TNFalpha and interferon gamma (IFNgamma) production, respectively. AM3 modified the intrahepatic polarisation pattern of the regulatory cytokines, decreasing the mRNA expression of transforming growth factor beta1 (TGFbeta1), interleukin 4 (IL4), and IFNgamma, and increasing that of IL10. Total and IFNgamma-producing natural killer (NK) cells were lowered by AM3 in the peripheral blood and liver of cirrhotic rats. The immunomodulatory effects of AM3 led to reduced hepatic fibrogenesis in cirrhotic rats, as shown by decreased area of liver fibrosis, hydroxyproline content and mRNA expression of procollagen alpha1(I). Besides, AM3 lowered portal pressure and systemic hyperaemia. Conclusions: The biological response modifier AM3 reverses the concurrent inflammatory immune system activation in peripheral blood and liver of experimental established cirrhosis, which results in reductions of hepatic fibrosis, portal pressure and peripheral vasodilation.
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