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The biological response modifier AM3 attenuates the inflammatory cell response and hepatic fibrosis in rats with biliary cirrhosis
  1. Agustín Albillos1,2,3,
  2. Mónica Nieto1,3,
  3. María Ubeda1,3,
  4. Leticia Muñoz1,3,
  5. Benito Fraile4,
  6. Eduardo Reyes1,3,
  7. Lourdes Lledó5,
  8. Ignacio Blanco6,
  9. Óscar Pastor7,
  10. Clara Salas8,
  11. Margaret Lario1,3,
  12. Jorge Monserrat1,3,
  13. Ramón Bataller3,9,
  14. Melchor Álvarez-Mon1,3,10
  1. 1Laboratorio Enfermedades del Sistema Inmune, Departamento de Medicina, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
  2. 2Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, Spain
  3. 3Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (Ciberehd), Instituto de Salud Carlos III, Spain
  4. 4Departamento de Biología Celular y Genética, Facultad de Ciencias Biológicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
  5. 5Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
  6. 6Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, Spain
  7. 7Servicio de Bioquímica Clínica, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, Spain
  8. 8Servicio de Anatomía Patológica, Hospital Universitario Puerta de Hierro-Majadahonda, Universidad Autónoma de Madrid, Madrid, Spain
  9. 9Servicio de Hepatología, Hospital Clinic, Instituto de Investigación Biomédica Augusto Pi Suñer, Barcelona, Spain
  10. 10Servicio de Enfermedades del Sistema Inmune y Oncología, Hospital Universitario Príncipe de Asturias, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
  1. Correspondence to Professor Agustín Albillos, Departamento de Medicina, Facultad de Medicina-Campus Universitario, Universidad de Alcalá, Carretera Madrid-Barcelona km. 33.600, 28871 Alcalá de Henares, Madrid, Spain; aalbillosm{at}meditex.es

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 α (TNFα).

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 TNFα and interferon γ (IFNγ) production, respectively. AM3 modified the intrahepatic polarisation pattern of the regulatory cytokines, decreasing the mRNA expression of transforming growth factor β1 (TGFβ1), interleukin 4 (IL4), and IFNγ, and increasing that of IL10. Total and IFNγ-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 α1(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.

  • Th1 polarisation
  • portal pressure
  • monocytes
  • T cells
  • biliary cirrhosis

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Footnotes

  • Linked articles 203109.

  • Funding MÚ is currently supported by a grant from the Spanish Ministry of Education (BES-2004-5534) and ML by a grant from la Junta de Comunidades de Castilla La Mancha (FPI 07/057). AA received grants from the Spanish Ministries of Education (no. BFU 2006-09280/BFI) and Health, Instituto de Salud Carlos III (no. EC08/00122), the Fundación Mutua Madrileña, and from the Spanish Ministry of Health, Instituto de Salud Carlos III (PI051871, Ciberehd). MÁ-M received grants from Comunidad de Madrid (MITIC-CM S-BIO-0189/2006) and from the Spanish Ministry of Health, Instituto de Salud Carlos III. Ciberhed is funded by the Instituto de Salud Carlos III.

  • Competing interests None.

  • Ethics approval Protocols involving animals were approved by the Ethics Committee for Research using Experimental Animals of the University of Alcalá in accordance with European legislation.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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