Treatment of cirrhotic rats with the immunomodulator AM3 ameliorates both their systemic proinflammatory state and their hyperdynamic circulation

  1. Nieto, M.
  2. Albillos, A.
  3. Muñoz, L.
  4. Reyes, E.
  5. Lledó, L.
  6. Úbeda, M.
  7. Sanz, E.
  8. de la Hera, A.
  9. Álvarez-Mon, M.
Actas:
40th Annual Meeting of the European-Association-for-the-Study-of-the-Liver

Editorial: ELSERVIER

ISSN: 0168-8278

Año de publicación: 2005

Volumen: 42

Páginas: 63-63

Congreso: 40th Annual Meeting of the European-Association-for-the-Study-of-the-Liver. April 13-17, 2005. Paris, France

Tipo: Aportación congreso

DOI: 10.1016/S0168-8278(05)81565-X GOOGLE SCHOLAR

Resumen

Traslocation of enteric bacteria and their products (LPS) play a key role in the pathogenesis of the immune dysfunction and increased production of profifftammatory cytoldnes, as tumor necrosis factor alpha (TNF), that are features of advanced drrhosis. TNF is involved in the hemodynamic derangement of cirrhosis. We have recently reported that the immunomod- ulator AM3 inhibits enteric bacteria-driven TNF production by monocytes, and that monocytes are tile major source of TNF overproduction in drrhotic patients. Aim: To investigate in bile duct-ligated (BDL) cirrhotic tats: 1) the acti- vation status and cytokine production in circulating irnmmle cells (proto- col I), and2) file effect of AM3 on the finmune system and hyperdynamic drculation (protocols II and III). In protocol I, sham and BDL tats were studied 6 wk after surgery. In protocols II and III, BDL rats were treated with a 3-wk AM3 course (3 mg/kg.d po) or placebo from 4th wk after surgery on. Results (meand-SEM, cells/~tl): Compared to controls, cirrhotic tats showed monocyte expansion (56174_1254 vs. 452_12, p < 0.01), including a massive increase of TNF-producing monocytes (33702_960 vs. 214_6, p < 0.01). Activated Th-lymphocytes were also expanded (CD4+CD134+, 922-26 vs. 32-0.9, p<0.01) and Thl polarized (interferon-¥ produc- ing, 352-9 vs. 4.22-0.02, p<0.01). AM3 reduced by more that 10-fold the abnormal monocyte expansion (to 552d-139, p<0.01) and their TNF production (to 249d-86, p < 0.01). Activated (to 43d-14, p < 0.01) and interferon-¥ producing (to 102_3, p < 0.01) Th-lymphocytes numbers were also improved. Notably, AM3 reduced serum TNF (654_ 14 vs. 382_9 pg/ml, p<0.05) and cardiac index (46d-9 vs. 52±11ml/min. 100g, p<0.01) and increased SVR by 352-8% (p < 0.01), whereas portal pressure was unchanged. Conclusion: In rats with established cirrhosis, AM3 markedly diminishes the expansion of monocytes and T-lymphocytes activated to TNF and interferon-¥ production, and serum TNE The AM3 immunomodulatory effects assodate with amelioration of tile hyperdynarnic circulation. (Texto publicado en: References. (Resumen, publicado en: Treatment of cirrhotic rats with the immunomodulator AM3 ameliorates both their systemic proinflammatory state and their hyperdynamic circulation. (2005). Journal of Hepatology, 42, 63. 10.1016/S0168-8278(05)81565-X).