Adenosine reverses a preestablished CCl4-induced micronodular cirrhosis through enhancing collagenolytic activity and stimulating hepatocyte cell proliferation in rats

Authors

  • Rolando Hernández-Muñoz,

    1. Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM). México 04510, D.F., Mexico
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  • Mauricio Díaz-Muñoz,

    1. Centro de Neurobiología, Campus UNAM-Juriquilla, Querétaro, Qro., Mexico
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  • Juan A. Suárez-Cuenca,

    1. Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM). México 04510, D.F., Mexico
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  • Cristina Trejo-Solís,

    1. Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM). México 04510, D.F., Mexico
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  • Verónica López,

    1. Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM). México 04510, D.F., Mexico
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  • Lourdes Sánchez-Sevilla,

    1. Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM). México 04510, D.F., Mexico
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  • Lucía Yáñez,

    1. Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM). México 04510, D.F., Mexico
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  • Victoria Chagoya De Sánchez Ph.D.

    Corresponding author
    1. Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM). México 04510, D.F., Mexico
    • Victoria Chagoya de Sánchez, PhD., Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Apdo, Postal 70-243, México 04510, D. F., Mexico. fax: (525) 622-5611
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Abstract

Cirrhosis is one of the most common causes of mortality worldwide, because hepatic dysfunction constitutes a potentially lethal condition. Having demonstrated the hepatoprotective effect of adenosine against CCl4-induced cirrhosis, the present study was aimed at assessing adenosine's effect on an already-established micronodular cirrhosis. Chronic administration of CCl4 (10 weeks) induced a cirrhotic state, characterized by increased liver fibronectin and collagen types I and III content, enhanced expression of α-1 (I) collagen mRNA, portal hypertension, and liver dysfunction. After CCl4 discontinuation (5 weeks), increased persitance of α-1 (I) collagen mRNA expression and deposition, enhanced proline incorporation into collagen and prolyl hydroxylase activity evidenced active fibrogenesis. Several weeks after CCl4 withdrawal, deposited collagen showed an enhanced type I/III ratio, which was associated with deficient collagenolytic activity in cirrhotic livers. Liver expression of some metalloproteinases (MMPs) and of tissue inhibitors of MMPs (TIMPs) also indicated decreased collagen breakdown in cirrhotic livers. Parameters indicative of oxidative stress (mainly protein oxidation) were persistently augmented. These events were coincident with diminished regenerative capacity of the cirrhotic liver. Intraperitoneal adenosine administration to CCl4-induced cirrhotic rats blocked active fibrogenesis and increased the collagen degradation (most probably by decreasing liver TIMPs levels), normalizing collagen-type ratios. In addition, the nucleoside promoted an effective hepatocyte's proliferation in the cirrhotic liver and accelerated normalization of parameters indicative of liver function and oxidative stress. Thus, adenosine readily reversed an experimental cirrhosis through stimulating liver collagenolytic and proliferative capacities, as well as by accelerating functional recovery.

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