RESUMEN
INTRODUCTION: Biliary atresia (BA) is a progressive obliteration of the extrahepatic bile ducts resulting in hepatic fibrosis. The underlying mechanisms have not been defined. We used an animal model of BA to evaluate mediators of extracellular matrix (ECM) processing to determine which factors may be involved. METHODS: Newborn BALB/c mice received an intraperitoneal injection with rhesus rotavirus or saline within 24 h of birth. Livers were harvested on days 7 and 14 for histology and immunohistochemistry (IHC). RNA expression was determined using quantitative real-time PCR. Human liver from patients with BA and those having a resection for nonfibrosing diseases was also evaluated. RESULTS: In experimental mice, mRNA expression for tissue inhibitor of metalloproteinase (TIMP)-1 and matrix metalloproteinase (MMP)-7 was increased 18-fold and 69-fold, respectively on day 7, with further increases on day 14. On day 14, mRNA expression for plasminogen activator inhibitor (PAI)-1 (38-fold), TIMP-4 (9.5-fold), and MMP-9 (5.5-fold) mRNA was also observed. Furthermore, integrin alpha(v) beta(6) mRNA expression was increased on days 7 (11-fold) and 14 (6-fold). Presence of integrin alpha(v) beta(6) protein was confirmed by IHC in both mouse and human specimens in the proliferating biliary epithelium. CONCLUSIONS: Our data suggest experimental BA is associated with increased mRNA expression of ECM degradation inhibitors, TIMP-1, PAI-1, and TIMP-4. MMP-7 and MMP-9 expression is also elevated in this model. Furthermore, increased gene expression of integrin alpha(v)beta(6) was demonstrated and IHC confirmed protein expression. Integrin alpha(v)beta(6) or the inhibitors of ECM breakdown may be attractive targets for future treatment strategies.
Asunto(s)
Antígenos de Neoplasias/genética , Atresia Biliar/patología , Matriz Extracelular/patología , Integrinas/genética , Animales , Animales Recién Nacidos , Atresia Biliar/enzimología , Atresia Biliar/genética , Atresia Biliar/virología , Modelos Animales de Enfermedad , Inmunohistoquímica , Metaloproteinasa 7 de la Matriz/genética , Ratones , Ratones Endogámicos BALB C , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Inhibidor Tisular de Metaloproteinasa-1/genética , Regulación hacia ArribaRESUMEN
BACKGROUND AND AIMS: Isolated intestinal transplantation has been limited by poor patient and graft survival. If high survival could be achieved and if parenteral nutrition-associated liver disease were reversible, this procedure could be more widely applied, with early liver dysfunction indicating the need for transplant evaluation. METHODS: Twenty-six patients who had failed parenteral nutrition received 28 isolated intestinal transplants. We analyzed patient and graft survival, the effect of sirolimus on the severity and frequency of rejection, and the reversibility of liver dysfunction after transplant. RESULTS: Three-year actuarial patient and primary graft survival were 88% and 71%, respectively. Two patients underwent successful retransplants. Twenty-two patients are alive at a mean of 21+/-15 (median 18; range 3-51) months. Actuarial survival with freedom from parenteral support is 81% at 3 years (21 of 26 patients). Actuarial freedom from parenteral support among survivors is 95.5% at 3 years (21 of 22 patients). Early rejection was less frequent with sirolimus (34% vs. 70% without sirolimus) (P=0.007). Moderate and severe rejection was less frequent with sirolimus (1/11 episodes vs. 9/17 episodes without sirolimus) (P=0.05). No grafts were lost after introduction of sirolimus. In all four patients with advanced liver dysfunction, fibrosis and cholestasis regressed within 1 year. CONCLUSIONS: High patient survival and parenteral nutrition-free survival can be achieved after isolated intestinal transplantation. Sirolimus treatment has eliminated graft loss. Parenteral nutrition-associated liver disease is reversible with intestinal transplantation. Refractory liver dysfunction in patients receiving parenteral nutrition should prompt consideration for isolated intestinal transplantation.