Tacrolimus modulates liver and pancreas nitric oxide synthetase and heme-oxygenase isoforms and cytokine production after endotoxemia.

Cytoprotective effects of tacrolimus are due to its unspecific anti-inflammatory and anti-oxidant properties. Neither the exact mechanisms nor if there is any organ-specificity or dose-dependent response have not been yet elucidated. Our aim was to evaluate the effect of tacrolimus on oxidative stress and mediator production in liver and pancreatic tissue secondary to endotoxemia. Wistar rats were pretreated with intraperitoneal injection of tacrolimus (0.07, 0.15, and 0.3mg/kg) 24h before Escherichia coli LPS was administrated. Animals were sacrificed 24h after LPS administration and iNOS, eNOS, and nNOS and type 1 and 2 heme-oxygenase (HO) expression were measured. TNF-α and IL-1 tissue expression and plasmatic NO, CO, TNF-α, and IL-1 were also determined. LPS exposure increased iNOS expression in both organs, eNOS did not show variations and liver nNOS expression was significantly lower. Tacrolimus diminished both pancreas and liver iNOS and nNOS expression. Both liver and pancreatic eNOS expression augmented when tacrolimus was administrated. High doses of tacrolimus were correlated with ameliorated liver HO-1 plus HO-2 and pancreas HO-1 expression after LPS stimulation. Tacrolimus treatment diminished TNF-α but not IL-1 expression increase after LPS challenge in hepatic tissue. Pancreatic TNF-α and IL-1 values diminished partially when high doses were employed. Plasmatic NO, CO, TNF-α, and IL-1 concentrations increase after LPS challenge was diminished when highest doses of tacrolimus were given. In conclusion, tacrolimus exerts a protective effect on commonly observed harmful phenomena after LPS stimulation by modulating liver and pancreas oxidative enzyme expression and cytokine production.

Antiapoptotic effect of tacrolimus on cytokine-challenged human islets.

Our goal was to investigate whether previously related antiapoptotic and anti-inflammatory effects of tacrolimus could be useful in protecting human islets cultured in the presence of several proinflammatory mediators. Human islets obtained from cadaveric donors after intraductal infusion with collagenase, mechanical digestion, and continuous Ficoll gradient purification were cultured in RPMI-1640 medium for 24 h. Escherichia coli lipopolysaccharide (10 microg/ml) or interleukin-1 (50 UI/ml) + gamma-IF (1000 UI/ml) and low-dose tacroliumus (5 ng/ml) were added. Homogenized samples (300 IE) from five different donors where assigned to four different experimental groups (control, treatment, cytokines, and cytokines + treatment). To evaluate islet damage and apoptotic response, nucleosome content, Bcl-2 protein levels, caspase-3, -8, and -9 levels, and insulin concentration were measured. Also, TNF-alpha and IL-6 levels where assessed as indicators of the inflammatory response. All proapoptotic markers, TNF-alpha, and IL-6 levels were augmented after both LPS and cytokine stimulation. Tacrolimus reduced significantly all of them and restored baseline values of nucleosome and caspase-9 in both experiments and Bcl-2 and caspase-3 when IL-1 + gamma-IF was added. Twenty-four-hour insulin concentration diminished when LPS or IL-1 + gamma-IF were present. Tacrolimus treatment restored insulin levels in both experiments. These results suggest that in vitro apoptotic events and media insulin concentration decrease after proinflammatory stimulation can be reverted using low-dose tacrolimus.

[Current status of islet transplantation]. / Estado actual del trasplante de islotes pancreáticos.

Due to the numerous advances in islet transplantation in the last few years, clinical outcomes following this procedure are continually improving. Novel immunosuppression protocols, improved donor and recipient selection, and careful attention to the process of organ extraction, preservation and islet isolation have contributed to long-term success. The present article reviews the results of clinical islet transplantation and their relationship with the different advances introduced. The use of new islet sources such as living and non-heart-beating donors, as well as recent advances in our knowledge of the mechanisms of rejection and its prevention, are also reviewed.

Estado actual del trasplante de islotes pancreáticos / Current status of islet transplantation

El trasplante de islotes pancreáticos mejora día a día sus resultados clínicos gracias a numerosas mejoras en el proceso desarrolladas en los últimos años. Tanto los nuevos protocolos de inmunosupresión como la selección de los donantes y receptores, así como un especial cuidado en la obtención, preservación y procesamiento de los páncreas, han hecho posible conseguir controles glucémicos prolongados. Uno de los objetivos principales de esta revisión es presentar la evolución de los resultados en humanos a medida que estos cambios han ido introduciéndose. Asimismo, se revisa el empleo de nuevas fuentes de islotes, como son el donante vivo y el donante a corazón parado, junto con los nuevos hallazgos en el conocimiento de los mecanismos de rechazo y las nuevas opciones terapéuticas desarrolladas para prevenirlo (AU)

Due to the numerous advances in islet transplantation in the last few years, clinical outcomes following this procedure are continually improving. Novel immunosuppression protocols, improved donor and recipient selection, and careful attention to the process of organ extraction, preservation and islet isolation have contributed to long-term success. The present article reviews the results of clinical islet transplantation and their relationship with the different advances introduced. The use of new islet sources such as living and non-heart-beating donors, as well as recent advances in our knowledge of the mechanisms of rejection and its prevention, are also reviewed (AU)