Tacrolimus (Fk506) Down-Regulates Free Radical Tissue Levels, Serum Cytokines, and Neutrophil Infiltration After Severe Liver Ischemia

García-Criado, Francisco Javier; Palma-Vargas, Juan; Valdunciel-Garcia, J. J.; Toledo, Alexander H.; Misawa, Keiko; Gómez‐Alonso, Alberto; Toledo-Pereyra, L. H.

doi:10.1097/00007890-199708270-00008

Cited by 77 publications

(50 citation statements)

References 17 publications

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“…[23][24][25] More recently, it was documented to reduce expression of adhesion molecules, with a demonstrated reduction in leukocyte rolling and adhesion. 19 In conclusion, although complete elucidation of the role of tacrolimus in hepatic I/R injury deserves further investigation, in this trial, the first prospective randomized trial conducted in the clinical arena, we show that use of a flush solution containing tacrolimus results in superior early graft function and decreased hepatocellular injury.…”

Section: Discussionmentioning

confidence: 56%

“…11,18 Some investigators have suggested that neutrophil infiltration and cumulative free radical release are the most important mediators of I/R injury. 19,20 Tacrolimus, as an immunomodulatory agent, is likely to have a profound effect on the inflammation avenue of I/R injury. It has been shown to block early activation of the transcription factor nuclear factor-B.…”

Section: Discussionmentioning

confidence: 99%

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Tacrolimus as a liver flush solution to ameliorate the effects of ischemia/reperfusion injury following liver transplantation

Stella

2003

Liver Transplantation

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The goal of this report is to evaluate in a prospective randomized fashion the effect of flushing hepatic allografts with tacrolimus before transplantation. A prospective, double-blinded, randomized trial was performed. Twenty patients receiving orthotopic liver transplants from October 2000 to October 2001 were randomized into two groups. Group 1 (active) was administered tacrolimus, 20 ng/mL, plus Plasma-lyte A (Baxter Healthcare Corp, Deerfield, IL) liver flush solution; and group 2 (placebo) was administered only Plasma-lyte A. Ischemia/ reperfusion injury was assessed in both groups after transplantation by means of serum laboratory values to assess hepatocellular damage, synthetic function, and ion transport capacity. Peak values were recorded for each parameter, and their distributions were compared. There were no statistically significant differences between groups for age, sex, total ischemia time, or cause of liver disease. Global multivariate comparison of peak changes in all measures of liver function indicated liver injury was significantly lower with tacrolimus treatment than placebo (P ‫؍‬ .01). The sample median for group 1 was less than for group 2 in all parameters measured. Individual statistical comparison showed that peak changes from baseline aspartate aminotransferase and activated partial thromboplastin time values were significantly improved (P < .05) with tacrolimus treatment than placebo treatment. In this prospective, double-blinded, randomized trial, we show that flushing the liver before transplantation with Plasmalyte A containing tacrolimus results in superior early graft function and decreased hepatocellular injury after reperfusion compared with flushing with Plasma-lyte A alone. (Liver Transpl 2003;9:144-149.)

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Tacrolimus as a liver flush solution to ameliorate the effects of ischemia/reperfusion injury following liver transplantation

Stella

2003

Liver Transplantation

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“…43 Several investigators have documented decreased free radical production in association with amelioration of I-R injury when tacrolimus is administered before ischemia. [44][45][46] Although these studies document an end result of tacrolimus pretreatment as suppression of free radical elaboration, they offer little insight to the mechanisms responsible for such effects. Maintenance of cellular ATP content, suppressed free radical elaboration, and possible antioxidant activities are all possible mechanisms acting to produce tacrolimus-induced free radical protection.…”

Section: Free Radical-mediated Injurymentioning

confidence: 99%

“…107 Although not specifically studied, this mechanism is a possible means for tacrolimus to inhibit apoptosis, being a well-documented inhibitor of TNF-␣. 44,[71][72][73][74] Inhibition of calcineurin-mediated dephosphorylation of NOS causes decreased NOS activity. 107 Recent studies in a cancer model have shown inducible NOS activity to correlate directly with apoptosis.…”

Section: Apoptosis Versus Necrosismentioning

confidence: 99%

Effects of tacrolimus on ischemia-reperfusion injury

Stella

2003

Liver Transplantation

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In addition to efficacious immunosuppression for the benefit of organ transplantation, tacrolimus has diverse actions that result in amelioration of ischemia-reperfusion injury. Knowledge is accumulating rapidly on the mechanisms through which tacrolimus exerts these cytoprotective effects, including alterations in microcirculation, free radical metabolism, calcium-activated pathways, inflammatory cascades, mitochondrial stability, apoptosis, stress-response proteins, and tissue recovery. Within the nucleus, actions mediating the effects of tacrolimus appear to be dominantly influenced by interactions with the transcription factor, nuclear factor-B. Because tacrolimus is a cornerstone agent in immunosuppression regimens throughout the world and knowledge of its cellular mechanisms is evolving, it is important to update the clinical literature with this information. We reviewed the published literature with intent to portray the interactions of tacrolimus in the intricate cellular mechanisms initiated by ischemia and reperfusion. (Liver Transpl 2003;9: 105-116.)

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“…Increased levels of ROS are known to be involved in the pathogenesis of IRI. The application of FK506 (tacrolimus) in vivo is associated with a reduction of ROS (29). FK506 (tacrolimus) has also been found to exert anti-apoptotic effects by preventing Fas-induced apoptosis in human hepatocytes in vitro (33), as well as in an in vivo model of IRI in rats (34).…”

Section: Discussionmentioning

confidence: 99%

Experimental Studies on Protective Effects of FK506 Against Hepatic Ischemia-Reperfusion Injury

Sawada

Inoue

Tanabe³

et al. 2016

J. Med. Invest.

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: Purposes ; FK506 (strong immunosuppressive agent) was investigated experimentally whether to protect the hepatic IRI. Methods ; Warm ischemic experiment using pigs and rats were performed and examined whether FK506 is effective. Results ; The results obtained are as follows. 1. Warm ischemia allowed time of the pigs without FK506 was 150 minutes, but as for that of FK506 group, the extension of 30 minutes was got in 180 minutes. 2. Biliary excretion rate of BSP after reperfusion were better in the group of 180 minutes ischemia with FK506 than in without FK506 group. 3. Chemiluminescence intensity in the peripheral neutrophils and adhered and infiltrated leukocytes in the liver were suppressed markedly by FK506. 4. The vascular endothelium with the scanning electron microscope was relatively preserved in the FK506 group comparing to the placebo group on 30 minutes after reperfusion. 5. Stress gastric ulcer was controlled and myeloperoxidase activity in the gastric mucosa was suppressed by FK506. Conclusion ; Based on the results of theses experiments, it was suggested that FK506 has a protective effect on IRI by suppressing : the impairment of sinusoidal endothelial cells ; the activation of KCs ; the disturbance of micro-circulation ; oxidative stress ; inflammation ; and the accumulation of leukocytes.

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Tacrolimus (Fk506) Down-Regulates Free Radical Tissue Levels, Serum Cytokines, and Neutrophil Infiltration After Severe Liver Ischemia

Cited by 77 publications

References 17 publications

Tacrolimus as a liver flush solution to ameliorate the effects of ischemia/reperfusion injury following liver transplantation

Tacrolimus as a liver flush solution to ameliorate the effects of ischemia/reperfusion injury following liver transplantation

Effects of tacrolimus on ischemia-reperfusion injury

Experimental Studies on Protective Effects of FK506 Against Hepatic Ischemia-Reperfusion Injury

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