FK506 Maintains Cellular Calcium Homeostasis in Ischemia–Reperfusion Injury of the Canine Liver

Dhar, Dipok Kumar; Takemoto, Yoshinari; Nagasue, Naofumi; Uchida, Masaaki; Ono, Takashi; Nakamura, Teruhisa

doi:10.1006/jsre.1996.0023

Cited by 33 publications

(17 citation statements)

References 1 publication

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“…12 Tacrolimus has been shown to decrease calcium concentrations within the mitochondria during ischemia and reperfusion, which resulted in maintenance of mitochondrial function and regulation of the enzymatic systems responsible for initiation of inflammatory pathways. 13 Free radical production after reperfusion from the products of ATP breakdown that accumulate during ischemia is an important mechanism for cellular injury. 14,15 In a rat model of hepatic I/R injury, improved survival was found after two thirds partial hepatectomy with restoration of hepatic ATP contents when tacrolimus pretreatment was used.…”

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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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: 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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“…"Total" Ca 2+ includes all forms of Ca 2+ (bound and free) compared with [Ca 2+ ] cyt , which refers only to "free" (ionized, unbound) Ca 2+ in the cytoplasmic space. "Total" Ca 2+ has been measured in sections of liver tissue using x-ray probe microanalysis (64) or 45 Ca 2+ autoradiography (65) and in whole-cell homogenates using atomic absorption spectroscopy (66,67). The increase in total hepatocyte Ca 2+ was found to be associated with an increase in total mitochondrial Ca 2+ (measured in isolated mitochondria by atomic absorption spectroscopy) (64,66).…”

Section: Intracellular Ca 2+ As a Mediator Of Hepatocyte Injury Inducmentioning

confidence: 99%

Hepatic Ischemia-Reperfusion Injury: Roles of Ca2+ and Other Intracellular Mediators of Impaired Bile Flow and Hepatocyte Damage

et al. 2006

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Liver resection and liver transplantation have been successful in the treatment of liver tumors and end-stage liver disease. This success has led to an expansion in the pool of patients potentially treatable by liver surgery and, in the case of transplantation, to a shortage of liver donors. At present, there are significant numbers of potential candidates for liver resection and liver donation who have fatty livers, are aged, or have livers damaged by chemotherapy. All of these are at high risk for ischemic reperfusion (IR) injury. The aims of this review are to assess current knowledge of the clinical effectiveness of ischemic preconditioning and intermittent ischemia in reducing IR damage in liver surgery; to evaluate the use of bile flow as a sensitive indicator of IR liver damage; and to analyze the molecular mechanisms, especially intracellular Ca2+, involved in IR injury and ischemic preconditioning. It is concluded that bile flow is a sensitive indicator of IR injury. Together with reactive oxygen species (ROS) and other extracellular and intracellular signaling molecules, intracellular Ca2+ in hepatocytes plays a key role in the normal regulation of bile flow and in IR-induced injury and cell death. Ischemic preconditioning is an effective strategy to reduce IR injury but there is considerable scope for improvement, especially in patients with fatty and aged livers. The development of effective new strategies to reduce IR injury will depend on improved understanding of the molecular mechanisms involved, especially by gaining a better perspective of the relative importance of the various intrahepatocyte signaling pathways involved.

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“…Tacrolimus administered before ischemia has been shown to suppress intramitochondrial calcium concentration, maintain mitochondrial function, and regulate enzymatic systems that initiate inflammatory pathways. 54 However, compared with cyclosporine A, tacrolimus has been shown to be 3,000-fold less effective in the inhibition of mitochondrial release of calcium. 52 These data may imply that attenuation of calcium-mediated pathways is not among the primary effects of tacrolimus, at least compared with cyclosporine.…”

Section: Calcium-mediated Pathwaysmentioning

confidence: 99%

“…In the canine liver model, tacrolimus pretreatment has been shown to inhibit accumulation of intracellular calcium, measured at 15 and 30 minutes after reperfusion, with a resultant decrease in hepatocellular injury. 54 …”

Section: Calcium-mediated Pathwaysmentioning

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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FK506 Maintains Cellular Calcium Homeostasis in Ischemia–Reperfusion Injury of the Canine Liver

Cited by 33 publications

References 1 publication

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

Hepatic Ischemia-Reperfusion Injury: Roles of Ca2+ and Other Intracellular Mediators of Impaired Bile Flow and Hepatocyte Damage

Effects of tacrolimus on ischemia-reperfusion injury

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