BACKGROUND: Hormonal resuscitation, specifically administration of levothyroxine (T4) and methylprednisolone (steroid, i.e., the "T4 Protocol") in organ transplant donors, is becoming increasingly used. Previous studies have shown that this maximizes the number of usable organs by reducing metabolic disturbances post-brain death. However, anecdotal evidence has shown that steatotic livers are adversely affected by this protocol. Therefore, we sought to investigate the hypothesis that the use of T4 and steroid is detrimental to steatotic livers in a model of total hepatic warm ischemia-reperfusion (I/R). METHODS: We subjected 8- to -10-week-old male C57BL/6 and ob/ob mice to injections of T4 and steroid 48 hr before 15 min of total hepatic ischemia, followed by 24 hr of reperfusion. RESULTS: We saw a significant decrease in survival in ob/ob animals given T4 and steroid as compared with single-treated or vehicle-treated animals. This decrease in survival was accompanied by a dramatic increase in liver necrosis (as measured on a scale from 0 to 3) in these animals as compared with controls. Previous work in our lab has shown that uncoupling protein-2 is a major mediator of I/R in steatotic animals, as it upsets normal energy homeostasis. Following with this hypothesis, we see a dramatic increase in uncoupling protein-2 levels in the combination treated animals, which is accompanied by a concomitant decrease in ATP levels after reperfusion. CONCLUSIONS: The T4 protocol is detrimental to steatotic livers subjected to I/R, likely because of a decreased ability to recover after reperfusion caused by decreased ability to form ATP.
BACKGROUND: Hormonal resuscitation, specifically administration of levothyroxine (T4) and methylprednisolone (steroid, i.e., the "T4 Protocol") in organ transplant donors, is becoming increasingly used. Previous studies have shown that this maximizes the number of usable organs by reducing metabolic disturbances post-brain death. However, anecdotal evidence has shown that steatotic livers are adversely affected by this protocol. Therefore, we sought to investigate the hypothesis that the use of T4 and steroid is detrimental to steatotic livers in a model of total hepatic warm ischemia-reperfusion (I/R). METHODS: We subjected 8- to -10-week-old male C57BL/6 and ob/ob mice to injections of T4 and steroid 48 hr before 15 min of total hepatic ischemia, followed by 24 hr of reperfusion. RESULTS: We saw a significant decrease in survival in ob/ob animals given T4 and steroid as compared with single-treated or vehicle-treated animals. This decrease in survival was accompanied by a dramatic increase in liver necrosis (as measured on a scale from 0 to 3) in these animals as compared with controls. Previous work in our lab has shown that uncoupling protein-2 is a major mediator of I/R in steatotic animals, as it upsets normal energy homeostasis. Following with this hypothesis, we see a dramatic increase in uncoupling protein-2 levels in the combination treated animals, which is accompanied by a concomitant decrease in ATP levels after reperfusion. CONCLUSIONS: The T4 protocol is detrimental to steatotic livers subjected to I/R, likely because of a decreased ability to recover after reperfusion caused by decreased ability to form ATP.
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