Browsing by Author "Leuvenink, Henri G. D."

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    Anti-Apoptotic Effects of 3,3’,5-Triiodo-L-Thyronine in the Liver of Brain-Dead Rats
    (2015) Rebolledo Acevedo, Rolando Arturo; Van Erp, Anne C.; Ottens, Petra J.; Wiersema-Buist, Janneke; Leuvenink, Henri G. D.; Romanque, Pamela
    Background: Thyroid hormone treatment in brain-dead organ donors has been extensively studied and applied in the clinical setting. However, its clinical applicability remains controversial due to a varying degree of success and a lack of mechanistic understanding about the therapeutic effects of 3,3’,5-Triiodo-L-thyronine (T3). T3 pre-conditioning leads to anti-apoptotic and pro-mitotic effects in liver tissue following ischemia/reperfusion injury. Therefore, we aimed to study the effects of T3 pre-conditioning in the liver of brain-dead rats. Methods: Brain death (BD) was induced in mechanically ventilated rats by inflation of a Fogarty catheter in the epidural space. T3 (0.1 mg/kg) or vehicle was administered intraperitoneally 2 h prior to BD induction. After 4 h of BD, serum and liver tissue were collected. RT-qPCR, routine biochemistry, and immunohistochemistry were performed. Results: Brain-dead animals treated with T3 had lower plasma levels of AST and ALT, reduced Bax gene expression, and less hepatic cleaved Caspase-3 activation compared to brain-dead animals treated with vehicle. Interestingly, no differences in the expression of inflammatory genes (IL-6, MCP-1, IL-1β) or the presence of pro-mitotic markers (Cyclin-D and Ki-67) were found in brain-dead animals treated with T3 compared to vehicle-treated animals. Conclusion: T3 pre-conditioning leads to beneficial effects in the liver of brain-dead rats as seen by lower cellular injury and reduced apoptosis, and supports the suggested role of T3 hormone therapy in the management of brain-dead donors.
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    Prednisolone has a positive effect on the kidney but not on the liver of brain dead rats: a potencial role in complement activation
    (2014) Rebolledo Acevedo, Rolando Arturo; Liu, Bo; Akhtar, Mohammed Z.; Ottens, Petra J.; Zhang, Jian-Ning; Ploeg, Rutger J.; Leuvenink, Henri G. D.
    Background: Contradictory evidence has been published on the effects of steroid treatments on the outcomes of kidney and liver transplantation from brain dead (BD) donors. Our study aimed to evaluate this disparity by investigating the effect of prednisolone administration on BD rats. Methods: BD induction was performed in ventilated rats by inflating a Fogarty catheter placed in the epidural space. Prednisolone (22.5 mg/kg) was administered 30 min prior to BD induction. After four hours of determination of BD: serum, kidney and liver tissues samples were collected and stored. RT-qPCR, routine biochemistry and immunohistochemistry were performed. Results: Prednisolone treatment reduced circulating IL-6 and creatinine plasma levels but not serum AST, ALT or LDH. Polymorphonuclear influx assessed by histology, and inflammatory gene expression were reduced in the kidney and liver. However, complement component 3 (C3) expression was decreased in kidney but not in liver. Gene expression of HSP-70, a cytoprotective protein, was down-regulated in the liver after treatment. Conclusions: This study shows that prednisolone decreases inflammation and improves renal function, whilst not reducing liver injury. The persistence of complement activation and the negative effect on protective cellular mechanisms in the liver may explain the disparity between the effects of prednisolone on the kidney and liver of BD rats. The difference in the molecular and cellular responses to prednisolone administration may explain the contradictory evidence of the effects of prednisolone on different organ types from brain dead organ donors.
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    Slow induction of brain death leads to decreased renal function and increased hepatic apoptosis in rats
    (2016) Rebolledo, Rolando; Hoeksma, Dane.; Hottenrott, Christina M. V.; Bodar, Yves J. L.; Ottens, Petra J.; Wiersema Buist, Janneka.; Leuvenink, Henri G. D.
    Abstract Background Donor brain death (BD) is an independent risk factor for graft survival in recipients. While in some patients BD results from a fast increase in intracranial pressure, usually associated with trauma, in others, intracranial pressure increases more slowly. The speed of intracranial pressure increase may be a possible risk factor for renal and hepatic graft dysfunction. This study aims to assess the effect of speed of BD induction on renal and hepatic injury markers. Methods BD induction was performed in 64 mechanically ventilated male Fisher rats by inflating a 4.0F Fogarty catheter in the epidural space. Rats were observed for 0.5, 1, 2 or 4 h following BD induction. Slow induction was achieved by inflating the balloon-catheter at a speed of 0.015 ml/min until confirmation of BD. Fast induction was achieved by inflating the balloon at 0.45 ml/min for 1 min. Plasma, kidney and liver tissue were collected for analysis. Results Slow BD induction led to higher plasma creatinine at all time points compared to fast induction. Furthermore, slow induction led to increased renal mRNA expression of IL-6, and renal MDA values after 4 h of BD compared to fast induction. Hepatic mRNA expression of TNF-α, Bax/Bcl-2, and protein expression of caspase-3 was significantly higher due to slow induction after 4 h of BD compared to fast induction. PMN infiltration was not different between fast and slow induction in both renal and hepatic tissue. Conclusion Slow induction of BD leads to poorer renal function compared to fast induction. Renal inflammatory and oxidative stress markers were increased. Liver function was not affected by speed of BD induction but hepatic inflammatory and apoptosis markers increased significantly due to slow induction compared to fast induction. These results provide initial proof that speed of BD induction influences detrimental renal and hepatic processes which could signify different donor management strategies for patients progressing to BD at different speeds.Abstract Background Donor brain death (BD) is an independent risk factor for graft survival in recipients. While in some patients BD results from a fast increase in intracranial pressure, usually associated with trauma, in others, intracranial pressure increases more slowly. The speed of intracranial pressure increase may be a possible risk factor for renal and hepatic graft dysfunction. This study aims to assess the effect of speed of BD induction on renal and hepatic injury markers. Methods BD induction was performed in 64 mechanically ventilated male Fisher rats by inflating a 4.0F Fogarty catheter in the epidural space. Rats were observed for 0.5, 1, 2 or 4 h following BD induction. Slow induction was achieved by inflating the balloon-catheter at a speed of 0.015 ml/min until confirmation of BD. Fast induction was achieved by inflating the balloon at 0.45 ml/min for 1 min. Plasma, kidney and liver tissue were collected for analysis. Results Slow BD induction led to higher plasma creatinine at all time points compared to fast induction. Furthermore, slow induction led to increased renal mRNA expression of IL-6, and renal MDA values after 4 h of BD compared to fast induction. Hepatic mRNA expression of TNF-α, Bax/Bcl-2, and protein expression of caspase-3 was significantly higher due to slow induction after 4 h of BD compared to fast induction. PMN infiltration was not different between fast and slow induction in both renal and hepatic tissue. Conclusion Slow induction of BD leads to poorer renal function compared to fast induction. Renal inflammatory and oxidative stress markers were increased. Liver function was not affected by speed of BD induction but hepatic inflammatory and apoptosis markers increased significantly due to slow induction compared to fast induction. These results provide initial proof that speed of BD induction influences detrimental renal and hepatic processes which could signify different donor management strategies for patients progressing to BD at different speeds.
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    Steroid Anti-Inflammatory Effects Did Not Improve Organ Quality in Brain-Dead Rats
    (2015) Rebolledo Acevedo, Rolando Arturo; Liu, Bo; Akhtar, Mohammed Z.; Ottens, Petra J.; Zhang, Jian-Ning; Ploeg, Rutger J.; Leuvenink, Henri G. D.
    Effect of glucocorticoid administration on improving the outcomes of kidney and liver allografts has not been clearly elucidated. This study investigated the effect of prednisolone administration after onset of brain death (BD) on kidney and liver in a controlled rat model of BD. BD was induced in rats by inflating an epidurally placed balloon catheter. Animals were treated with saline or prednisolone (5, 12.5, or 22.5 mg/kg) one hour after the onset of BD. After 4 hours of BD, experiments were terminated and serum and tissues were collected. Tissue gene and protein expression were measured for markers of inflammation, apoptosis, and cellular stress response markers. Prednisolone caused a reduction of plasma levels of IL-6, while the tissue expression of IL-6, IL-1β, and MCP-1 in both kidney and liver were also reduced. Creatinine plasma levels, complement (C3) expression, HSP-70, HO-1, Bcl2/BAX ratio, and PMN influx did not significantly change in kidney nor liver. Plasma AST and LDH levels were increased in the prednisolone treated group. Our results demonstrate prednisolone can has an anti-inflammatory effect mediated through reducing serum circulating cytokines. However, this anti-inflammatory effect does not translate into improved kidney function and indeed was associated with increased liver injury markers.
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    The Crosstalk between ROS and Autophagy in the Field of Transplantation Medicine
    (2017) Van Erp, Anne C.; Hoeksma, Dane; Rebolledo Acevedo, Rolando Arturo; Ottens, Petra J.; Jochmans, Ina; Monbaliu, Diethard; Pirenne, Jacques; Leuvenink, Henri G. D.; Decuypere, Jean Paul