| 1. |
- Adrian, Katrin, 1966, et al.
(författare)
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Cytokine release during long-term extracorporeal circulation in an experimental model.
- 1998
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Ingår i: Artificial organs. - 0160-564X. ; 22:10, s. 859-63
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to determine the degree of leukocyte activation, as measured by cytokine release, in circulating blood during experimental extracorporeal circulation. Complete in vitro extracorporeal membrane oxygenation (ECMO) circuits were used, and 9 experiments were performed. Whole blood stored at 37 degrees C was used as the control. Blood samples were withdrawn before the start of perfusion and at 24 h of perfusion. Statistically significant releases of interleukin (IL)-1beta, IL-8, and IL-1 receptor antagonist were observed in the perfusion circuits compared to both the control blood and baseline values. Also, increases in plasma tumor necrosis factor (TNF)alpha and IL-6 were seen after 24 h of perfusion although these changes did not reach statistical significance. These results indicate that extracorporeal circulation induced leukocyte activation and cytokine release. These reactions might, as an additional trauma, deteriorate the situation in an already severely ill patient. A search for methods to counteract this untoward activation seems warranted.
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| 2. |
- Adrian, Katrin, 1966, et al.
(författare)
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The effect of albumin priming solution on platelet activation during experimental long-term perfusion.
- 1998
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Ingår i: Perfusion. - 0267-6591. ; 13:3, s. 187-91
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to evaluate the effect of albumin priming on platelet consumption and activation during long-term perfusion. Two identical in vitro extracorporeal membrane oxygenation circuits were used; one was primed with Ringer's solution containing human serum albumin, the other with Ringer's solution only. Fresh heparinized human blood was pooled, divided between the two systems and circulated for 24 h at 37 degrees C. Platelet count, plasma concentration of betathromboglobulin (BTG), platelet membrane density of glycoprotein (GP) Ib and of GPIIb/IIIa were assayed before the start and at 0.5, 1, 3, 12 and 24 h of perfusion. In total, seven experiments were performed. We found that during the first hour of perfusion, slightly higher platelet counts (p = 0.058) and lower BTG values (p = 0.0005) were observed in the circuits primed with albumin, compared to the control circuits. No statistically significant differences were observed for the platelet membrane expression of GPIb and GPIIb/IIIa. We conclude that albumin priming appears to transiently prevent platelet consumption and activation during long-term perfusion.
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| 3. |
- Friberg, Hans, et al.
(författare)
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Cyclosporin A, but not FK 506, protects mitochondria and neurons against hypoglycemic damage and implicates the mitochondrial permeability transition in cell death
- 1998
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Ingår i: The Journal of Neuroscience. - 0270-6474. ; 18:14, s. 5151-5159
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Tidskriftsartikel (refereegranskat)abstract
- Induction of the mitochondrial permeability transition (MPT) has been implicated in cellular apoptosis and in ischemia-reperfusion injury. During MPT, a channel in the inner mitochondrial membrane, the mitochondrial megachannel, opens and causes isolated mitochondria to swell. MPT and mitochondrial swelling is inhibited by cyclosporin A (CsA), which may also inhibit apoptosis in some cells. Treatment with CsA (50 mg/kg, i.v.) showed a robust reduction of brain damage when administered 30 min before insulin- induced hypoglycemic isoelectricity of 30 min duration. Ultrastructural examination of the dentate gyrus revealed a marked swelling of dendrites and mitochondria during the hypoglycemic insult. In CsA-treated animals, mitochondria resumed a normal and contracted appearance during and after the hypoglycemic insult. Treatment with FK 506 (2 mg/kg, i.v.), a compound with immunosuppressive action similar to that of CsA, was not protective. Studies on the swelling kinetics of isolated mitochondria from the hippocampus showed that CsA, but not FK 506, inhibits calcium ion-induced MPT. We conclude that CsA treatment during hypoglycemic coma inhibits the MPT and reduces damage and that mitochondria and the MPT are likely to be involved in the development of hypoglycemic brain damage in the rat.
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| 4. |
- Friberg, Hans, et al.
(författare)
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Differences in the activation of the mitochondrial permeability transition among brain regions in the rat correlate with selective vulnerability
- 1999
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042. ; 72:6, s. 2488-2497
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondria from different regions of the brain were prepared, and the activation of the mitochondrial permeability transition (MPT) by calcium was investigated by monitoring the associated mitochondrial swelling. In general, the properties of the MPT in brain mitochondria were found to be qualitatively similar to those observed in liver and heart mitochondria. Thus, swelling was inhibited by adenine nucleotides (AdNs) and low pH (<7.0), whereas thiol reagents and alkalosis facilitated swelling. Cyclosporin A and its nonimmunosuppressive analogue N-methyl-Val-4-cyclosporin A (PKF 220- 384.) both inhibited swelling and prevented the translocation of cyclophilin D from the matrix to the membranes of cortical mitochondria. However, the calcium sensitivity of the MPT differed in mitochondria from three brain regions (hippocampus > cortex > cerebellum) and is correlated with the susceptibility of these regions to ischemic damage. Depleting mitochondria of AdNs by treatment with pyrophosphate ions sensitized the MPT to [Ca2+] and abolished regional differences, implying regional differences in mitochondrial AdN content. This was confirmed by measurements showing significant differences in AdN content among regions (cerebellum > cortex > hippocampus). Our data add to recent evidence that the MPT may be involved in neuronal death.
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| 5. |
- Friberg, Hans
(författare)
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Ischemic and Hypoglycemic Brain Damage, Involvement of the Mitochondrial Permeability Transition Pore
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Brain damage from ischemia-reperfusion and hypoglycemia are major causes of morbidity and mortality. Therapeutic strategies include hypothermia, glutamate-receptor blockade, immunosuppression and lately treatment aiming at preserving mitochondrial integrity and function. Mitochondria are the main producers of cellular energy but mitochondria also participate in cell signaling and take an active part in the life/death decision of a cell. Oxidative stress and high mitochondrial calcium loads can trigger the formation of a large pore in the mitochondrial inner membrane, the mitochondrial permeability transition pore. The consequent disruption of the mitochondrial membrane potential, osmotic swelling and loss of metabolites and mitochondrial proteins through a ruptured outer membrane may lead to immediate or delayed cell death. In this study we demonstrate that isolated mitochondria from different brain regions have different sensitivity to calcium-induced permeability transition and furthermore that this correlates with the selective vulnerability of these regions to ischemia-reperfusion injury. Also, important modulators of the pore such as Bcl-2 and free radical production are altered after ischemia. Thus, Bcl-2 levels decrease at 4h and at 24h after forebrain ischemia in parallel with a 50% increase of free radical production in mitochondria isolated from the vulnerable hippocampus. These alterations are not seen in isolated mitochondria from the more resistant cortex region. We also show that cyclosporin A and MeValCsA, potent blockers of the mitochondrial permeability transition pore, protect neurons from oxygen/glucose deprivation in vitro and from ischemia-reperfusion injury in vivo. Moreover, cyclosporin A protects mitochondria and neurons from hypoglycemic brain damage. We conclude that calcium-induced mitochondrial permeability transition differs between brain regions and that mitochondria from different regions respond differentially to ischemic stress. The results of the present thesis support the view that the mitochondrial permeability transition pore is of importance in the development of brain injury after ischemia-reperfusion and hypoglycemia.
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| 6. |
- Khaspekov, Leonid, et al.
(författare)
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Cyclosporin A and its nonimmunosuppressive analogue N-Me-Val-4-cyclosporin A mitigate glucose/oxygen deprivation-induced damage to rat cultured hippocampal neurons
- 1999
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X. ; 11:9, s. 3194-3198
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Tidskriftsartikel (refereegranskat)abstract
- When mouse hippocampal neuronal cultures, 2-3 weeks in vitro, were transiently exposed to combined glucose and oxygen deprivation (100% argon, 5% CO2, in glucose-free medium) for 90 min, extensive neuronal degeneration had occurred after 24 h of reoxygenation. When these cultures were preincubated with cyclosporin A, a calcineurin inhibitor and a blocker of the mitochondrial permeability transition, neuronal death diminished by 30-50%. Similarly, the cyclosporin A analogue, N-Me-Val-4-cyclosporin A, a potent blocker of the mitochondrial permeability transition with no significant calcineurin blocking activity, decreased cell death by 70-80%. Both cyclosporin A and N-Me-Val-4-cyclosporin A markedly attenuated calcium-induced swelling of isolated mouse brain mitochondria by blocking the mitochondrial permeability transition. The potassium thiocyanate-stabilized binding of cyclophilin D to mouse brain mitochondrial membranes was completely prevented by cyclosporin A and N-Me-Val-4-cyclosporin A. Our results strongly suggest that the mitochondrial permeability transition is involved in oxygen/glucose deprivation-induced cell death in vitro. Cyclophilin D and other components of the mitochondrial permeability transition may be important targets for neuroprotective and anti-ischaemic drugs.
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| 7. |
- Mellgren, Karin, 1962, et al.
(författare)
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Blood platelet activation and membrane glycoprotein changes during extracorporeal life support (ECLS). In vitro studies.
- 1995
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Ingår i: The International journal of artificial organs. - 0391-3988. ; 18:6, s. 315-21
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate an in vitro model for investigation of platelet function parameters in an extracorporeal system. Two different perfusion pumps were compared, a roller pump (Polystan) and a centrifugal pump (Biomedicus). A continuous increase in glycoprotein (GP)1b-negative platelets was observed in both circuits. A marked increase of plasma beta-thromboglobulin thromboglobulin concentration and a decrease of the intracellular pool of serotonin was observed, indicating a marked release of alpha as well as of dense granules. The plasma concentration of glycocalicin increased in parallel with a reduced platelet surface expression of GP1b, suggesting that the loss of GP1b is caused by proteolysis rather than by a downregulation of this receptor protein. It is concluded that ECLS results in a pronounced platelet degranulation and causes changes of important membrane receptors which might explain some of the bleeding problems observed in patients treated with ECLS. No significant difference was noted between the roller pump and the centrifugal pump. Trial of strategies, e.g., protease inhibitors and nitric oxide to revert this untoward effect of ECLS are highly warranted.
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| 8. |
- Mellgren, Karin, 1962, et al.
(författare)
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Nitric oxide in the oxygenator sweep gas reduces platelet activation during experimental perfusion.
- 1996
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Ingår i: The Annals of thoracic surgery. - 0003-4975. ; 61:4, s. 1194-8
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Tidskriftsartikel (refereegranskat)abstract
- Hemorrhage is a major complication experienced in 10% to 35% of neonates treated with extracorporeal life support (ECLS). The increased bleeding tendency is partly due to an ECLS-induced thrombocytopenia and impaired platelet function. In the present study, we evaluated the effect of nitric oxide on the ECLS-induced platelet consumption and activation.
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| 9. |
- Mellgren, Karin, 1962, et al.
(författare)
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Platelet activation and degradation in an experimental extracorporeal system. A comparison between a silicone membrane and a hollow-fibre oxygenator.
- 1996
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Ingår i: Perfusion. - 0267-6591. ; 11:5, s. 383-8
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Tidskriftsartikel (refereegranskat)abstract
- Blood platelets are rapidly activated in contact with biomaterials and, therefore, can be used as markers of the biocompatibility of various components in an extracorporeal system. In the present work two different oxygenators, one membrane oxygenator (Avecor) and one hollow-fibre oxygenator ("Lilliput', Dideco) were compared. Complete in vitro extracorporeal membrane oxygenation circuits were perfused with fresh, heparinized human blood for 24 h. Eight experiments were performed with the hollow-fibre oxygenator and five experiments with the membrane oxygenator. Blood gases, electrolytes, glucose and haematocrit were kept within physiological limits. Platelet count, plasma concentration of beta-thromboglobulin, platelet serotonin content, platelet membrane glycoprotein lb and its degradation product glycocalicin, as well as plasma haemoglobin concentration were assayed. As regards most of these variables, significant differences in favour of the hollow-fibre oxygenator were observed.
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| 10. |
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