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- Thorlacius, Karin, et al.
(författare)
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Protective effect of fasudil, a Rho-kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury.
- 2006
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Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 79:5, s. 923-931
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Tidskriftsartikel (refereegranskat)abstract
- Rho-kinase signaling regulates important features of inflammatory reactions. Herein, we investigated the effect and mechanisms of action of the Rho-kinase inhibitor fasudil in endotoxemic liver injury. C57/BL/6 mice were challenged with lipopolysaccharide (LPS) and D-galactosamine, with or without pretreatment with the Rho-kinase inhibitor fasudil. Six hours after endotoxin challenge, leukocyte-endothelium interactions in the hepatic microvasculature were studied by use of intravital fluorescence microscopy and tumor necrosis factor {alpha} (TNF-{alpha}); CXC chemokines as well as liver enzymes and apoptosis were determined. Administration of fasudil reduced LPS-induced leukocyte adhesion in postsinusoidal venules and sequestration in sinusoids. Moreover, we found that fasudil abolished extravascular infiltration of leukocytes as well as production of TNF-{alpha} and CXC chemokines in the liver of endotoxemic mice. Liver enzymes and hepatocellular apoptosis were markedly reduced, and sinusoidal perfusion was improved significantly in endotoxemic mice pretreated with fasudil. Our novel data document that fasudil is a potent inhibitor of endotoxin-induced expression of TNF-{alpha} and CXC chemokines as well as leukocyte infiltration and hepatocellular apoptosis in the liver. Based on the present findings, it is suggested that inhibition of the Rho-kinase signaling pathway may be a useful target in the treatment of septic liver injury.
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| 2. |
- Thorlacius, Karin
(författare)
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Anaesthetics and the blood vessel wall. Actions of propofol and sevoflurane on sympathetic and endothelial control of smooth muscle function.
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The anaesthetics we use today dose-dependently decrease the mean arterial pressure partly due to direct or indirect effects on the blood vessels. In the present thesis human omental arteries and veins and rat femoral arteries were investigated in vitro concerning the effects of the intravenous anaesthetic propofol and the volatile anaesthetic sevoflurane on the function of the perivascular sympathetic nerves and the endothelial cells. The effects of propofol on the kinetics of the neuronal uptake of noradrenaline were studied in the rat femoral artery. At lower propofol concentrations we found a decrease in the affinity of the noradrenaline transporters, which results in an uptake inhibition. At higher propofol concentrations this inhibition is counteracted by an increase in the efficiency of the uptake. The effects of propofol on endothelium-dependent relaxation (induced by substance P) were studied in human omental arteries and veins. Propofol, at a clinically relevant concentration, was found to promote endothelium-dependent relaxation mediated via hyperpolarization in human omental arteries and via both nitric oxide and hyperpolarization in human omental veins. The effects of sevoflurane on sympathetic neurotransmission were studied in human omental arteries and veins. We found that sevoflurane depresses the sympathetic neuromuscular transmission by lowering the neuronal noradrenaline release and noradrenaline sensitivity in the arteries and by lowering the noradrenaline release in the veins. The effects of sevoflurane on endothelium-dependent relaxation (induced by substance P) were studied in human omental arteries and veins. Sevoflurane was found to promote endothelium-dependent relaxation in human omental arteries and veins probably via an enhancement of the response of smooth muscle cells to relaxing mediators.
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| 6. |
- Winsnes, Annika
(författare)
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Evaluating an experimental model consecutive to abdominal wall hernia repair outcome
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Abdominal wall hernia is a common surgically treated condition. Patients with primary umbilical hernia are operated with suture or mesh repair, but recurrence and complication rates have been debated.Larger abdominal wall hernias need implantation of reinforcing material for repair. Synthetic implants are dominating. In complex hernia cases neither synthetic nor biologic implants are optimal. A randomized controlled trial has revealed satisfactory results from autologous full thickness skin grafts (FTSGs) in onlay position. Further application intraperitoneally (IPOM) in laparoscopic surgery and for repair of parastomal hernia in humans, must be based on a translational concept including animal and morphologic studies since the IPOM position has not been evaluated systematically. This thesis aims to be a link in a translational chain, focused on establishing an experimental model for FTSG evaluation.Problem formulations: - Does synthetic mesh decrease the probability of recurrence and/or complications in primary umbilical hernia?- Can FTSG be evaluated for IPOM versus onlay position in a transgenic mouse model using luminescence from substrate activated by the enzyme luciferase expressed in donor tissue?- How does the FTSG in IPOM position perform compared to FTSG in onlay position?Results:Recurrence rate at a median of 6.8 years follow-up was 9% for suture- and 8% for mesh repair, odds ratio (OR) 0.9, 95% confidence interval (CI) 0.40-2.02, in 306 patients investigated patients. Surgical complications were in favor of suture repair, OR 6.6, 95% CI 2.29-20.38.In an experimental evaluation of FTSG, 20 mice received intervention with either onlay or IPOM graft. Survival of FTSG was revealed for 8 weeks by luminescence detection. All animals regained weight within 8 days in median. At sacrifice 8 weeks postoperatively, adhesions were evaluated by a modified Jenkins’ scale. No onlay mice displayed adhesions while two IPOM mice had firm and one dense adhesions. Inflammatory response evaluated in four animals expressing nuclear factor ĸB (NF-ĸB) showed a peak at day 2 and returned to stable low levels from day 5 until end of the 33-day follow up. FTSG in IPOM position showed similar morphology and immunohistochemistry stain patterns as controls in onlay position. There was a low expression of the inflammatory markers tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and myeloperoxidase. Vascular structures were visualized by von Willebrand factor-stain. In Picrosirius red stain, collagen bundles in dermis of FTSG in both IPOM and onlay position was thicker, compared to internal controls. FTSG extracellular matrix had metamorphosed mainly into thick collagen bundles, with partially degraded skin appendages. Matrix metalloproteinases (MMP)-stain from MMP-1, MMP-8 and MMP-9 were not co-distributed with their respective collagen substrates.Conclusions:Synthetic mesh does not decrease the probability of recurrence but significantly increase complications in repair of small umbilical hernia. FTSG can be evaluated in IPOM and onlay position in an experimental transgenic mouse model. The two positions were similar in terms of graft survival, few adhesions, micro-vessel formation, low grade inflammation, cyst formation and collagen distribution. FTSG implanted in IPOM position does not exhibit any systematic differences from onlay position, thus from this perspective no difference in biomechanical behavior can be anticipated.
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