| 1. |
- Adori, Csaba, et al.
(författare)
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Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:30
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Tidskriftsartikel (refereegranskat)abstract
- Hepatic nerves have a complex role in synchronizing liver metabolism. Here, we used three-dimensional (3D) immunoimaging to explore the integrity of the hepatic nervous system in experimental and human nonalcoholic fatty liver disease (NAFLD). We demonstrate parallel signs of mild degeneration and axonal sprouting of sympathetic innervations in early stages of experimental NAFLD and a collapse of sympathetic arborization in steatohepatitis. Human fatty livers display a similar pattern of sympathetic nerve degeneration, correlating with the severity of NAFLD pathology. We show that chronic sympathetic hyperexcitation is a key factor in the axonal degeneration, here genetically phenocopied in mice deficient of the Rac-1 activator Vav3. In experimental steatohepatitis, 3D imaging reveals a severe portal vein contraction, spatially correlated with the extension of the remaining nerves around the portal vein, enlightening a potential intrahepatic neuronal mechanism of portal hypertension. These fundamental alterations in liver innervation and vasculature uncover previously unidentified neuronal components in NAFLD pathomechanisms.
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| 2. |
- Asif, Sana, et al.
(författare)
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Oxygen-charged HTK-F6H8 emulsion reduces ischemia : reperfusion injury in kidneys from brain-dead pigs
- 2012
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Ingår i: Journal of Surgical Research. - : Elsevier BV. - 0022-4804 .- 1095-8673. ; 178:2, s. 959-967
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Tidskriftsartikel (refereegranskat)abstract
- Background:Prolonged cold ischemia is frequently associated with a greater risk of delayed graft function and enhanced graft failure. We hypothesized that media, combining a high oxygen-dissolving capacity with specific qualities of organ preservation solutions, would be more efficient in reducing immediate ischemia-reperfusion injury from organs stored long term compared with standard preservation media.Methods:Kidneys retrieved from brain-dead pigs were flushed using either cold histidine-tryptophan-ketoglutarate (HTK) or oxygen-precharged emulsion composed of 75% HTK and 25% perfluorohexyloctane. After 18 h of cold ischemia the kidneys were transplanted into allogeneic recipients and assessed for adenosine triphosphate content, morphology, and expression of genes related to hypoxia, environmental stress, inflammation, and apoptosis.Results:Compared with HTK-flushed kidneys, organs preserved using oxygen-precharged HTK-perfluorohexyloctane emulsion had increased elevated adenosine triphosphate content and a significantly lower gene expression of hypoxia inducible factor-1 alpha, vascular endothelial growth factor, interleukin-1 alpha, tumor necrosis factor-alpha, interferon-alpha, JNK-1, p38, cytochrome-c, Bax, caspase-8, and caspase-3 at all time points assessed. In contrast, the mRNA expression of Bcl-2 was significantly increased.Conclusions:The present study has demonstrated that in brain-dead pigs the perfusion of kidneys with oxygen-precharged HTK-perfluorohexyloctane emulsion results in significantly reduced inflammation, hypoxic injury, and apoptosis and cellular integrity and energy content are well maintained. Histologic examination revealed less tubular, vascular, and glomerular changes in the emulsion-perfused tissue compared with the HTK-perfused counterparts. The concept of perfusing organs with oxygen-precharged emulsion based on organ preservation media represents an efficient alternative for improved organ preservation.
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| 3. |
- Forkel, Marianne, et al.
(författare)
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Composition and functionality of the intrahepatic innate lymphoid cell-compartment in human nonfibrotic and fibrotic livers
- 2017
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 47:8, s. 1280-1294
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Tidskriftsartikel (refereegranskat)abstract
- Human innate lymphoid cells have been described to exist in different organs, with functional deregulation of these cells contributing to several disease states. Here, we performed the first detailed characterization of the phenotype, tissue-residency properties, and functionality of ILC1s, ILC2s, and ILC3s in the human adult and fetal liver. In addition, we investigated changes in the ILC compartment in liver fibrosis. A unique composition of tissue-resident ILCs was observed in nonfibrotic livers as compared with that in mucosal tissues, with NKp44− ILC3s accounting for the majority of total intrahepatic ILCs. The frequency of ILC2s, representing a small fraction of ILCs in nonfibrotic livers, increased in liver fibrosis and correlated directly with the severity of the disease. Notably, intrahepatic ILC2s secreted the profibrotic cytokine IL-13 when exposed to IL-33 and thymic stromal lymphopoetin (TSLP); these cytokines were produced by hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells in response to TLR-3 stimulation. In summary, the present results provide the first detailed characterization of intrahepatic ILCs in human adult and fetal liver. The results indicate a role for ILC2s in human liver fibrosis, implying that targeting ILC2s might be a novel therapeutic strategy for its treatment.
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| 4. |
- Iwata, Takashi, et al.
(författare)
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Microdialysis monitoring for evaluation of the influence exertedby pneumoperitoneum on the kidney: an experimental study
- 2008
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Ingår i: Surgical Endoscopy. - : Springer Science and Business Media LLC. - 0930-2794 .- 1432-2218. ; 22, s. 938-942
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundLaparoscopic donor nephrectomy hasbecome the first choice for living donor kidney transplantation,offering advantages over open donor nephrectomy.This study aimed to evaluate kidney tissue metabolismduring and after pneumoperitoneum using a microdialysistechnique.MethodsEight pigs underwent laparotomy and implantationof two microdialysis catheters: one in the cortex andone in the medulla of the left kidney. After laparotomy, theabdominal wall was closed, and pneumoperitoneum wasinduced with a constant standard pressure of 16 to 18mmHg for 4 h, followed by rapid desufflation. In microdialysissamples collected from intrarenal catheters,markers of ischemia (glucose, lactate, pyruvate, and lactate–pyruvate ratio) and the marker of cell membraneinjury (glycerol) were monitored.ResultsThere were no changes in glucose, lactate, orpyruvate level before, during, or after pneumoperitoneum,either in the cortex or in the medulla. Additionally, thecalculated lactate–pyruvate ratio did not show signs ofischemia during or after pneumoperitoneum. However,with regard to the marker of cell injury, glycerol increasedin the medulla after decompression from 22.57 ± 3.76 to35.67 ± 5.43 mmol/l (p < 0.01). This release of glycerol inthe medulla was significantly higher than in the cortex(area under the curve [AUC], 22.18 ± 4.87 vs34.79 ± 7.88 mmol/l;p < 0.01).ConclusionsThe pattern of metabolic changes monitoredin the kidney during and after pneumoperitoneum indicatessome kind of cell injury predominant in the medulla withoutany signs of kidney ischemia. This nonischemic injury couldbe related to hyperperfusion of the kidney after decompressionor injury to cells attributable to mechanical cellexpansion at the point of rapid decompression.
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| 5. |
- Jorns, Carl
(författare)
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Hepatocyte transplantation : experimental and clinical studies
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hepatocyte transplantation is an experimental treatment for patients with end-stage liver disease and inborn metabolic liver disorders. Studies in animal models and human trials have shown that allogenic hepatocytes infused through the portal vein physiologically integrate into the liver parenchyma, replacing missing liver function. Current research data provide a proof of principle for clinical hepatocyte transplantation in a wide range of liver diseases. However, most patients ultimately undergo whole organ liver transplantation due to insufficient graft function. Thus, the efficacy and long-term results of clinical hepatocyte transplantation must be improved before this treatment can be introduced into routine clinical care. The present thesis summarizes experimental and clinical studies with the general aim of identifying current limitations and improving outcomes of hepatocyte transplantation. Paper I investigates strategies for improving short-term preservation of isolated human hepatocytes. Human hepatocytes are usually cold stored for prolonged periods between isolation and infusion. We found that isolated human hepatocytes undergo cell death and lose hepatocyte-specific function during this cold storage period. An alternative technique of liver tissue storage and repeated isolations led to improved viability and function of isolated hepatocytes before infusion. In Papers II and III, a hepatocyte transplantation model was established in the ApoE knockout mouse. Clinically relevant animal models are necessary for developing new treatment strategies. The ApoE knockout mouse is an ideal model of an inherited metabolic liver disease. ApoE is mainly produced by hepatocytes and its deficiency results in extrahepatic disease. ApoE (−/−) mice display severe hypercholesterolemia leading to premature atherosclerosis. We observed that transplanted wild-type hepatocytes integrated into the liver and excreted ApoE, and that this serum ApoE correlated with hepatic donor cell engraftment. Transplantation without preconditioning treatment resulted in serum ApoE levels of 1–2% of wild-type levels, which did not affect hypercholesterolemia. However, pretreatment with retrorsine gave donor hepatocytes a growth advantage, resulting in progressive repopulation of up to 55% of the recipient liver. This increased repopulation by donor hepatocytes led to normalization of hypercholesterolemia and prevention of atherosclerosis. Paper IV evaluated the safety and efficacy of partial hepatectomy preconditioning with hepatocyte transplantation in two patients with Crigler-Najjar syndrome type I. Partial hepatectomy in combination with hepatocyte transplantation was safe and induced a regenerative response. Serum bilirubin decreased to approximately 50% of pretransplant concentrations, and allograft function was further confirmed by detection of bilirubin diglucuronides in bile after transplantation. However, both patients lost graft function in association with the emergence of donor-specific HLA antibodies.
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| 6. |
- Kannisto, Kristina, et al.
(författare)
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LXR Driven Induction of HDL-Cholesterol is Independent of Intestinal Cholesterol Absorption and ABCA1 Protein Expression
- 2014
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Ingår i: Lipids. - : Wiley. - 0024-4201 .- 1558-9307. ; 49:1, s. 71-83
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Tidskriftsartikel (refereegranskat)abstract
- We investigated whether: (1) liver X receptor (LXR)-driven induction of high-density lipoprotein cholesterol (HDL-C) and other LXR-mediated effects on cholesterol metabolism depend on intestinal cholesterol absorption; and (2) combined treatment with the LXR agonist GW3965 and the cholesterol absorption inhibitor ezetimibe results in synergistic effects on cholesterol metabolism that could be beneficial for treatment of atherosclerosis. Mice were fed 0.2 % cholesterol and treated with GW3965+ezetimibe, GW3965 or ezetimibe. GW3965+ezetimibe treatment elevated serum HDL-C and Apolipoprotein (Apo) AI, effectively reduced the intestinal cholesterol absorption and increased the excretion of faecal neutral sterols. No changes in intestinal ATP-binding cassette (ABC) A1 or ABCG5 protein expression were observed, despite increased mRNA expression, while hepatic ABCA1 was slightly reduced. The combined treatment caused a pronounced down-regulation of intestinal Niemann-Pick C1-like 1 (NPC1L1) and reduced hepatic and intestinal cholesterol levels. GW3965 did not affect the intestinal cholesterol absorption, but increased serum HDL-C and ApoAI levels. GW3965 also increased Apoa1 mRNA levels in primary mouse hepatocytes and HEPA1-6 cells. Ezetimibe reduced the intestinal cholesterol absorption, ABCA1 and ABCG5, but did not affect the serum HDL-C or ApoAI levels. Thus, the LXR-driven induction of HDL-C and ApoAI was independent of the intestinal cholesterol absorption and increased expression of intestinal or hepatic ABCA1 was not required. Inhibited influx of cholesterol via NPC1L1 and/or low levels of intracellular cholesterol prevented post-transcriptional expression of intestinal ABCA1 and ABCG5, despite increased mRNA levels. Combined LXR activation and blocked intestinal cholesterol absorption induced effective faecal elimination of cholesterol.
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| 7. |
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| 8. |
- Kvedaraite, Egle, et al.
(författare)
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Intestinal stroma guides monocyte differentiation to macrophages through GM-CSF
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Stromal cells support epithelial cell and immune cell homeostasis and play an important role in inflammatory bowel disease (IBD) pathogenesis. Here, we quantify the stromal response to inflammation in pediatric IBD and reveal subset-specific inflammatory responses across colon segments and intestinal layers. Using data from a murine dynamic gut injury model and human ex vivo transcriptomic, protein and spatial analyses, we report that PDGFRA+CD142−/low fibroblasts and monocytes/macrophages co-localize in the intestine. In primary human fibroblast-monocyte co-cultures, intestinal PDGFRA+CD142−/low fibroblasts foster monocyte transition to CCR2+CD206+ macrophages through granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocyte-derived CCR2+CD206+ cells from co-cultures have a phenotype similar to intestinal CCR2+CD206+ macrophages from newly diagnosed pediatric IBD patients, with high levels of PD-L1 and low levels of GM-CSF receptor. The study describes subset-specific changes in stromal responses to inflammation and suggests that the intestinal stroma guides intestinal macrophage differentiation.
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| 9. |
- Nordström, Johan, et al.
(författare)
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First European Case of Simultaneous Liver and Pancreas Transplantation as Treatment of Wolcott-Rallison Syndrome in a Small Child
- 2020
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Ingår i: Transplantation. - 1534-6080. ; 104:3, s. 522-525
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The concept of organ transplantation as treatment for complex genetic conditions, including Wolcott-Rallison syndrome (WRS), continues to show promise. Liver transplantation is essential for survival of patients with WRS, and pancreas transplantation cures their type I diabetes mellitus. METHODS: The recipient, a 3-year-old girl weighing 14 kg at the time of transplantation, suffered from major complications of WRS, including repetitive liver failure episodes and poorly controlled diabetes. The patient underwent a nonacute, combined, simultaneous liver and pancreas transplantation from a pediatric donor without using the en bloc technique. RESULTS: Well-preserved graft functions at 2-year follow-up with normal liver and pancreas function. CONCLUSIONS: This is the first case report of simultaneous liver and pancreas transplantation as treatment of WRS in a small child in Europe. Two-year follow-up demonstrates that organ transplantation can halt life-threating recurrent liver failure episodes and cure type 1 diabetes.
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| 10. |
- von Zur-Mühlen, Bengt, Docent, 1966-, et al.
(författare)
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Open Randomized Multicenter Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation
- 2019
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Ingår i: Transplantation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0041-1337 .- 1534-6080. ; 103:3, s. 630-637
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Tidskriftsartikel (refereegranskat)abstract
- Background. When transplanted human pancreatic islets are exposed to blood during intraportal infusion, an innate immune response is triggered. This instant blood-mediated inflammatory reaction (IBMIR) activates the coagulation and complement cascades and leads to the destruction of 25% of all transplanted islets within minutes, contributing to the need, in most patients, for islets from more than 1 donor. Low molecular dextran sulfate (LMW-DS) has been shown in experimental settings to inhibit IBMIR. Methods. The Clinical Islet Transplantation consortium 01 study was a phase II, multicenter, open label, active control, randomized study. Twenty-four subjects were randomized to peritransplant intraportal and systemic treatment with either LMW-DS or heparin, targeting an activated partial thromboplastin time of 150 +/- 10 seconds and 50 +/- 5 seconds, respectively. C-peptide response was measured with a mixed meal tolerance test at 75 and 365 days after transplant. Results. Low molecular dextran sulfate was safe and well tolerated with similar observed adverse events (mostly attributed to immunosuppression) as in the heparin arm. There was no difference in the primary endpoint (stimulated C-peptide 75 +/- 5 days after the first transplant) between the 2 arms (1.33 +/- 1.10 versus 1.56 +/- 1.36 ng/mL, P = 0.66). Insulin requirement, metabolic parameters, Clarke and HYPO score, quality of life, and safety were similar between the 2 treatments groups. Conclusions. Even with low dosing, LMW-DS showed similar efficacy in preventing IBMIR to promote islet engraftment when compared to "state-of-the art" treatment with heparin. Furthermore, no substantial differences in the efficacy and safety endpoints were detected, providing important information for future studies with more optimal dosing of LMW-DS for the prevention of IBMIR in islet transplantation.
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