murine-cervical-heart-transplantation-model-using-modified-cuff

Murine Cervical Heart Transplantation Model Using a Modified Cuff Technique

Mouse models are of special interest in research since a wide variety of monoclonal antibodies and commercially defined inbred and knockout strains are ...

mouse-model-for-pancreas-transplantation-using-modified-cuff

Mouse Model for Pancreas Transplantation Using a Modified Cuff Technique

Mouse models have several advantages in transplantation research, including easy handling, a variety of genetically well-defined strains, and the ...

Innsbruck Medical University

Medical University Innsbruck

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La isquemia puede producir fugas en la anastomosis esofagog&aacute;strica despu&eacute;s esofagectom&iacute;a. El objetivo de este estudio fue investigar los cambios dependientes del tiempo de la microcirculaci&oacute;n g&aacute;strica despu&eacute;s de condicionar isqu&eacute;mica.

Funcional densidad capilar en acondicionado isqu&eacute;mica: implicaciones para la resecci&oacute;n del es&oacute;fago con el conducto g&aacute;strico.

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Ischemia may lead to leakage at the esophagogastric anastomosis after esophagectomy. The aim of this study was to investigate time dependent changes of gastric microcirculation after ischemic conditioning.

Functional capillary density in ischemic conditioning: implications for esophageal resection with the gastric conduit.

Isch&eacute;mie peut entra&icirc;ner des fuites &agrave; l&#39;anastomose esophagogastric apr&egrave;s OESOPHAGECTOMIE. Le but de cette &eacute;tude &eacute;tait d&#39;&eacute;tudier les modifications d&eacute;pendant de l&#39;heure de la microcirculation gastrique apr&egrave;s conditionnement isch&eacute;mique.

Fonctionnelle de densit&eacute; capillaire dans le conditionnement isch&eacute;mique : implications pour la r&eacute;section oesophagienne avec le tube gastrique.

Isch&auml;mie f&uuml;hren zu Leckage an der Esophagogastric Anastomose nach &Ouml;sophagektomie. Ziel dieser Studie war Zeit abh&auml;ngigen Ver&auml;nderungen der Magen Mikrozirkulation nach isch&auml;mische Konditionierung zu untersuchen.

Funktionale Kapillar Dichte in isch&auml;mische Konditionierung: Implikationen f&uuml;r esophageal Resektion mit dem Magen Conduit.

Ischemia pu&ograve; portare a perdite all&#39;anastomosi seppure dopo esofagectomia. Lo scopo di questo studio era di indagare i cambiamenti di tempo dipendente della microcircolazione gastrico dopo Condizionamento ischemico.

Funzionale densit&agrave; capillare nel condizionamento ischemico: implicazioni per la resezione esofagea con tubo gastrico.

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Depletion of the nitric oxide synthase cofactor tetrahydrobiopterin (H4B) during ischemia and reperfusion is associated with severe graft pancreatitis. Since clinically feasible approaches to prevent ischemia reperfusion injury (IRI) by H4B-substitution are missing we investigated its therapeutic potential in a murine pancreas transplantation model using different treatment regimens. Grafts were subjected to 16 h cold ischemia time (CIT) and different treatment regimens: no treatment, 160 μM H4B to perfusion solution, H4B 50 mg/kg prior to reperfusion and H4B 50 mg/kg before recovery of organs. Nontransplanted animals served as controls. Recipient survival and endocrine graft function were assessed. Graft microcirculation was analyzed 2 h after reperfusion by intravital fluorescence microscopy. Parenchymal damage was assessed by histology and nitrotyrosine immunohistochemistry, H4B tissue levels by high pressure liquid chromatography (HPLC). Compared to nontransplanted controls prolonged CIT resulted in significant microcirculatory deterioration. Different efficacy according to route and timing of administration could be observed. Only donor pretreatment with H4B resulted in almost completely abrogated IRI-related damage showing graft microcirculation comparable to nontransplanted controls and restored intragraft H4B levels, resulting in significant reduction of parenchymal damage (p < 0.002) and improved survival and endocrine function (p = 0.0002 each). H4B donor pretreatment abrogates ischemia-induced parenchymal damage and represents a promising strategy to prevent IRI following pancreas transplantation.

Donor pretreatment with tetrahydrobiopterin saves pancreatic isografts from ischemia reperfusion injury in a mouse model.

Tetrahydrobiopterin has been shown to efficiently abrogate ischemia reperfusion injury (IRI). However, it is unclear, whether its beneficial action relies on cofactor activity of one of the five known tetrahydrobiopterin-dependent reactions or on its antioxidative capacity. We therefore compared tetrahydrobiopterin with the pterin derivate tetrahydroneopterin (similar biochemical properties, but no nitric oxide synthase cofactor activity) and the antioxidants vitamin C and 5-methyltetrahydrofolate. Donor mice were pretreated with tetrahydrobiopterin, tetrahydroneopterin, vitamin C, or 5-methyltetrahydrofolate. Pancreatic grafts were subjected to 16-h cold ischemia time and implanted in syngeneic recipients. Untreated and nontransplanted animals served as controls. Following 2-h reperfusion, microcirculation was analyzed by intravital fluorescence microscopy. Graft damage was assessed by histology and nitrotyrosine immunostaining, and tetrahydrobiopterin levels were determined by HPLC. Recipient survival served as ultimate readout. Prolonged cold ischemia time resulted in microcirculatory breakdown. Only tetrahydrobiopterin pretreatment succeeded to preserve the capillary net, whereas all other compounds showed no beneficial effects. Along with increased intragraft tetrahydrobiopterin levels during recovery and implantation, only tetrahydrobiopterin pretreatment led to significant reduction of IRI-related parenchymal damage enabling recipient survival. These results show a striking superiority of tetrahydrobiopterin in preventing lethal IRI compared with related compounds and suggest nitric oxide synthases as treatment target.

Prevention of lethal murine pancreas ischemia reperfusion injury is specific for tetrahydrobiopterin.

Current treatment guidelines preclude liver transplantation for patients with BCLC B (intermediate stage) HCC, and expanding transplantation criteria for selected patients beyond early stage HCC remains controversial. The aim of this study was to determine stage-dependent HCC recurrence and overall survival rates in transplant recipients and the impact of response to neoadjuvant treatment on outcome.

Excellent post-transplant survival in patients with intermediate stage hepatocellular carcinoma responding to neoadjuvant therapy.

Delayed graft function is a prevalent clinical problem in renal transplantation for which there is no objective system to predict occurrence in advance. It can result in a significant increase in the necessity for hospitalisation post-transplant and is a significant risk factor for other post-transplant complications.

Identification of Molecular Markers of Delayed Graft Function Based on the Regulation of Biological Ageing.

Transplant vasculopathy (TV) represents a major obstacle to long-term graft survival and correlates with severity of ischemia reperfusion injury (IRI). Donor administration of the nitric oxide synthases (NOS) co-factor tetrahydrobiopterin has been shown to prevent IRI. Herein, we analysed whether tetrahydrobiopterin is also involved in TV development. Using a fully allogeneic mismatched (BALB/c to C57BL/6) murine aortic transplantation model grafts subjected to long cold ischemia time developed severe TV with intimal hyperplasia (α-smooth muscle actin positive cells in the neointima) and endothelial activation (increased P-selectin expression). Donor pretreatment with tetrahydrobiopterin significantly minimised these changes resulting in only marginal TV development. Severe TV observed in the non-treated group was associated with increased protein oxidation and increased occurrence of endothelial NOS monomers in the aortic grafts already during graft procurement. Tetrahydrobiopterin supplementation of the donor prevented all these early oxidative changes in the graft. Non-treated allogeneic grafts without cold ischemia time and syngeneic grafts did not develop any TV. We identified early protein oxidation and impaired endothelial NOS homodimer formation as plausible mechanistic explanation for the crucial role of IRI in triggering TV in transplanted aortic grafts. Therefore, targeting endothelial NOS in the donor represents a promising strategy to minimise TV.

Impaired Endothelial Nitric Oxide Synthase Homodimer Formation Triggers Development of Transplant Vasculopathy - Insights from a Murine Aortic Transplantation Model.

ArticleTotal : 2	Year
Publication title Cited by 26	2014
Publication title Cited by 6	2017

Article	Year
Functional capillary density in ischemic conditioning: implications for esophageal resection with the gastric conduit. American journal of surgery\| PubMed ID: 18367142	2008
Donor pretreatment with tetrahydrobiopterin saves pancreatic isografts from ischemia reperfusion injury in a mouse model. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons\| PubMed ID: 20883557	2010
Prevention of lethal murine pancreas ischemia reperfusion injury is specific for tetrahydrobiopterin. Transplant international : official journal of the European Society for Organ Transplantation\| PubMed ID: 22805419	2012
Excellent post-transplant survival in patients with intermediate stage hepatocellular carcinoma responding to neoadjuvant therapy. Liver international : official journal of the International Association for the Study of the Liver\| PubMed ID: 26386273	2016
Identification of Molecular Markers of Delayed Graft Function Based on the Regulation of Biological Ageing. PloS one\| PubMed ID: 26734715	2016
Impaired Endothelial Nitric Oxide Synthase Homodimer Formation Triggers Development of Transplant Vasculopathy - Insights from a Murine Aortic Transplantation Model. Scientific reports\| PubMed ID: 27883078	2016
Outcome in Pancreas Grafts After BK Virus Viremia in Simultaneous Pancreas-Kidney Transplants: A Single-Center Case Report. Transplantation direct\| PubMed ID: 28573189	2017

Manuel Maglione

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