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1. Renal auto-transplantation promotes cortical microvascular network remodeling in a preclinical porcine model

Author

Maïga, Souleymane, Allain, Geraldine, Hauet, Thierry, Roumy, Jerome, Baulier, Edouard, Scepi, Michel, Dierick, Manuel, van Hoorebeke, Luc, Hannaert, Patrick, Guy, Franck, Favreau, Frédéric, Camussi, Giovanni, Pinet, Nicolas, Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, CHU de Bordeaux Pellegrin [Bordeaux], CHU Poitiers, Service de chirurgie cardio-thoracique, Poitiers, 86000, France, Service de Biochimie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Génétique, Expérimentation et Système Innovants (GenESI), Institut National de la Recherche Agronomique (INRA), Fédération Hospitalo-universitaire SUrvival oPtimization in ORgan Transplantation (FHU SUPORT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT)-Université de Tours (UT)-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universiteit Gent = Ghent University (UGENT), Center for X-ray Tomography [Ghent] (UGCT), Department of Physics and Astronomy [Ghent], Universiteit Gent = Ghent University (UGENT)-Universiteit Gent = Ghent University (UGENT), Institut International de Paléoprimatologie, Paléontologie Humaine : Evolution et Paléoenvironnement (IPHEP), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours-Université de Tours, Ghent University [Belgium] (UGENT), Ghent University [Belgium] (UGENT)-Ghent University [Belgium] (UGENT), Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers, Università degli studi di Torino (UNITO), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Cellules Dendritiques, Immunomodulation et Greffes, Universiteit Gent = Ghent University [Belgium] (UGENT), Universiteit Gent = Ghent University [Belgium] (UGENT)-Universiteit Gent = Ghent University [Belgium] (UGENT), Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), and Université de Tours (UT)-Université de Tours (UT)

Subjects
modèle animal, Physiology, Swine, lcsh:Medicine, Kidney, Vascular Medicine, HYPERCHOLESTEROLEMIA, Ischemia, Animal Cells, Blood Flow, Medicine and Health Sciences, Renal Transplantation, FAILURE, lcsh:Science, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Graft Survival, rein, transplantation d'organe, cochon, Organ Preservation, Body Fluids, Blood, Reperfusion Injury, PIG KIDNEYS, Anatomy, Cellular Types, Renal Ischemia, Research Article, LONG-TERM, Excretion, Surgical and Invasive Medical Procedures, Transplantation, Autologous, Urinary System Procedures, Animals, Humans, ALLOGRAFT-REJECTION, ENDOTHELIAL INJURY, Transplantation, Blood Cells, TRANSPLANTATION, lcsh:R, Biology and Life Sciences, Kidneys, Renal System, Organ Transplantation, Cell Biology, X-Ray Microtomography, MICROCIRCULATION, Fibrosis, Kidney Transplantation, COLD ISCHEMIA/REPERFUSION, DYSFUNCTION, Disease Models, Animal, Microvessels, lcsh:Q, Physiological Processes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Developmental Biology
Abstract

International audience; The vascular network is a major target of ischemia-reperfusion, but has been poorly investigated in renal transplantation. The aim of this study was to characterize the remodeling of the renal vascular network that follows ischemia-reperfusion along with the most highly affected cortex section in a preclinical renal transplantation model. There were two experimental groups. The first was a grafted kidney group consisting of large white pigs for which the left kidney was harvested, cold flushed, preserved for 24 h in the University of Wisconsin’s preservation solution, and then auto-transplanted (n = 5); the right kidney was removed to mimic the situation of human kidney transplantation. The second group (uni-nephrectomized kidney group) consisted of animals that underwent only right nephrectomy, but not left renal transplantation (n = 5). Three months after autotransplantation, the kidneys were studied by X-ray microcomputed tomography. Vessel morphology and density and tortuosity of the network were analyzed using a 3D image analysis method. Cortical blood flow was determined by laser doppler analysis and renal function and tissue injury assessed by plasma creatinine levels and histological analysis. Renal ischemia-reperfusion led to decreased vascular segment volume associated with fewer vessels of less than 30 μm, particularly in the inner cortex:0.79 ± 0.54% in grafted kidneys vs. 7.06 ± 1.44% in uni-nephrectomized kidneys, p < 0.05. Vessels showed higher connectivity throughout the cortex (the arborescence factor of the whole cortex was less in grafted than uni-nephrectomized kidneys 0.90 ± 0.04 vs. 1.07 ± 0.05, p < 0.05, with an increase in the number of bifurcations). Furthermore, cortical blood flow decreased early in kidney grafts and remained low three months after auto-transplantation. The decrease in microvasculature correlated with a deterioration of renal function, proteinuria, and tubular dysfunction, and was associated with the development of fibrous tissue. This work provides new evidence concerning the impact of ischemia-reperfusion injuries on the spectrum of renal vascular diseases and could potentially guide future therapy to preserve microvessels in transplantation ischemia-reperfusion injury.

Published
2017

2. Cyclodextrin Curcumin Formulation Improves Outcome in a Preclinical Pig Model of Marginal Kidney Transplantation

Author

Jaakko Parkkinen, Thierry Hauet, T. Saintyves, G. Allain, P. Delpech, P. Couturier, C. Billault, Lauri Vaahtera, R. Thuillier, Sébastien Giraud, Etienne Marchand, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération pour L'étude de l'Ischémie Reperfusion en Transplantation, Consortium for Organ Preservation in Europe, COPE, Service de Biochimie [Poitiers], CHU Poitiers, Service de chirurgie cardio-thoracique, Poitiers, 86000, France, Fédération pour L'étude de l'Ischémie Réperfusion en Transplantation (FLIRT), Service de Chirurgie Urologie [Angoulême], Centre hospitalier d'Angoulême, Service d'Urologie [Poitiers], Groupement Scientifique - Ibisa (Ibisa), Institut National de la Recherche Agronomique (INRA), Service d'urologie et transplantation rénales [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de Chirurgie Vasculaire [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Fédération Hospitalière Tours-Poitiers-CHU Trousseau [APHP], Pediatric Psychiatry [Helsinki], Pediatric Research Center [Helsinki], Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Service d'Urologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Region Poitou Charentes, Poitiers, CHU de Poitiers, Inserm, Societe Francophone de Transplantation, French Foundation of Transplantation, Agence de Biomedecine, Fondation de l'Avenir, and Finnish Academy

Subjects
Graft Rejection, Male, Pathology, Adenosine, Swine, Chemistry, Pharmaceutical, Pharmacology, Antioxidants, chemistry.chemical_compound, 0302 clinical medicine, Fibrosis, Insulin, Immunology and Allergy, Pharmacology (medical), Cells, Cultured, Kidney transplantation, ischemia reperfusion injury, 0303 health sciences, Kidney, Reverse Transcriptase Polymerase Chain Reaction, Anti-Inflammatory Agents, Non-Steroidal, Prostate, Flow Cytometry, Glutathione, 3. Good health, Kidney Tubules, medicine.anatomical_structure, Reperfusion Injury, 030220 oncology & carcinogenesis, medicine.medical_specialty, Curcumin, Allopurinol, preservation, Blotting, Western, Organ Preservation Solutions, kidney transplantation, Real-Time Polymerase Chain Reaction, Endothelial activation, 03 medical and health sciences, Raffinose, medicine, Animals, Humans, Viaspan, RNA, Messenger, graft outcome, 030304 developmental biology, Inflammation, Cyclodextrins, Transplantation, business.industry, medicine.disease, Disease Models, Animal, Oxidative Stress, chemistry, business, Reperfusion injury, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Decreasing organ quality is prompting research toward new methods to alleviate ischemia reperfusion injury (IRI). Oxidative stress and nuclear factor kappa beta (NF‐κB) activation are well‐described elements of IRI. We added cyclodextrin‐complexed curcumin (CDC), a potent antioxidant and NF‐κB inhibitor, to University of Wisconsin (UW) solution (Belzer's Solution, Viaspan), one of the most effective clinically approved preservative solutions. The effects of CDC were evaluated on pig endothelial cells and in an autologous donation after circulatory death (DCD) kidney transplantation model in large white pigs. CDC allowed rapid and lasting uptake of curcumin into cells. In vitro, CDC decreased mitochondrial loss of function, improved viability and lowered endothelial activation. In vivo, CDC improved function recovery, lowered histological injury and doubled animal survival (83.3% vs. 41.7%). At 3 months, immunohistochemical staining for epithelial‐to‐mesenchymal transition (EMT) and fibrosis markers was intense in UW grafts while it remained limited in the UW + CDC group. Transcriptional analysis showed that CDC treatment protected against up‐regulation of several pathophysiological pathways leading to inflammation, EMT and fibrosis. Thus, use of CDC in a preclinical transplantation model with stringent IRI rescued kidney grafts from an unfavorable prognosis. As curcumin has proved well tolerated and nontoxic, this strategy shows promise for translation to the clinic

Published
2014

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