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      Kidney graft outcome using an anti-Xa therapeutic strategy in an experimental model of severe ischaemia-reperfusion injury

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          Abstract

          Deceased after cardiac death donors represent an important source of organs to reduce organ shortage in transplantation. However, these organs are subjected to more ischaemia-reperfusion injury (IRI). Reducing IRI by targeting coagulation is studied here in an experimental model.

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          Ischemia and reperfusion--from mechanism to translation.

          Holger Eltzschig, Tobias Eckle (2011)
          Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea. Ischemia-reperfusion injury is also a major challenge during organ transplantation and cardiothoracic, vascular and general surgery. An imbalance in metabolic supply and demand within the ischemic organ results in profound tissue hypoxia and microvascular dysfunction. Subsequent reperfusion further enhances the activation of innate and adaptive immune responses and cell death programs. Recent advances in understanding the molecular and immunological consequences of ischemia and reperfusion may lead to innovative therapeutic strategies for treating patients with ischemia and reperfusion-associated tissue inflammation and organ dysfunction.
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            Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury.

            Melanie Königshoff, Malvina A Krupiczojc, C J Scotton … (2009)
            Uncontrolled activation of the coagulation cascade contributes to the pathophysiology of several conditions, including acute and chronic lung diseases. Coagulation zymogens are considered to be largely derived from the circulation and locally activated in response to tissue injury and microvascular leak. Here we report that expression of coagulation factor X (FX) is locally increased in human and murine fibrotic lung tissue, with marked immunostaining associated with bronchial and alveolar epithelia. FXa was a potent inducer of the myofibroblast differentiation program in cultured primary human adult lung fibroblasts via TGF-beta activation that was mediated by proteinase-activated receptor-1 (PAR1) and integrin alphavbeta5. PAR1, alphavbeta5, and alpha-SMA colocalized to fibrotic foci in lung biopsy specimens from individuals with idiopathic pulmonary fibrosis. Moreover, we demonstrated a causal link between FXa and fibrosis development by showing that a direct FXa inhibitor attenuated bleomycin-induced pulmonary fibrosis in mice. These data support what we believe to be a novel pathogenetic mechanism by which FXa, a central proteinase of the coagulation cascade, is locally expressed and drives the fibrotic response to lung injury. These findings herald a shift in our understanding of the origins of excessive procoagulant activity and place PAR1 central to the cross-talk between local procoagulant signaling and tissue remodeling.
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              Contribution of Large Pig for Renal Ischemia-Reperfusion and Transplantation Studies: The Preclinical Model

              A S Giraud, F. Favreau, N. Chatauret … (2011)
              Animal experimentation is necessary to characterize human diseases and design adequate therapeutic interventions. In renal transplantation research, the limited number of in vitro models involves a crucial role for in vivo models and particularly for the porcine model. Pig and human kidneys are anatomically similar (characterized by multilobular structure in contrast to rodent and dog kidneys unilobular). The human proximity of porcine physiology and immune systems provides a basic knowledge of graft recovery and inflammatory physiopathology through in vivo studies. In addition, pig large body size allows surgical procedures similar to humans, repeated collections of peripheral blood or renal biopsies making pigs ideal for medical training and for the assessment of preclinical technologies. However, its size is also its main drawback implying expensive housing. Nevertheless, pig models are relevant alternatives to primate models, offering promising perspectives with developments of transgenic modulation and marginal donor models facilitating data extrapolation to human conditions.
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                Author and article information

                Journal
                Title: British Journal of Surgery
                Abbreviated Title: Br J Surg
                Publisher: Wiley
                ISSN: 00071323
                Publication date Created: January 2015
                Publication date (Print): January 2015
                Publication date (Electronic): November 17 2014
                Volume: 102
                Issue: 1
                Pages: 132-142
                Affiliations
                [1 ]Institut National de la Santé et de la Recherche Médicale (INSERM) U1082; Poitiers France
                [2 ]Faculté de Médecine et de Pharmacie, Université de Poitiers; Poitiers France
                [3 ]Service de Biochimie; Poitiers France
                [4 ]Service d'Urologie; Poitiers France
                [5 ]Service d'Anapathomopathologie; Poitiers France
                [6 ]Association du Service de Santé au Travail de la Vienne 86; Poitiers France
                [7 ]Service d'Hematologie, Centre Hospitalier Universitaire (CHU) de Poitiers; Poitiers France
                [8 ]University Hospital Federation Tours Poitiers Limoges ‘SUrvival oPtimization in ORgan Transplantation’, Direction des Affaires Medicales CHU Poitiers; Poitiers France
                [9 ]IBiSA Plateforme ‘Experimental Surgery and Transplantation’, Institut National de la Recherche Agronomique, Unité Expérimentale Génétique, Expérimentations et Systèmes Innovants, Domaine Expérimental du Magneraud; Surgères France
                Article
                DOI: 10.1002/bjs.9662
                PubMed ID: 25402331
                SO-VID: a45c5734-213c-4689-b688-ca2c960f461b
                Copyright © © 2014
                License:

                http://doi.wiley.com/10.1002/tdm_license_1.1

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