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1. Airway microbiota signals anabolic and catabolic remodeling in the transplanted lung

Author

Stéphane Mouraux, Eric Bernasconi, Céline Pattaroni, Angela Koutsokera, John-David Aubert, Johanna Claustre, Christophe Pison, Pierre-Joseph Royer, Antoine Magnan, Romain Kessler, Christian Benden, Paola M. Soccal, Benjamin J. Marsland, Laurent P. Nicod, J. Jougon, J.-F. Velly, H. Rozé, E. Blanchard, C. Dromer, M. Antoine, M. Cappello, M. Ruiz, Y. Sokolow, F. Vanden Eynden, G. Van Nooten, L. Barvais, J. Berré, S. Brimioulle, D. De Backer, J. Créteur, E. Engelman, I. Huybrechts, B. Ickx, T.J.C. Preiser, T. Tuna, L. Van Obberghe, N. Vancutsem, J.-L. Vincent, P. De Vuyst, I. Etienne, F. Féry, F. Jacobs, C. Knoop, J.L. Vachiéry, P. Van den Borne, I. Wellemans, G. Amand, L. Collignon, M. Giroux, D. Angelescu, O. Chavanon, R. Hacini, A. Pirvu, P. Porcu, P. Albaladejo, C. Allègre, A. Bataillard, D. Bedague, E. Briot, M. Casez-Brasseur, D. Colas, G. Dessertaine, M. Durand, G. Francony, A. Hebrard, M.R. Marino, B. Oummahan, D. Protar, D. Rehm, S. Robin, M. Rossi-Blancher, C. Augier, P. Bedouch, A. Boignard, H. Bouvaist, A. Briault, B. Camara, J. Claustre, S. Chanoine, M. Dubuc, S. Quétant, J. Maurizi, P. Pavèse, C. Pison, C. Saint-Raymond, N. Wion, C. Chérion, R. Grima, O. Jegaden, J.-M. Maury, F. Tronc, C. Flamens, S. Paulus, J.-F. Mornex, F. Philit, A. Senechal, J.-C. Glérant, S. Turquier, D. Gamondes, L. Chalabresse, F. Thivolet-Bejui, C. Barnel, C. Dubois, A. Tiberghien, F. Le Pimpec-Barthes, A. Bel, P. Mordant, P. Achouh, V. Boussaud, R. Guillemain, D. Méléard, M.O. Bricourt, B. Cholley, V. Pezella, G. Brioude, X.B. D'Journo, C. Doddoli, P. Thomas, D. Trousse, S. Dizier, M. Leone, L. Papazian, F. Bregeon, A. Basire, B. Coltey, N. Dufeu, H. Dutau, S. Garcia, J.Y. Gaubert, C. Gomez, S. Laroumagne, A. Nieves, L.C. Picard, M. Reynaud-Gaubert, V. Secq, G. Mouton, O. Baron, P. Lacoste, C. Perigaud, J.C. Roussel, I. Danner, A. Haloun, A. Magnan, A. Tissot, T. Lepoivre, M. Treilhaud, K. Botturi-Cavaillès, S. Brouard, R. Danger, J. Loy, M. Morisset, M. Pain, S. Pares, D. Reboulleau, P.-J. Royer, D. Fabre, E. Fadel, O. Mercier, S. Mussot, F. Stephan, P. Viard, J. Cerrina, P. Dorfmuller, S.M. Ghigna, Ph. Hervén, F. Le Roy Ladurie, J. Le Pavec, V. Thomas de Montpreville, L. Lamrani, Y. Castier, P. Cerceau, P. Augustin, S. Jean-Baptiste, S. Boudinet, P. Montravers, O. Brugière, G. Dauriat, G. Jébrak, H. Mal, A. Marceau, A.-C. Métivier, G. Thabut, E. Lhuillier, C. Dupin, V. Bunel, P. Falcoz, G. Massard, N. Santelmo, G. Ajob, O. Collange, O. Helms, J. Hentz, A. Roche, B. Bakouboula, T. Degot, A. Dory, S. Hirschi, S. Ohlmann-Caillard, L. Kessler, R. Kessler, A. Schuller, K. Bennedif, S. Vargas, J. Stauder, S. Ali-Azouaou, P. Bonnette, A. Chapelier, P. Puyo, E. Sage, J. Bresson, V. Caille, C. Cerf, J. Devaquet, V. Dumans-Nizard, M.-L. Felten, M. Fischler, A.-G. Si Larbi, M. Leguen, L. Ley, N. Liu, G. Trebbia, S. De Miranda, B. Douvry, F. Gonin, D. Grenet, A.M. Hamid, H. Neveu, F. Parquin, C. Picard, A. Roux, M. Stern, F. Bouillioud, P. Cahen, M. Colombat, C. Dautricourt, M. Delahousse, B. D'Urso, J. Gravisse, A. Guth, S. Hillaire, P. Honderlick, M. Lequintrec, E. Longchampt, F. Mellot, A. Scherrer, L. Temagoult, L. Tricot, M. Vasse, C. Veyrie, L. Zemoura, J. Berjaud, L. Brouchet, M. Dahan, F.O. Mathe, H. Benahoua, M. DaCosta, I. Serres, V. Merlet-Dupuy, M. Grigoli, A. Didier, M. Murris, L. Crognier, O. Fourcade, T. Krueger, H.B. Ris, M. Gonzalez, Ph. Jolliet, C. Marcucci, M. Chollet, F. Gronchi, C. Courbon, C. Berutto, O. Manuel, A. Koutsokera, J.-D. Aubert, L.P. Nicod, S. Mouraux, E. Bernasconi, C. Pattaroni, B.J. Marsland, P.M. Soccal, T. Rochat, L.M. Lücker, S. Hillinger, I. Inci, W. Weder, R. Schuepbach, M. Zalunardo, C. Benden, M.M. Schuurmans, A. Gaspert, D. Holzmann, N. Müller, C. Schmid, B. Vrugt, A. Fritz, D. Maier, K. Deplanche, D. Koubi, F. Ernst, T. Paprotka, M. Schmitt, B. Wahl, J.-P. Boissel, G. Olivera-Botello, C. Trocmé, B. Toussaint, S. Bourgoin-Voillard, M. Sève, M. Benmerad, V. Siroux, R. Slama, C. Auffray, D. Charron, D. Lefaudeux, J. Pellet, Division of Pulmonary Medicine, Medical University Vienna, Clinique Universitaire de Pneumologie, Pôle Thorax et Vaisseaux, Centre Hospitalier Universitaire de Grenoble, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Pneumologie, Nouvel Hôpital Civil Strasbourg, Division Pulmonary Medicine, University hospital of Zurich [Zurich], Geneva University Hospital (HUG), Rochat, Thierry, and Licker, Marc

Subjects
0301 basic medicine, Male, THP-DM, THP1-derived macrophages, Microbiota/immunology, Anabolism, Fibroblasts/immunology/pathology, [SDV]Life Sciences [q-bio], Bacteria/classification/immunology, Matrix metalloproteinase, SPP1, Secreted phosphoprotein 1, Immunology and Allergy, Lung, Lung/immunology/microbiology/pathology, ddc:616, medicine.diagnostic_test, Microbiota, Airway remodeling, respiratory system, Middle Aged, 3. Good health, Extracellular Matrix, macrophages, rRNA, Ribosomal RNA, Extracellular Matrix/immunology/pathology, Female, PDGFD, Platelet-derived growth factor D, THBS1, Thrombospondin 1, Lung Transplantation, Signal Transduction, Airway Remodeling/immunology, CFU, Colony-forming unit, Adult, BAL, Bronchoalveolar lavage, Immunology, COPD, Chronic obstructive pulmonary disease, MMP, Matrix metallopeptidase, Biology, Macrophages/immunology/pathology, KEGG, Kyoto Encyclopedia of Genes and Genomes, CHI3L1, Article, Proinflammatory cytokine, 03 medical and health sciences, CLAD, Chronic lung allograft dysfunction, fibroblasts, Thrombospondin 1, GO, Gene Ontology, medicine, microbiota, Humans, IGF, Insulin-like growth factor, Thrombospondin, Signal Transduction/immunology, Matrix, Bacteria, Catabolism, Macrophages, IQR, Interquartile range, Fibroblasts, matrix, respiratory tract diseases, 030104 developmental biology, Bronchoalveolar lavage, CHI3L1, Chitinase 3-like 1, SysCLAD, System prediction of Chronic Lung Allograft Dysfunction, KO, KEGG ortholog
Abstract

Background Homeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling. Objective This study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation. Methods Microbiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture. Results We identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg, Staphylococcus, Pseudomonas, and Corynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg, Prevotella, Streptococcus, and Veillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition. Conclusions Host-microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome., Graphical abstract

Published
2018

2. Viva Europa, a Land of Excellence in Research and Innovation for Health and Wellbeing

Author

Sonia Abdelhak, Mehmet Ozturk, Bento Soares, Bernd Schmeck, Samir K. Brahmachari, Andrey Lisistsa, Leroy Hood, Philippe Sabatier, Carole Goble, Pierre Hainaut, Marion Koopmans, Alain Cozzone, Christian Bréchot, Nathan Price, Vitaly Volpert, David Supple, Elissa Epel, Peter Hunter, Bartha Maria Knoppers, Ursula Klingmüller, Timothy Radstake, Zhu Chen, Mathias Uhlén, Johann Pellet, Steve Webb, Anna Norrby-Teglund, Vincent Lotteau, Dominique Charron, Josep Roca, Jean-Marie Lehn, Maria Manuela Nogueira, François Gros, Françoise Argoul, Ferran Sanz, Martine Raes, Antoine Magnan, Peter J. M. Openshaw, Alain Fischer, Shlomo Sasson, Peter J. Sterk, Francis Lévi, Hiroaki Kitano, Susanna Palkonen, Ross Arena, Albert-László Barabási, Michel Goldman, Ian M. Adcock, Andrea Gelemanovic, Sai-Juan Chen, Christian Pristipino, Jacques Demotes, Jesper Tegnér, Anders Bjartell, Laurent P. Nicod, Yves Moreau, Walter Kolch, Laurent Nottale, Emiel F.M. Wouters, Ismail Serageldin, Ratko Djukanovic, Jean-François Deleuze, Anita Simonds, Alfredo Cesario, Ana Conesa, Stylianos E. Antonarakis, David Harrison, Hans Hoffmann, Sylvie van der Werf, Yves Jacob, Marta Cascante, Andres Metspalu, James N’Dow, Alvar Agusti, Herman Goossens, Bertrand Boutron, Rudi Balling, Francisco Nobrega, Jacques S. Beckmann, Menno de Jong, Margarida Amaral, Alberto Di Meglio, Niklas Blomberg, Fan Chung, Denis Noble, Doron Lancet, Charles Auffray, Giulio Superti-Furga, Takashi Gojobori, Christopher E. Brightling, Thomas Bourgeron, Ugur Dogrusoz, Damjana Rozman, Karine Clément, Yi-Ke Guo, Bongani M. Mayosi, Ozren Polasek, Martine Laville, Michael Sagner, Manlio Vinciguerra, Pablo Villoslada, Silvio Parodi, European Institute for Systems Biology and Medicine (EISBM), University of Illinois [Chicago] (UIC), University of Illinois System, Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, University of Barcelona, Universidade de Lisboa, Université de Genève = University of Geneva (UNIGE), Université de Bordeaux (UB), Center for Systems Biomedicine [Falkensee], Central European University [Budapest, Hongrie] (CEU), Université de Lausanne = University of Lausanne (UNIL), University of Lund, Lund University [Lund], ELIXIR Hub [Cambridge], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CSIR Institute of Genomics and Integrative Biology [New Delhi] (IGIB), Institut Pasteur [Paris] (IP), University of Leicester, Institute of Biomedicine of University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Shangaï Jiao Tong University [Shangaï], Imperial College London, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centro de Investigación Príncipe Felipe (CIPF), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Fondation Jean Dausset CEPH, European Clinical Research Infrastructures Network [Paris] (ECRIN), Ecrin, CHU Necker - Enfants Malades [AP-HP], Collège de France (CdF (institution)), Académie des Sciences [Paris], Institut de France, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Hospices Civils de Lyon (HCL), Université de Strasbourg (UNISTRA), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), Observatoire de Paris - Site de Meudon (OBSPM), Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Camille Jordan (ICJ), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Modélisation mathématique, calcul scientifique (MMCS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL)

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, SISTA, Excellence, 030220 oncology & carcinogenesis, media_common.quotation_subject, Political science, [SDV]Life Sciences [q-bio], General Medicine, Public administration, media_common
Abstract

ispartof: Progress in preventive medicine pages:1-2 status: published

Published
2017

3. Airway Microbiota Determines Innate Cell Inflammatory or Tissue Remodeling Profiles in Lung Transplantation

Author

Christian Benden, Laurent P. Nicod, Eric Bernasconi, Céline Pattaroni, Romain Kessler, Angela Koutsokera, Benjamin J. Marsland, Antoine Magnan, Christophe Pison, Paola M. Soccal, John-David Aubert, Division of Pulmonary Medicine, Medical University Vienna, Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Strasbourg, Division Pulmonary Medicine, University hospital of Zurich [Zurich], Service de Pneumologie, University of Zurich, and Bernasconi, Eric

Subjects
0301 basic medicine, Male, Pathology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Cell, Respiratory System, Airway Remodeling/physiology, microbiome, Critical Care and Intensive Care Medicine, airway remodeling, 0302 clinical medicine, Respiratory System/microbiology, Macrophage, Polymerase, ddc:616, biology, Microbiota, Graft Survival, Middle Aged, Graft Survival/physiology, 3. Good health, macrophages, medicine.anatomical_structure, surgical procedures, operative, Female, medicine.symptom, 10178 Clinic for Pneumology, 2706 Critical Care and Intensive Care Medicine, Bronchoalveolar Lavage Fluid, Lung Transplantation, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Inflammation, 610 Medicine & health, Bronchoalveolar Lavage Fluid/microbiology, 03 medical and health sciences, medicine, Lung transplantation, Humans, Microbiome, Inflammation/microbiology/physiopathology, Lung, business.industry, Transplantation, 030104 developmental biology, 030228 respiratory system, 2740 Pulmonary and Respiratory Medicine, Immunology, biology.protein, Microbiota/physiology, business
Abstract

In lung transplant recipients, long-term graft survival relies on the control of inflammation and tissue remodeling to maintain graft functionality and avoid chronic lung allograft dysfunction. Although advances in clinical practice have improved transplant success, the mechanisms by which the balance between inflammation and remodeling is maintained are largely unknown.To assess whether host-microbe interactions in the transplanted lung determine the immunologic tone of the airways, and consequently could impact graft survival.Microbiota DNA and host total RNA were isolated from 203 bronchoalveolar lavages obtained from 112 patients post-lung transplantation. Microbiota composition was determined using 16S ribosomal RNA analysis, and expression of a set of genes involved in prototypic macrophage functions was quantified using real-time quantitative polymerase chain reaction.We show that the characteristics of the pulmonary microbiota aligned with distinct innate cell gene expression profiles. Although a nonpolarized activation was associated with bacterial communities consisting of a balance between proinflammatory (e.g., Staphylococcus and Pseudomonas) and low stimulatory (e.g., Prevotella and Streptococcus) bacteria, "inflammatory" and "remodeling" profiles were linked to bacterial dysbiosis. Mechanistic assays provided direct evidence that bacterial dysbiosis could lead to inflammatory or remodeling profiles in macrophages, whereas a balanced microbial community maintained homeostasis.The crosstalk between bacterial communities and innate immune cells potentially determines the function of the transplanted lung offering novel pathways for intervention strategies.

Published
2016

4. Chronic Lung Allograft Dysfunction: A Systematic Review of Mechanisms

Author

Laurent P. Nicod, Adrien Tissot, Angela Koutsokera, Jean-Pierre Boissel, Gustavo Olivera-Botello, Christophe Pison, Pierre-Joseph Royer, John-David Aubert, Eric Bernasconi, Antoine Magnan, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire [Grenoble] (CHU), University of Zurich, and Royer, Pierre-Joseph

Subjects
Time Factors, 2747 Transplantation, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Bronchiolitis obliterans, 610 Medicine & health, chemical and pharmacologic phenomena, 030230 surgery, Adaptive Immunity, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, medicine, lung transplantation, Lung transplantation, Innate, Animals, humans, Bronchiolitis Obliterans, Lung, Immune mechanisms, Transplantation, business.industry, Systems Biology, Multifactorial disease, Graft Survival, Immunity, Syndrome, Acquired immune system, medicine.disease, Allografts, Immunity, Innate, 3. Good health, medicine.anatomical_structure, surgical procedures, operative, Treatment Outcome, 030228 respiratory system, Immunology, Chronic Disease, Immune reaction, 10178 Clinic for Pneumology, business
Abstract

International audience; Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. Chronic lung allograft dysfunction manifests as bronchiolitis obliterans syndrome or the recently described restrictive allograft syndrome. Although numerous risk factors have been identified so far, the physiopathological mechanisms of CLAD remain poorly understood. We investigate here the immune mechanisms involved in the development of CLAD after lung transplantation. We explore the innate or adaptive immune reactions induced by the allograft itself or by the environment and how they lead to allograft dysfunction. Because current literature suggests bronchiolitis obliterans syndrome and restrictive allograft syndrome as 2 distinct entities, we focus on the specific factors behind one or the other syndromes. Chronic lung allograft dysfunction is a multifactorial disease that remains irreversible and unpredictable so far. We thus finally discuss the potential of systems-biology approach to predict its occurrence and to better understand its underlying mechanisms.

Published
2016

5. Chronic effects of air pollution on lung function in lung transplant patients (SysCLAD)

Author

M. Dahan, Valérie Siroux, Sacha Mussot, F. Meleux, Claire Dromer, Christophe Pison, Christiane Knoop, V. Boussaud, Isabelle Danner-Boucher, L. Malherbe, Jean-François Mornex, Carine Gomez, Antoine Magnan, Ronald C. Kessler, Rémy Slama, Meriem Benmerad, Johanna Claustre, Olivier Brugière, Laurent P. Nicod, A. Roux, K. Botturi, and Institut National de l'Environnement Industriel et des Risques (INERIS)

Subjects
Pulmonary and Respiratory Medicine, Transplantation, medicine.medical_specialty, Lung, business.industry, Air pollution, medicine.disease_cause, Gastroenterology, medicine.anatomical_structure, Internal medicine, [SDE]Environmental Sciences, Medicine, Surgery, Transplant patient, Cardiology and Cardiovascular Medicine, business, Lung function
Published
2015

6. Prediction of chronic lung allograft dysfunction: a systems medicine challenge

Author

Michel SEVE, Jean-Marc Rolain, Remy Slama, Jean-michel Maury, Kevin Deplanche, Laurent P Nicod, Richard Danger, Pierre-Joseph Royer, Olaf Mercier, Olivier CHAVANON, Marc Leone, David Holzmann, Andreas Fritz, Marc Vasse, Valérie SIROUX, Sandrine Bourgoin-Voillard, Oriol Manuel, Swiss Transplant Cohort Study STCS, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Institute for Systems Biology and Medicine (EISBM), CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), PROteomics and METabolomics Platform [Grenoble] (PROMETHEE), Service de Pneumologie [lausanne], Université de Lausanne = University of Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), GATC Biotech AG [Konstanz], Finovatis [Lyon], Biomax Informatics [Planegg], Evaluation et modélisation des effets thérapeutiques, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Institute of Cellular Medicine [Newcastle], Newcastle University [Newcastle], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université de Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de chirurgie cardio-vasculaire et thoracique, University of Zurich, and Pison, Christophe

Subjects
Pulmonary and Respiratory Medicine, Graft Rejection, medicine.medical_specialty, Vital capacity, 10255 Clinic for Thoracic Surgery, medicine.medical_treatment, Bronchiolitis obliterans, Systems Theory, 610 Medicine & health, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 03 medical and health sciences, FEV1/FVC ratio, Pleural disease, 0302 clinical medicine, Pulmonary Medicine, Medicine, Lung transplantation, Humans, Computer Simulation, Bronchiolitis Obliterans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Lung, business.industry, Respiratory disease, medicine.disease, Allografts, Diagnosis of exclusion, 3. Good health, Surgery, medicine.anatomical_structure, Phenotype, Treatment Outcome, 030228 respiratory system, 2740 Pulmonary and Respiratory Medicine, Chronic Disease, 10178 Clinic for Pneumology, Primary Graft Dysfunction, business, Respiratory Insufficiency, Algorithms, Lung Transplantation
Abstract

The International Society for Heart and Lung Transplantation registry recorded that 3631 adult heart-lung transplants and 39 835 adult lung transplants have been performed in centres throughout the world up to 2012, establishing lung transplantation (LT) as the standard of care for selected patients with end-stage respiratory disease [1]. The long-term success of LT is limited by chronic lung allograft dysfunction (CLAD), of which the two most common phenotypes are an abnormal remodelling of the small airways resulting in progressive airflow obstruction called bronchiolitis obliterans syndrome (BOS) and, less frequently, a restrictive ventilatory process referred to as restrictive allograft syndrome (RAS) [2, 3]. Almost 50% of LT recipients will develop CLAD within 5 years post-LT, rising to 75% after 10 years [1]. Despite a range of therapeutic approaches, median survival figures from the time of diagnosis remain very poor at ∼2 years, resulting in 27% overall 10-year survival, the poorest long-term survival after solid-organ transplantations for the period of 2000–2008 in the USA [4]. In clinical practice, CLAD is a diagnosis of exclusion once the possible confounding diseases related either to allograft, such as persistent acute rejection, azithromycin-reversible allograft dysfunction, infection, anastomotic stricture, disease recurrence, and/or to extra-allograft complications, such as pleural disease, diaphragm dysfunction or native lung hyperinflation, have been ruled out. CLAD diagnosis relies on persistent and irreversible decline ≥20% in post-bronchodilator mean of two best forced expiratory volume in 1 s (FEV1) and/or forced vital capacity (FVC) measurements for >3 weeks, accordingly to a new proposed classification for CLAD. [3]. Pulmonary functional tests are used to define CLAD since pathology samplings display important limitations [3]. Treating CLAD remains a challenge because underlying molecular events and triggers are not well understood and unfortunately are …

Published
2014

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