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1. Blood Gene Expression Predicts Bronchiolitis Obliterans Syndrome

Author

Richard Danger, Pierre-Joseph Royer, Damien Reboulleau, Eugénie Durand, Jennifer Loy, Adrien Tissot, Philippe Lacoste, Antoine Roux, Martine Reynaud-Gaubert, Carine Gomez, Romain Kessler, Sacha Mussot, Claire Dromer, Olivier Brugière, Jean-François Mornex, Romain Guillemain, Marcel Dahan, Christiane Knoop, Karine Botturi, Aurore Foureau, Christophe Pison, Angela Koutsokera, Laurent P. Nicod, Sophie Brouard, Antoine Magnan, The COLT and SysCLAD Consortia, J. Jougon, J.-F. Velly, H. Rozé, E. Blanchard, C. Dromer, M. Antoine, M. Cappello, R. Souilamas, 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, E. Arnaud-Crozat, V. Bach, P.-Y. Brichon, P. Chaffanjon, O. Chavanon, A. de Lambert, J. P. Fleury, S. Guigard, K. Hireche, A. Pirvu, P. Porcu, R. Hacini, 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, P. Bedouch, A. Boignard, H. Bouvaist, A. Briault, B. Camara, S. Chanoine, M. Dubuc, S. Lantuéjoul, 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, M. Adda, M. Badier, F. Bregeon, B. Coltey, X. B. D’Journo, S. Dizier, C. Doddoli, N. Dufeu, H. Dutau, J. M. Forel, J. Y. Gaubert, C. Gomez, M. Leone, A. Nieves, B. Orsini, L. Papazian, L. C. Picard, M. Reynaud-Gaubert, A. Roch, J. M. Rolain, E. Sampol, V. Secq, P. Thomas, D. Trousse, M. Yahyaoui, 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, E. Durand, A. Foureau, Ph. Dartevelle, D. Fabre, E. Fadel, O. Mercier, S. Mussot, F. Stephan, P. Viard, J. Cerrina, P. Dorfmuller, S. Feuillet, M. Ghigna, Ph. Hervén, F. Le Roy Ladurie, J. Le Pavec, V. Thomas de Montpreville, L. Lamrani, Y. Castier, P. Cerceau, F. Francis, G. Lesèche, N. Allou, P. Augustin, S. Boudinet, M. Desmard, G. Dufour, P. Montravers, O. Brugière, G. Dauriat, G. Jébrak, H. Mal, A. Marceau, A.-C. Métivier, G. Thabut, B. Ait Ilalne, 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, 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. Le Balle, O. Mathe, H. Benahoua, A. Didier, A. L. Goin, M. Murris, L. Crognier, O. Fourcade, T. Krueger, H. B. Ris, M. Gonzalez, J.-D. Aubert, L. P. Nicod, B. J. Marsland, T. C. Berutto, T. Rochat, P. Soccal, Ph. Jolliet, A. Koutsokera, C. Marcucci, O. Manuel, E. Bernasconi, M. Chollet, F. Gronchi, C. Courbon, Zurich S. Hillinger, I. Inci, P. Kestenholz, W. Weder, R. Schuepbach, M. Zalunardo, C. Benden, U. Buergi, L. C. Huber, B. Isenring, M. M. Schuurmans, A. Gaspert, D. Holzmann, N. Müller, C. Schmid, B. Vrugt, T. Rechsteiner, A. Fritz, D. Maier, K. Desplanche, D. Koubi, F. Ernst, T. Paprotka, M. Schmitt, B. Wahl, J.-P. Boissel, G. Olivera-Botello, C. Trocmé, B. Toussaint, S. Bourgoin-Voillard, M. Séve, M. Benmerad, V. Siroux, R. Slama, C. Auffray, D. Charron, and J. Pellet

Subjects
lung transplantation, bronchiolitis obliterans syndrome, gene expression, biomarkers, blood, Immunologic diseases. Allergy, RC581-607
Abstract

Bronchiolitis obliterans syndrome (BOS), the main manifestation of chronic lung allograft dysfunction, leads to poor long-term survival after lung transplantation. Identifying predictors of BOS is essential to prevent the progression of dysfunction before irreversible damage occurs. By using a large set of 107 samples from lung recipients, we performed microarray gene expression profiling of whole blood to identify early biomarkers of BOS, including samples from 49 patients with stable function for at least 3 years, 32 samples collected at least 6 months before BOS diagnosis (prediction group), and 26 samples at or after BOS diagnosis (diagnosis group). An independent set from 25 lung recipients was used for validation by quantitative PCR (13 stables, 11 in the prediction group, and 8 in the diagnosis group). We identified 50 transcripts differentially expressed between stable and BOS recipients. Three genes, namely POU class 2 associating factor 1 (POU2AF1), T-cell leukemia/lymphoma protein 1A (TCL1A), and B cell lymphocyte kinase, were validated as predictive biomarkers of BOS more than 6 months before diagnosis, with areas under the curve of 0.83, 0.77, and 0.78 respectively. These genes allow stratification based on BOS risk (log-rank test p

Published
2018
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2. 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

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