title: T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction.
abstract: Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-β. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-β-induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD.
authors.affiliation: UMR_S 1087 CNRS UMR_6291, l'Institut du Thorax, Université de Nantes, CHU de Nantes, Centre National de Référence Mucoviscidose Nantes-Roscoff, Nantes, France.
authors.forename: M
authors.initials: M
authors.lastname: Pain
authors.affiliation: UMR_S 1087 CNRS UMR_6291, l'Institut du Thorax, Université de Nantes, CHU de Nantes, Centre National de Référence Mucoviscidose Nantes-Roscoff, Nantes, France.
authors.forename: P-J
authors.initials: PJ
authors.lastname: Royer
authors.affiliation: UMR_S 1087 CNRS UMR_6291, l'Institut du Thorax, Université de Nantes, CHU de Nantes, Centre National de Référence Mucoviscidose Nantes-Roscoff, Nantes, France.
authors.forename: J
authors.initials: J
authors.lastname: Loy
authors.affiliation: UMR_S 1087 CNRS UMR_6291, l'Institut du Thorax, Université de Nantes, CHU de Nantes, Centre National de Référence Mucoviscidose Nantes-Roscoff, Nantes, France.
authors.forename: A
authors.initials: A
authors.lastname: Girardeau
authors.affiliation: UMR_S 1087 CNRS UMR_6291, l'Institut du Thorax, Université de Nantes, CHU de Nantes, Centre National de Référence Mucoviscidose Nantes-Roscoff, Nantes, France.
authors.forename: A
authors.initials: A
authors.lastname: Tissot
authors.affiliation: UMR_S 1087 CNRS UMR_6291, l'Institut du Thorax, Université de Nantes, CHU de Nantes, Centre National de Référence Mucoviscidose Nantes-Roscoff, Nantes, France.
authors.forename: P
authors.initials: P
authors.lastname: Lacoste
authors.affiliation: Hôpital Foch, Suresnes, Université Versailles Saint-Quentin-en-Yvelines, UPRES EA220, Versailles, France.
authors.forename: A
authors.initials: A
authors.lastname: Roux
authors.affiliation: CHU de Marseille, Aix Marseille Université, Marseille, France.
authors.forename: M
authors.initials: M
authors.lastname: Reynaud-Gaubert
authors.affiliation: CHU de Strasbourg, Strasbourg, France.
authors.forename: R
authors.initials: R
authors.lastname: Kessler
authors.affiliation: Centre Chirurgical Marie Lannelongue, Service de Chirurgie Thoracique, Vasculaire et Transplantation Cardiopulmonaire, Le Plessis Robinson, France.
authors.forename: S
authors.initials: S
authors.lastname: Mussot
authors.affiliation: CHU de Bordeaux, Bordeaux, France.
authors.forename: C
authors.initials: C
authors.lastname: Dromer
authors.affiliation: Hôpital Bichat, Service de Pneumologie et Transplantation Pulmonaire, Paris, France.
authors.forename: O
authors.initials: O
authors.lastname: Brugière
authors.affiliation: Université de Lyon, INRA, UMR754, Lyon, Hospices Civils de Lyon, Lyon, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Mornex
authors.affiliation: Hôpital Européen George Pompidou, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Guillemain
authors.affiliation: CHU de Toulouse, Toulouse, France.
authors.forename: M
authors.initials: M
authors.lastname: Dahan
authors.affiliation: Hôpital Erasme, Bruxelles, Belgique.
authors.forename: C
authors.initials: C
authors.lastname: Knoop
authors.affiliation: UMR_S 1087 CNRS UMR_6291, l'Institut du Thorax, Université de Nantes, CHU de Nantes, Centre National de Référence Mucoviscidose Nantes-Roscoff, Nantes, France.
authors.forename: K
authors.initials: K
authors.lastname: Botturi
authors.affiliation: Clinique Universitaire Pneumologie, Pôle Thorax et Vaisseaux, CHU de Grenoble, Université de Grenoble, INSERM U1055, Grenoble, France.
authors.forename: C
authors.initials: C
authors.lastname: Pison
authors.affiliation: Université de Nantes, INSERM U1064 and Institut de Transplantation Urologie Néphrologie du Centre Hospitalier Universitaire Hôtel Dieu, Nantes, France.
authors.forename: R
authors.initials: R
authors.lastname: Danger
authors.affiliation: Université de Nantes, INSERM U1064 and Institut de Transplantation Urologie Néphrologie du Centre Hospitalier Universitaire Hôtel Dieu, Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Brouard
authors.affiliation: UMR_S 1087 CNRS UMR_6291, l'Institut du Thorax, Université de Nantes, CHU de Nantes, Centre National de Référence Mucoviscidose Nantes-Roscoff, Nantes, France.
authors.forename: A
authors.initials: A
authors.lastname: Magnan
mesh_terms: D000328:Adult; D064591:Allografts; D015415:Biomarkers / Q000097:blood*; D001980:Bronchi / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000097:blood / Q000175:diagnosis* / Q000209:etiology; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D008137:Longitudinal Studies; D008171:Lung Diseases / Q000150:complications* / Q000601:surgery; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D054390:Receptors, CCR2 / Q000378:metabolism*; D012307:Risk Factors; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015415:Biomarkers; C515334:CCR2 protein, human; D016207:Cytokines; D054390:Receptors, CCR2; D016212:Transforming Growth Factor beta; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: bronchiolitis obliterans (BOS); lung (allograft) function/dysfunction; lung transplantation/pulmonology; rejection: chronic; translational research/science