| Affiliation: | 1. 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;2. H?pital Foch, Suresnes, Université Versailles Saint‐Quentin‐en‐Yvelines, UPRES EA220, Versailles, France;3. CHU de Marseille, Aix Marseille Université, Marseille, France;4. CHU de Strasbourg, Strasbourg, France;5. Centre Chirurgical Marie Lannelongue, Service de Chirurgie Thoracique, Vasculaire et Transplantation Cardiopulmonaire, Le Plessis Robinson, France;6. CHU de Bordeaux, Bordeaux, France;7. H?pital Bichat, Service de Pneumologie et Transplantation Pulmonaire, Paris, France;8. Université de Lyon, INRA, UMR754, Lyon, Hospices Civils de Lyon, Lyon, France;9. H?pital Européen George Pompidou, Paris, France;10. CHU de Toulouse, Toulouse, France;11. H?pital Erasme, Bruxelles, Belgique;12. Clinique Universitaire Pneumologie, P?le Thorax et Vaisseaux, CHU de Grenoble, Université de Grenoble, INSERM U1055, Grenoble, France;13. Université de Nantes, INSERM U1064 and Institut de Transplantation Urologie Néphrologie du Centre Hospitalier Universitaire H?tel Dieu, Nantes, France |
| 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. |
