title: Delay of airway epithelial wound repair in COPD is associated with airflow obstruction severity.
abstract: BACKGROUND
  Airway epithelium integrity is essential to maintain its role of mechanical and functional barrier. Recurrent epithelial injuries require a complex mechanism of repair to restore its integrity. In chronic obstructive pulmonary disease (COPD), an abnormal airway epithelial repair may participate in airway remodeling. The objective was to determine if airway epithelial wound repair of airway epithelium is abnormal in COPD.
  
  
  METHODS
  Patients scheduled for lung resection were prospectively recruited. Demographic, clinical data and pulmonary function tests results were recorded. Emphysema was visually scored and histological remodeling features were noted. Primary bronchial epithelial cells (BEC) were extracted and cultured for wound closure assay. We determined the mean speed of wound closure (MSWC) and cell proliferation index, matrix metalloprotease (MMP)-2, MMP-9 and cytokines levels in supernatants of BEC 18 hours after cell wounding. In a subset of patients, bronchiolar epithelial cells were also cultured for wound closure assay for MSWC analyze.
  
  
  RESULTS
  13 COPD and 7 non COPD patients were included. The severity of airflow obstruction and the severity of emphysema were associated with a lower MSWC in BEC (p = 0.01, 95% CI [0.15-0.80]; p = 0.04, 95% CI [-0.77;-0.03] respectively). Cell proliferation index was decreased in COPD patients (19 ± 6% in COPD vs 27 ± 3% in non COPD, p = 0.04). The severity of COPD was associated with a lower level of MMP-2 (7.8 ± 2 10(5) AU in COPD GOLD D vs 12.8 ± 0.13 10(5) AU in COPD GOLD A, p = 0.04) and a lower level of IL-4 (p = 0.03, 95% CI [0.09;0.87]). Moreover, higher levels of IL-4 and IL-2 were associated with a higher MSWC (p = 0.01, 95% CI [0.17;0.89] and p = 0.02, 95% CI [0.09;0.87] respectively). Clinical characteristics and smoking history were not associated with MSWC, cell proliferation index or MMP and cytokines levels. Finally, we showed an association of the MSWC of bronchial and corresponding bronchiolar epithelial cells obtained from the same patients (p = 0.02, 95% CI [0.12;0.89]).
  
  
  CONCLUSIONS
  Our results showed an abnormal bronchial epithelial wound closure process in severe COPD. Further studies are needed to elucidate the contribution and the regulation of this mechanism in the complex pathophysiology of COPD.
authors.affiliation: Department of Respiratory Diseases, University Hospital, 45 rue Cognacq Jay, 51100, Reims, France. jmperotin-collard@chu-reims.fr.|INSERM UMRS 903, University Hospital, Reims, France. jmperotin-collard@chu-reims.fr.
authors.forename: Jeanne-Marie
authors.initials: JM
authors.lastname: Perotin
authors.affiliation: INSERM UMRS 903, University Hospital, Reims, France. damien.adam@inserm.fr.
authors.forename: Damien
authors.initials: D
authors.lastname: Adam
authors.affiliation: Department of Respiratory Diseases, University Hospital, 45 rue Cognacq Jay, 51100, Reims, France. jvellaboucaud@chu-reims.fr.
authors.forename: Juliette
authors.initials: J
authors.lastname: Vella-Boucaud
authors.affiliation: Department of Cardio-Thoracic Surgery, University Hospital, Reims, France. gdelepine@chu-reims.fr.
authors.forename: Gonzague
authors.initials: G
authors.lastname: Delepine
authors.affiliation: Department of Cardio-Thoracic Surgery, University Hospital, Reims, France. ssandu@chu-reims.fr.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Sandu
authors.affiliation: Department of Respiratory Medicine, Hospital, Charlevilles-Mezières, France. acjonvel@ch-charleville-mezieres.fr.
authors.forename: Anne-Carole
authors.initials: AC
authors.lastname: Jonvel
authors.affiliation: Institut Jean Godinot, Reims, France. alain.prevost@reims.fnclcc.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Prevost
authors.affiliation: Department of Respiratory Medicine, Hospital, Chalons en Champagne, France. gberthiot@ch-chalonsenchampagne.fr.
authors.forename: Gérard
authors.initials: G
authors.lastname: Berthiot
authors.affiliation: Clinique Universitaire de Pneumologie, Pôle Thorax et Vaisseaux, CHU Grenoble; Inserm1055; Université Joseph Fourier, Grenoble, France. cpison@chu-grenoble.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pison
authors.affiliation: Department of Respiratory Diseases, University Hospital, 45 rue Cognacq Jay, 51100, Reims, France. flebargy@chu-reims.fr.
authors.forename: François
authors.initials: F
authors.lastname: Lebargy
authors.affiliation: INSERM UMRS 903, University Hospital, Reims, France. pbirembaut@chu-reims.fr.|Department of anatomopathology, Pol Bouin Laboratory, University Hospital, Reims, France. pbirembaut@chu-reims.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Birembaut
authors.affiliation: INSERM UMRS 903, University Hospital, Reims, France. christelle.coraux@univ-reims.fr.
authors.forename: Christelle
authors.initials: C
authors.lastname: Coraux
authors.affiliation: Department of Respiratory Diseases, University Hospital, 45 rue Cognacq Jay, 51100, Reims, France. gdeslee@chu-reims.fr.|INSERM UMRS 903, University Hospital, Reims, France. gdeslee@chu-reims.fr.
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Deslee
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D056151:Airway Remodeling; D001980:Bronchi / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D012720:Severity of Illness Index; D013997:Time Factors; D014945:Wound Healing
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9