Human airway surface epithelial regeneration is delayed and abnormal in cystic fibrosis.
Cystic fibrosis (CF) at an advanced stage of the disease is characterized by airway epithelial injury and remodelling. Whether CF remodelling is related to infection and inflammation or due to an abnormal regenerative process is still undecided. We have recently established the expression and secretion profiles of interleukin (IL)-8, matrix metalloproteinase (MMP)-7, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-1 during non-CF airway epithelial regeneration in a humanized nude mouse xenograft model. To enhance our understanding of CF remodelling, we compared the regeneration process of non-infected human CF and non-CF nasal epithelia. In both CF and non-CF situations, epithelial regeneration was characterized by successive steps of cell adhesion and migration, proliferation, pseudostratification, and terminal differentiation. However, histological examination of the grafts showed a delay in differentiation of the CF airway epithelium. Cell proliferation was higher in the regenerating CF epithelium, and the differentiated CF epithelium exhibited a pronounced height increase and basal cell hyperplasia in comparison with non-CF epithelium. In addition, while the number of goblet cells expressing MUC5AC was similar in CF and non-CF regenerated epithelia, the number of MUC5B-immunopositive goblet cells was lower in CF grafts. The expression of human IL-8, MMP-7, MMP-9, and TIMP-1 was enhanced in CF epithelium, especially early in the regenerative process. Together, our data strongly suggest that the regeneration of human CF airway surface epithelium is characterized by remodelling, delayed differentiation, and altered pro-inflammatory and MMP responses.
Hajj
R
R
INSERM U514, Reims, France; Université de Reims, IFR53, Reims, France.
Lesimple
P
P
Nawrocki-Raby
B
B
Birembaut
P
P
Puchelle
E
E
Coraux
C
C
D000293:Adolescent; D000328:Adult; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D016009:Chi-Square Distribution; D003550:Cystic Fibrosis / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016209:Interleukin-8 / Q000032:analysis; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration; D020545:Respiratory Mucosa / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D014132:Trachea / Q000201:enzymology / Q000637:transplantation; D014183:Transplantation, Heterologous
D004791:Enzyme Inhibitors; D016209:Interleukin-8; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9