Hajj R, Lesimple P, Nawrocki-Raby B, Birembaut P, Puchelle E, Coraux C
INSERM U514, Reims, France; Université de Reims, IFR53, Reims, France.
J Pathol. 2007 Feb;211(3):340-50. doi: 10.1002/path.2118.
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.
囊性纤维化（CF）疾病晚期的特征是气道上皮损伤和重塑。CF重塑是与感染和炎症相关，还是由于异常的再生过程所致，目前仍未确定。我们最近在人源化裸鼠异种移植模型中，建立了非CF气道上皮再生过程中白细胞介素（IL）-8、基质金属蛋白酶（MMP）-7、MMP-9和金属蛋白酶组织抑制剂（TIMP）-1的表达和分泌谱。为了加深对CF重塑的理解，我们比较了未感染的人CF和非CF鼻上皮的再生过程。在CF和非CF两种情况下，上皮再生均以细胞黏附、迁移、增殖、假复层化和终末分化的连续步骤为特征。然而，移植物的组织学检查显示CF气道上皮的分化延迟。再生的CF上皮中的细胞增殖更高，与非CF上皮相比，分化的CF上皮表现出明显的高度增加和基底细胞增生。此外，虽然CF和非CF再生上皮中表达MUC5AC的杯状细胞数量相似，但CF移植物中MUC5B免疫阳性杯状细胞的数量较少。人IL-8、MMP-7、MMP-9和TIMP-1在CF上皮中的表达增强，尤其是在再生过程的早期。总之，我们的数据强烈表明，人CF气道表面上皮的再生具有重塑、分化延迟以及促炎和MMP反应改变的特征。
