Airway epithelial shedding: Morphological and functional aspects in vivo

Sammanfattning: Epithelial damage may contribute to the pathology in airway diseases such as asthma and rhinitis. However, the distribution of epithelial shedding in inflammatory airway diseases and, particularly, the ensuing repair processes are largely unknown. In the present studies we have developed novel in vivo techniques to explore epithelial repair mechanisms and associated tissue responses occuring in guinea-pig trachea after mechanical-induced epithelial shedding or an allergic inflammation. The results emerging from the studies of mechanichal shedding and repair include: morphological characterisation of prompt dedifferentiation of both ciliated and secretory epithelial cells into repair cells that with a high speed migrate to cover the denuded basement membrane. Another major finding was that epithelial shedding, by itself, evoked several disease-like tissue responses such as plasma exudation, hypersecretion, and infiltration and activation of neutrophils and eosinophils. Repeated treatment with a potent topical glucocorticoid (budesonide) did not affect the speedy epithelial restitution and its associated tissue responses. A novel technique was developed to selectively remove columnar epithelial cells to demonstrate that also airway basal cells have a capacity to promptly assume a barrier structure. In vivo allergen challenge, selectively of the large airways, produced crater-like damage sites in the epithelium. Dedifferentiated repair cells were present at the floor and the borders of these damage sites. Activated granulocytes and extravasated plasma proteins abounded in the airways, particularly in association with the damage sites. In conclusion this thesis demonstrates that epithelial repair after mechanical or allergen-induced epithelial shedding is a speedy an efficient process with the participation of basal, secretory, and ciliated cells in a milieu of plasma exudates and leukocytes. This thesis further shows that in allergic inflammation patchy epithelial damage areas are dynamic sites where damage and repair processes occur simultaneously and where plasma exudates and activated leukocytes accumulate. If transferable to human airways the present observations on sequelae to epithelial shedding suggest that epithelial restitution processes quickly restore a barrier structure but causes also effects that significantly contribute to the pathology and pathophysiology observed in inflammatory airway diseases.