Glucocorticoids increase repair potential in a novel in vitro human airway epithelial wounding model.
Airway epithelial damage is a cardinal feature of chronic asthma. Agents which enhance epithelial repair without triggering uncontrolled fibrosis of the mesenchyme would be predicted to be useful in the management of asthma. We have developed a repeat wound model using mucociliated human bronchial epithelial cell (HBEC) cultures to define the key pathways involved in airway epithelial repair, and to study the effects of potential therapeutic agents on epithelial repair in a chronic setting. We show that repair occurs primarily by cell migration to close a defect; this process requires activation of the EGF receptor (EGFR) and subsequent tyrosine kinase signalling. Migration is accompanied by up-regulation of CD44 in motile cells at the wound margins with proliferation of non-migrating cells adjacent to the wound area. In long-term studies beta2 adrenoceptor agonists and phosphodiesterase (PDE) inhibitors have no effect on repair potential, in contrast chronic treatment with the glucocorticoid dexamethasone extends the lifespan of repeatedly wounded differentiated cultures. We suggest part of the beneficial effects of glucocorticoids in asthma is related to this ability to prolong repair potential following repeated episodes of epithelial injury.
Wadsworth
Samuel J
SJ
Division of Therapeutics and Molecular Medicine, D floor, South Block, Queens Medical Centre, University Hospital, Nottingham, NG7 2UH, United Kingdom. Sam.Wadsworth@nottingham.ac.uk
Nijmeh
Hala S
HS
Hall
Ian P
IP
D001249:Asthma / Q000188:drug therapy / Q000473:pathology; D001980:Bronchi / Q000293:injuries / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D008954:Models, Biological; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
D005938:Glucocorticoids; D018960:Hyaluronan Receptors; D003907:Dexamethasone; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases