Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium.
Rhinovirus (RV), which causes exacerbation in patients with chronic airway diseases, readily infects injured airway epithelium and has been reported to delay wound closure. In this study, we examined the effects of RV on cell repolarization and differentiation in a model of injured/regenerating airway epithelium (polarized, undifferentiated cells). RV causes only a transient barrier disruption in a model of normal (mucociliary-differentiated) airway epithelium. However, in the injury/regeneration model, RV prolongs barrier dysfunction and alters the differentiation of cells. The prolonged barrier dysfunction caused by RV was not a result of excessive cell death but was instead associated with epithelial-to-mesenchymal transition (EMT)-like features, such as reduced expression of the apicolateral junction and polarity complex proteins, E-cadherin, occludin, ZO-1, claudins 1 and 4, and Crumbs3 and increased expression of vimentin, a mesenchymal cell marker. The expression of Snail, a transcriptional repressor of tight and adherence junctions, was also up-regulated in RV-infected injured/regenerating airway epithelium, and inhibition of Snail reversed RV-induced EMT-like features. In addition, compared with sham-infected cells, the RV-infected injured/regenerating airway epithelium showed more goblet cells and fewer ciliated cells. Inhibition of epithelial growth factor receptor promoted repolarization of cells by inhibiting Snail and enhancing expression of E-cadherin, occludin, and Crumbs3 proteins, reduced the number of goblet cells, and increased the number of ciliated cells. Together, these results suggest that RV not only disrupts barrier function, but also interferes with normal renewal of injured/regenerating airway epithelium by inducing EMT-like features and subsequent goblet cell hyperplasia.
1 Departments of Pediatrics and Communicable Diseases and.
Andrea N
AN
Faris
1 Departments of Pediatrics and Communicable Diseases and.
Shyamala
S
Ganesan
1 Departments of Pediatrics and Communicable Diseases and.
Asamanja
A
Chattoraj
1 Departments of Pediatrics and Communicable Diseases and.
Sangbrita S
SS
Chattoraj
1 Departments of Pediatrics and Communicable Diseases and.
Adam T
AT
Comstock
1 Departments of Pediatrics and Communicable Diseases and.
Benjamin L
BL
Unger
1 Departments of Pediatrics and Communicable Diseases and.|2 Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
Marc B
MB
Hershenson
1 Departments of Pediatrics and Communicable Diseases and.
Umadevi S
US
Sajjan
Crumbs polarity complex; barrier function; epithelial growth factor receptor; epithelial-to-mesenchymal transition; goblet cell hyperplasia