Asthma as a disease of the airway epithelium: Protocadherin-1 and E-cadherine in
allergic airway inflammation and hyperreactivity
Martijn C. Nawijn1,2
(1) University of Groningen, University Medical Center Groningen, Department of Pathology
& Medical Biology, laboratory of Experimental Pulmonology and Inflammation Research
(EXPIRE), Groningen, The Netherlands
(2) University of Groningen, University Medical Center Groningen, GRIAC Research
Institute, Groningen, the Netherlands
Abstract
The airway epithelium in altered in asthma, with a reduced expression of tight and adherens
junctions proteins, increased permeability to small molecules and increased release of proinflammatory mediators in vitro. The identification of a large number of airway-epithelially
expressed genes as asthma genes in genetic and genomic analyses indicates a possible
contribution of the airway epithelium to the inception of asthma. It is, however, currently
unknown whether the impaired barrier function and reduced expression of adherens and tight
junction proteins in the airway epithelium of asthmatic patients is a cause or a consequence of
the disease.
Here, we show that loss of the adherens junction molecule E-cadherin or the human asthma
and BHR gene Protocadherin-1 directly affects the barrier function and inflammatory
phenotype of the airway epithelium and induces spontaneous phenotypes remiscent of asthma
as well as an increased susceptibility to allergens in vivo. Mice with conditional loss of Ecadherin in the airway epithelium (Cdh1fl/fl Cre+) were compared to Cre-negative littermate
controls (Cdh1fl/fl Cre-). Naïve mice were examined for lung anatomy and inflammation on
day of birth and at 2 weeks (2W), 4W, 6W and 8W of age, and after House Dust Mite
treatment (HDM) in 4W old mice. Mice deficient for the human asthma gene Pcdh1 were
studies at baseline and after HDM challenges at 8 weeks of age in comparison to wild-type
littermates.
Cdh1fl/fl Cre+ mice were viable and displayed no gross abnormalities in lung development.
However, pro-inflammatory activation of the airway epithelium was evident from CCL17 and
CCL20 production, and inflammatory dendritic cells and eosinophil accumulated in lungs of
naïve Cdh1fl/fl Cre+ mice from W2 onwards. Cdh1fl/fl Cre+ mice display spontaneous and
progressive hypoplasia of ciliated and secretory airway epithelial cells in the bronchioles from
birth onwards, associated with spontaneous goblet cell metaplasia at later ages. Exposure of
Cdh1fl/fl Cre+ mice to HDM at 4W of age induced strongly exaggerated eosinophilic airway
inflammation in compared to Cre- littermates controls.
The human asthma gene PCDH1 was found to encode an adhesion molecule of the cadherin
superfamily. PCDH1 was found to contribute to airway epithelial barrier function at baseline
as well as during wound repair. Loss of PCDH1 in vivo resulted in a airway
hyperresponsiveness at baseline as well as an exaggerated inflammatory response to HDM
exposure.
These data show that loss of airway epithelial integrity is not merely a consequence of
asthma, but can in itself cause airway structural and inflammatory phenotypes reminiscent of
asthma. The validation of these phenotypes in mice lacking a human asthma gene that
contributes to airway epithelial barrier function underscores the relevance of these
translational studies for human disease, identifying airway epithelial integrity as a target for
novel therapeutic interventions.