Dysfunction of the physical barrier of the airway epithelium may contribute to the development of asthma and to disease progression. The nature and mechanisms for epithelial barrier dysfunction in asthma are incompletely understood. This is in part related to the current limited understanding epithelial tight junctions in the airways. Recent discoveries highlight the diversity of tight junction structure and function, and it is clea that tissue-specific differences in tight junction claudin proteins account for differences in epithelial barrier properties in the various tissues of the body. This proposal seeks to define for the first time the role of claudin- 18, the only lung-specific tight junction protein, in airway barier function and asthma. We have found that asthmatics have a deficiency in claudin-18 in the airway epithelium compared with healthy controls. Moreover, untreated asthmatics show an increase in airway epithelial claudin-18 expression with the initiation of steroid treatment. Consistent with this observation, our newly generated claudin-18 knock out mice show a marked susceptibility to antigen sensitization and many features of asthma. Because claudin-18 knock out mice have increased epithelial permeability and claudin-18 knock down results in increased permeability in cultured airway cells, this protein may be a critical component of the airway barrier. Loss of claudin-18 may result in increased antigen exposure and immune activation. Studies in the knock out mouse will allow us to address the hypothesis that an epithelial barrier defect is a primary contributor asthma severity. Importantly, we have also found that IL-13 induces a specific decrease in claudin-18 in primary human airway epithelial cells. Therefore, the specific loss of claudin-18 in response to IL-13 may contribute to epithelial barrie defects in asthma. We will examine the role of claudin-18 maintaining airway epithelial barrier function and determine if the loss of claudin-18 is sufficient to increase airway epithelial permeability to environmental antigen and induce a more severe asthma phenotype in the mouse model of aspergillus sensitization. In cell culture studies using primary human airway epithelial cells grown on an air-liquid interface, we will also investigate the mechanisms for the IL-13-mediated decrease in claudin-18, and the specific contribution of claudin-18 to the airway epithelial permeability barrier. In translational studies using human samples and clinical data collected by the UCSF Airway Tissue Bank, we will investigate the hypothesis that asthmatics with more severe disease have lower levels of claudin-18 and determine if claudin-18 deficiency is associated with asthma Th2 phenotype.

Public Health Relevance

The proposed work will examine the contribution of airway epithelial barrier dysfunction to the development of asthma and asthma severity. Specifically, asthmatic subjects have been found to be deficient in the lung- specific tight junction protein claudin-18.1. We will examine how inflammation reduces the levels of this protein and the consequences of claudin-18.1 deficiency in the development of asthma to determine if future novel therapies targeting this pathway could be successful.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL111707-01A1
Application #
8370482
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2012-08-15
Project End
2014-05-31
Budget Start
2012-08-15
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$222,300
Indirect Cost
$72,300
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Sweerus, Kelly; Lachowicz-Scroggins, Marrah; Gordon, Erin et al. (2017) Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma. J Allergy Clin Immunol 139:72-81.e1
Brune, Kieran; Frank, James; Schwingshackl, Andreas et al. (2015) Pulmonary epithelial barrier function: some new players and mechanisms. Am J Physiol Lung Cell Mol Physiol 308:L731-45
Frank, James A; Matthay, Michael A (2014) TGF-? and lung fluid balance in ARDS. Proc Natl Acad Sci U S A 111:885-6
Frank, James A (2012) Claudins and alveolar epithelial barrier function in the lung. Ann N Y Acad Sci 1257:175-83