title: Glucocorticoids Regulate Tight Junction Permeability of Lung Epithelia by Modulating Claudin 8.
abstract: The lung epithelium constitutes a selective barrier that separates the airways from the aqueous interstitial compartment. Regulated barrier function controls water and ion transport across the epithelium and is essential for maintaining lung function. Tight junctions (TJs) seal the epithelial barrier and determine the paracellular transport. The properties of TJs depend especially on their claudin composition. Steroids are potent drugs used to treat a variety of airway diseases. Therefore, we addressed whether steroid hormones directly act on TJ properties in lung epithelia. Primary human tracheal epithelial cells and NCI-H441 cells, both cultivated under air-liquid interface conditions, were used as epithelial cell models. Our results demonstrate that glucocorticoids, but not mineralocorticoids, decreased paracellular permeability and shifted the ion permselectivity of TJs toward Cl(-). Glucocorticoids up-regulated claudin 8 (cldn8) expression via glucocorticoid receptors. Silencing experiments revealed that cldn8 is necessary to recruit occludin at the TJs. Immunohistochemistry on human lung tissue showed that cldn8 is specifically expressed in resorptive epithelia of the conducting and respiratory airways but not in the alveolar epithelium. We conclude that glucocorticoids enhance lung epithelia barrier function and increase paracellular Cl(-) selectivity via modulation of cldn8-dependent recruitment of occludin at the TJs. This mode of glucocorticoid action on lung epithelia might be beneficial to patients who suffer from impaired lung barrier function in various diseased conditions.
authors.affiliation: 1 Ulm University, Institute of General Physiology, Ulm, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Kielgast
authors.affiliation: 1 Ulm University, Institute of General Physiology, Ulm, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Schmidt
authors.affiliation: 2 Medizinische Hochschule Hannover, Institute of Pathology, Hannover, Germany; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Braubach
authors.affiliation: 1 Ulm University, Institute of General Physiology, Ulm, Germany.
authors.forename: Veronika E
authors.initials: VE
authors.lastname: Winkelmann
authors.affiliation: 1 Ulm University, Institute of General Physiology, Ulm, Germany.|3 Institut National de la Santé et de la Recherche Médicale, UMR_S938, Sorbonne Universités, Paris, France.
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Thompson
authors.affiliation: 1 Ulm University, Institute of General Physiology, Ulm, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Frick
authors.affiliation: 1 Ulm University, Institute of General Physiology, Ulm, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Dietl
authors.affiliation: 1 Ulm University, Institute of General Physiology, Ulm, Germany.
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Wittekindt
mesh_terms: D057167:Claudins / Q000378:metabolism*; D017097:Electric Impedance; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D057167:Claudins; D005938:Glucocorticoids; D034741:RNA, Small Interfering; C502011:claudin 8
keywords: claudin; epithelium; glucocorticoid; lung; tight junction