title: Differential effects of claudin-3 and claudin-4 on alveolar epithelial barrier function.
abstract: Alveolar barrier function depends critically on the claudin family tight junction proteins. Of the major claudins expressed by alveolar epithelial cells, claudin (Cldn)-3 and Cldn-4 are the most closely related by amino acid homology, yet they differ dramatically in the pattern of expression. Previously published reports have shown that Cldn-3 is predominantly expressed by type II alveolar epithelial cells; Cldn-4 is expressed throughout the alveolar epithelium and is specifically upregulated in response to acute lung injury. Using primary rat alveolar epithelial cells transduced with yellow fluorescent protein-tagged claudin constructs, we have identified roles for Cldn-3 and Cldn-4 in alveolar epithelial barrier function. Surprisingly, increasing expression of Cldn-3 decreased alveolar epithelial barrier function, as assessed by transepithelial resistance and dye flux measurements. Conversely, increasing Cldn-4 expression improved alveolar epithelial transepithelial resistance compared with control cells. Other alveolar epithelial tight junction proteins were largely unaffected by increased expression of Cldn-3 and Cldn-4. Taken together, these results demonstrate that, in the context of the alveolar epithelium, Cldn-3 and Cldn-4 have different effects on paracellular permeability, despite significant homology in their extracellular loop domains.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Mitchell
authors.forename: Christian E
authors.initials: CE
authors.lastname: Overgaard
authors.forename: Christina
authors.initials: C
authors.lastname: Ward
authors.forename: Susan S
authors.initials: SS
authors.lastname: Margulies
authors.forename: Michael
authors.initials: M
authors.lastname: Koval
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability; D062465:Claudin-3; D062506:Claudin-4; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D021381:Protein Transport; D011650:Pulmonary Alveoli / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D062465:Claudin-3; D062506:Claudin-4; C568124:Cldn3 protein, rat; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins