title: Claudin 4 knockout mice: normal physiological phenotype with increased susceptibility to lung injury.
abstract: Claudins are tight junction proteins that regulate paracellular ion permeability of epithelium and endothelium. Claudin 4 has been reported to function as a paracellular sodium barrier and is one of three major claudins expressed in lung alveolar epithelial cells (AEC). To directly assess the role of claudin 4 in regulation of alveolar epithelial barrier function and fluid homeostasis in vivo, we generated claudin 4 knockout (Cldn4 KO) mice. Unexpectedly, Cldn4 KO mice exhibited normal physiological phenotype although increased permeability to 5-carboxyfluorescein and decreased alveolar fluid clearance were noted. Cldn4 KO AEC monolayers exhibited unchanged ion permeability, higher solute permeability, and lower short-circuit current compared with monolayers from wild-type mice. Claudin 3 and 18 expression was similar between wild-type and Cldn4 KO alveolar epithelial type II cells. In response to either ventilator-induced lung injury or hyperoxia, claudin 4 expression was markedly upregulated in wild-type mice, whereas Cldn4 KO mice showed greater degrees of lung injury. RNA sequencing, in conjunction with differential expression and upstream analysis after ventilator-induced lung injury, suggested Egr1, Tnf, and Il1b as potential mediators of increased lung injury in Cldn4 KO mice. These results demonstrate that claudin 4 has little effect on normal lung physiology but may function to protect against acute lung injury.
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kage
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine.
authors.forename: Per
authors.initials: P
authors.lastname: Flodby
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine.
authors.forename: Danping
authors.initials: D
authors.lastname: Gao
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine.
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Departments of Surgery and Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center.
authors.forename: Crystal N
authors.initials: CN
authors.lastname: Marconett
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine.
authors.forename: Lucas
authors.initials: L
authors.lastname: DeMaio
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Departments of Physiology and Biophysics and Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California; Department of Biomedical Engineering and.
authors.forename: Kwang-Jin
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Pathology, Keck School of Medicine, University of Southern California; Mork Family Department of Chemical Engineering and Materials Science, Viterbi School of Engineering, University of Southern California, Los Angeles, California.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Crandall
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, zborok@med.usc.edu.
authors.forename: Zea
authors.initials: Z
authors.lastname: Borok
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000503:physiopathology; D056809:Alveolar Epithelial Cells / Q000502:physiology; D000818:Animals; D002199:Capillary Permeability; D002478:Cells, Cultured; D062506:Claudin-4 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D020022:Genetic Predisposition to Disease; D018496:Hyperoxia / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D010641:Phenotype; D059467:Transcriptome; D055397:Ventilator-Induced Lung Injury / Q000235:genetics* / Q000503:physiopathology
chemical_list: D062506:Claudin-4; C568158:Cldn4 protein, mouse
keywords: RNA sequencing; alveolar epithelial barrier; alveolar fluid clearance; permeability; ventilator-induced lung injury
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