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Am J Physiol Lung Cell Mol Physiol. 2014 Oct 1;307(7):L524-36. doi: 10.1152/ajplung.00077.2014. Epub 2014 Aug 8.

Claudin 4 knockout mice: normal physiological phenotype with increased susceptibility to lung injury.

Author information

1
Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine.
2
Departments of Surgery and Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center.
3
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.
4
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.
5
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.

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.

KEYWORDS:

RNA sequencing; alveolar epithelial barrier; alveolar fluid clearance; permeability; ventilator-induced lung injury

PMID:
25106430
PMCID:
PMC4187039
DOI:
10.1152/ajplung.00077.2014
[Indexed for MEDLINE]
Free PMC Article

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