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EDITORIAL FOCUS

Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury

¹The Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, ²San Francisco VA Medical Center, and ³NCIRE/Veterans Health Research Institute, San Francisco, California

Submitted 11 February 2009 ; accepted in final form 13 May 2009

Intact alveolar barrier function is associated with better outcomes in acute lung injury patients; however, the regulation of alveolar epithelial paracellular transport during lung injury has not been extensively investigated. This study was undertaken to determine whether changes in tight junction claudin expression affect alveolar epithelial barrier properties and to determine the mechanisms of altered expression. In anesthetized mice exposed to ventilator-induced lung injury, claudin-4 was specifically induced among tight junction structural proteins. Real-time PCR showed an eightfold increase in claudin-4 expression in the lung injury model. To examine the role of this protein in barrier regulation, claudin-4 function was inhibited with small interfering RNA (siRNA) and a blocking peptide derived from the binding domain of Clostridium perfringens enterotoxin (CPE_BD). Inhibition of claudin-4 decreased transepithelial electrical resistance but did not alter macromolecule permeability in primary rat and human epithelial cells. In mice, CPE_BD decreased air space fluid clearance >33% and resulted in pulmonary edema during moderate tidal volume ventilation that did not induce edema in control peptide-treated mice. In vitro phorbol ester induced a ninefold increase in claudin-4 expression that was dependent on PKC activation and the JNK MAPK pathway. These data establish that changes in alveolar epithelial claudin expression influence paracellular transport, alveolar fluid clearance rates, and susceptibility to pulmonary edema. We hypothesize that increased claudin-4 expression early in acute lung injury represents a mechanism to limit pulmonary edema and that the regulation of alveolar epithelial claudin expression may be a novel target for acute lung injury therapy.

alveolar epithelium; ion transport; paracellular transport; tight junction; pulmonary edema; acute respiratory distress syndrome

This article has been cited by other articles:

				M. Koval Tight junctions, but not too tight: fine control of lung permeability by claudins Am J Physiol Lung Cell Mol Physiol, August 1, 2009; 297(2): L217 - L218. [Full Text] [PDF]