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

Am J Physiol Lung Cell Mol Physiol. 2009 Aug;297(2):L219-27. doi: 10.1152/ajplung.00043.2009. Epub 2009 May 15.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Lung Injury / metabolism*
  • Acute Lung Injury / physiopathology
  • Animals
  • Carcinogens / pharmacology
  • Cells, Cultured
  • Claudin-4
  • Electric Impedance
  • Enterotoxins / pharmacology
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Oligonucleotide Array Sequence Analysis
  • Permeability
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / metabolism*
  • Pulmonary Edema / metabolism*
  • Pulmonary Edema / physiopathology
  • RNA, Small Interfering
  • Rats
  • Respiration, Artificial / adverse effects
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / metabolism*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tight Junctions / metabolism


  • CLDN4 protein, human
  • Carcinogens
  • Claudin-4
  • Cldn4 protein, mouse
  • Enterotoxins
  • Membrane Proteins
  • RNA, Small Interfering
  • enterotoxin, Clostridium
  • JNK Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate