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Am J Physiol Lung Cell Mol Physiol 286: L259-L267, 2004. First published August 1, 2003; doi:10.1152/ajplung.00187.2003
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EDITORIAL FOCUS

Increased iNOS activity is essential for pulmonary epithelial tight junction dysfunction in endotoxemic mice

Xiaonan Han,1 Mitchell P. Fink,1,2 Takashi Uchiyama,1 Runkuan Yang,1 and Russell L. Delude1,3

Departments of 1Critical Care Medicine, 3Pathology, and 2Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Submitted 13 June 2003 ; accepted in final form 28 July 2003

A murine endotoxemia model and cultured Calu-3 monolayers were used to test the hypothesis that excessive nitric oxide (NO) production secondary to induction of inducible NO synthase (iNOS) is a key factor leading to altered tight junction (TJ) protein expression and function in the pulmonary epithelium. C57Bl/6J mice were injected with either Escherichia coli 0111:B4 lipopolysaccharide (LPS; 2 mg/kg) or vehicle. Twelve hours later, leakage of FITC-dextran (Mr 4 kDa; FD4) from blood into bronchoalveolar lavage fluid was significantly increased in endotoxemic but not control mice. This decrease in bronchoalveolar barrier function was associated with upregulation of iNOS protein expression and NF-{kappa}B activation in lung tissue. Expression of the TJ proteins, zonula occludens (ZO)-1, ZO-2, ZO-3, and occludin, as assessed by immunoblotting and/or immunofluorescence, decreased in lung after the injection of mice with LPS. Treatment of endotoxemic mice with an isoform-selective iNOS inhibitor [L-N6-(1-iminoethyl)lysine; L-NIL] ameliorated LPS-induced changes in TJ protein expression and preserved bronchoalveolar epithelial barrier function. Incubating Calu-3 bronchiolar epithelial monolayers with cytomix (a mixture of 1,000 U/ml IFN-{gamma}, 10 ng/ml TNF-{alpha}, and 1 ng/ml IL-1{beta}) increased permeability to FD4, but adding L-NIL prevented this effect. These results suggest that decreased expression and mistargeting of TJ proteins in lung after systemic inflammation may be NO dependent.

zonula occludens-1; occludin; nitric oxide; permeability; multiple organ dysfunction syndrome; inducible nitric oxide synthase; lipopolysaccharide


Address for reprint requests and other correspondence: R. L. Delude, Dept. of Critical Care Medicine, 616 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261 (E-mail: deluder{at}ccm.upmc.edu).




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