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1 Departments Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2 Departments Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
3 Departments Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
* To whom correspondence should be addressed. E-mail: deluder{at}ccm.upmc.edu.
We tested the hypothesis that increased production of nitric oxide (NO.) by inducible NO. synthase (iNOS) is a key factor responsible for alterations in the expression, localization, and function of key tight junction (TJ) proteins in mice challenged with lipopolysaccharide (LPS, endotoxin). Endotoxemia was associated with hepatobiliary epithelial barrier dysfunction as evidenced by increased plasma-to-bile leakage of fluorescein isothiocyanate labeled-dextran (Mr 40kDa) and increased circulating levels of bile acids and conjugated bilirubin. Immunoblotting revealed decreased expression of zonula occludens (ZO)-1, ZO-2, ZO-3, and occludin in liver following injection of C57Bl/6J mice with 2 mg/kg Escherichia coli 0111:B4 LPS. NP-40 insoluble (i.e., TJ-associated) occludin and ZO-1 were virtually undetectable 12 and 18 h after injecting LPS. Immunofluorescence microscopy also revealed deranged subcellular localization of ZO-1 and occludin in endotoxemic mice. Pharmacological inhibition of iNOS activity using L-N(6)-(1-iminoethyl)lysine (5 mg/kg) or genetic ablation of iNOS ameliorated LPS-induced changes in hepatobiliary barrier function and these strategies partially preserved TJ protein expression and localization. Steady-state levels of occludin and ZO-3 transcripts decreased transiently after injecting LPS, but returned toward normal by 12 and 24 h after induction of endotoxemia, respectively. These results support the view that iNOS-dependent NO. production is an important factor contributing to hepatobiliary epithelial barrier dysfunction due to systemic inflammation, and suggests that iNOS induction may play a role in the development of cholestatic jaundice in patients with severe sepsis.
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