AJP - GI Watch the video to learn how APS reaches out to developing nations.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Gastrointest Liver Physiol 286: G126-G136, 2004. First published August 28, 2003; doi:10.1152/ajpgi.00231.2003
0193-1857/04 $5.00
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
286/1/G126    most recent
00231.2003v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (22)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Han, X.
Right arrow Articles by Delude, R. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Han, X.
Right arrow Articles by Delude, R. L.

INFLAMMATION/IMMUNITY/MEDIATORS

Increased iNOS activity is essential for hepatic 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 20 May 2003 ; accepted in final form 16 August 2003

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 FITC-labeled dextran (relative molecular mass 40 kDa) 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 after injection of C57Bl/6J mice with 2 mg/kg Escherichia coli 0111:B4 LPS. Nonidet P-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-N6-(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 resulting from systemic inflammation and suggest that iNOS induction may play a role in the development of cholestatic jaundice in patients with severe sepsis.

multiple organ dysfunction syndrome; jaundice; hyperbilirubinemia; endotoxemia; 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).




This article has been cited by other articles:


Home page
 GutHome page
X Han, X Ren, I Jurickova, K Groschwitz, B A Pasternak, H Xu, T A Wilson, S P Hogan, and L A Denson
Regulation of intestinal barrier function by signal transducer and activator of transcription 5b
Gut, January 1, 2009; 58(1): 49 - 58.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
G. A. Selkirk, T. M. McLellan, H. E. Wright, and S. G. Rhind
Mild endotoxemia, NF-{kappa}B translocation, and cytokine increase during exertional heat stress in trained and untrained individuals
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2008; 295(2): R611 - R623.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
E. Mazzon and S. Cuzzocrea
Role of TNF-{alpha} in ileum tight junction alteration in mouse model of restraint stress
Am J Physiol Gastrointest Liver Physiol, May 1, 2008; 294(5): G1268 - G1280.
[Abstract] [Full Text] [PDF]

Home page
 J. Histochem. Cytochem.Home page
J. J. Laurila, T. Karttunen, V. Koivukangas, P. A. Laurila, H. Syrjala, J. Saarnio, Y. Soini, and T. I. Ala-Kokko
Tight Junction Proteins in Gallbladder Epithelium: Different Expression in Acute Acalculous and Calculous Cholecystitis
J. Histochem. Cytochem., June 1, 2007; 55(6): 567 - 573.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
L.-M. Chen, C. Wang, M. Chen, M. R. Marcello, J. Chao, L. Chao, and K. X. Chai
Prostasin attenuates inducible nitric oxide synthase expression in lipopolysaccharide-induced urinary bladder inflammation
Am J Physiol Renal Physiol, September 1, 2006; 291(3): F567 - F577.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
X. Han, M. P. Fink, T. Uchiyama, R. Yang, and R. L. Delude
Increased iNOS activity is essential for pulmonary epithelial tight junction dysfunction in endotoxemic mice
Am J Physiol Lung Cell Mol Physiol, February 1, 2004; 286(2): L259 - L267.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2004 by the American Physiological Society.