HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 287/3/G734    most recent 00300.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Xu, J. Articles by Maher, J. J. Search for Related Content PubMed PubMed Citation Articles by Xu, J. Articles by Maher, J. J.

LIVER AND BILIARY TRACT

Limited role for CXC chemokines in the pathogenesis of -naphthylisothiocyanate-induced liver injury

¹Liver Center and Department of Medicine, University of California, San Francisco 94110; ²Center for Liver Diseases and Transplantation, Cedars-Sinai Medical Center, Los Angeles, California 90048

Submitted 16 June 2003 ; accepted in final form 22 April 2004

-Naphthylisothiocyanate (ANIT) is a hepatotoxin that causes severe neutrophilic inflammation around portal tracts and bile ducts. The chemotactic signals that provoke this inflammatory response are unknown. In this study, we addressed the possibility that ANIT upregulates CXC chemokines in the liver and that these compounds mediate hepatic inflammation and tissue injury after ANIT treatment. Mice treated with a single dose of ANIT (50 mg/kg) exhibited rapid hepatic induction of the CXC chemokine macrophage inflammatory protein-2 (MIP-2). MIP-2 derived primarily from hepatocytes, with no apparent contribution by biliary cells. In ANIT-treated mice, the induction of MIP-2 coincided with an influx of neutrophils to portal zones; this hepatic neutrophil recruitment was suppressed by 50% in mice that lack the receptor for MIP-2 (CXCR2^–/–). Interestingly, despite their markedly reduced degree of hepatic inflammation, CXCR2^–/– mice displayed just as much hepatocellular injury and cholestasis after ANIT treatment as wild-type mice. Moreover, after long-term exposure, ANIT CXCR2^–/– mice developed liver fibrosis that was indistinguishable from that in wild-type mice. In summary, our data show that CXC chemokines are responsible for some of the hepatic inflammation that occurs in response to ANIT but that these compounds are not essential to the pathogenesis of either acute or chronic ANIT hepatotoxicity.

hepatotoxicity; cholangiocyte; neutrophil; fibrosis; macrophage inflammatory protein-2

This article has been cited by other articles:

				S. K. Ramaiah and H. Jaeschke Role of Neutrophils in the Pathogenesis of Acute Inflammatory Liver Injury Toxicol Pathol, October 1, 2007; 35(6): 757 - 766. [Abstract] [Full Text] [PDF]

				P. Kodali, P. Wu, P. A. Lahiji, E. J. Brown, and J. J. Maher ANIT toxicity toward mouse hepatocytes in vivo is mediated primarily by neutrophils via CD18 Am J Physiol Gastrointest Liver Physiol, August 1, 2006; 291(2): G355 - G363. [Abstract] [Full Text] [PDF]

				N. D. Kim, J.-O. Moon, A. L. Slitt, and B. L. Copple Early Growth Response Factor-1 Is Critical for Cholestatic Liver Injury Toxicol. Sci., April 1, 2006; 90(2): 586 - 595. [Abstract] [Full Text] [PDF]

				R. B. Dorman, J. S. Gujral, M. L. Bajt, A. Farhood, and H. Jaeschke Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia Am J Physiol Gastrointest Liver Physiol, May 1, 2005; 288(5): G880 - G886. [Abstract] [Full Text] [PDF]