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Am J Physiol Gastrointest Liver Physiol (December 2, 2004). doi:10.1152/ajpgi.00317.2004
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Submitted on July 16, 2004
Accepted on November 24, 2004

GENERATION AND FUNCTIONAL SIGNIFICANCE OF CXC CHEMOKINES FOR NEUTROPHIL-INDUCED LIVER INJURY DURING ENDOTOXEMIA

Robert B. Dorman1, Jaspreet S. Gujral2, Mary Lynn Bajt2, Anwar Farhood3, and Hartmut Jaeschke2*

1 Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
2 Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Liver Research Institute, University of Arizona, Tucson, AZ, USA
3 Department of Pathology, University of Texas Health Science Center, Houston, TX, USA

* To whom correspondence should be addressed. E-mail: Jaeschke{at}email.arizona.edu.

The hypothesis was tested that the neutrophil chemoattractant CXC chemokines KC and MIP-2 are involved in neutrophil transmigration and liver injury in C3Heb/FeJ mice treated with 700 mg/kg galactosamine (Gal) and/or 100 µg/kg endotoxin (ET). Hepatic KC and MIP-2 mRNA levels and plasma CXC chemokine concentrations were dramatically increased 1.5 h after Gal/ET or ET alone and gradually declined up to 7 h. Murine recombinant cytokines (TNF-{alpha}, IL-1{alpha}, IL-1{beta}), but not Gal/ET, induced CXC chemokine formation in the endotoxin-resistant C3H/HeJ strain. To assess the functional importance of KC and MIP-2, C3Heb/FeJ mice were treated with Gal/ET and either control IgG or a combination of anti-KC and anti-MIP2 antibodies. Anti-CXC chemokine antibodies did not attenuate hepatocellular apoptosis, sinusoidal neutrophil sequestration and extravasation, or liver injury at 7 h. Furthermore, there was no difference in liver injury between Balb/cJ wild-type and CXC receptor-2 gene knock-out mice (CXCR2-/-) treated with Gal/ET. The higher neutrophil counts in livers of CXCR2-/- mice compared to wildtype animals after Gal/ET treatment was caused by the elevated number of neutrophils located in sinusoids of untreated CXCR2-/- animals. The pancaspase inhibitor Z-VAD-fmk eliminated Gal/ET-induced apoptosis, neutrophil extravasation and injury but not CXC chemokine formation. Thus, Gal/ET induced massive, cytokine-dependent CXC chemokine formation in the liver. However, neutrophil extravasation and injury occurred in response to apoptotic cell injury between 6-7 h and was independent of CXC chemokine formation.




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