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(American Journal of Pathology. 2006;169:784-794.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060010

Kupffer Cells and Their Mediators

The Culprits in Producing Distant Organ Damage after Trauma-Hemorrhage

Frank Hildebrand*, William J. Hubbard*, Mashkoor A. Choudhry*, Michael Frink*, Hans-Christoph Pape{dagger}, Steven L. Kunkel{ddagger} and Irshad H. Chaudry*

From the Department of Surgery,* Center for Surgical Research, University of Alabama at Birmingham, Birmingham, Alabama; the Department of Orthopedic Surgery,{dagger} University of Pittsburgh, Pittsburgh, Pennsylvania; and the Department of Pathology,{ddagger} University of Michigan Medical Center, Ann Arbor, Michigan

Posttraumatic activation of macrophages enhances development of systemic inflammation/immunosuppression and organ dysfunction. We hypothesized that Kupffer cells are the main source of monocyte chemoattractant protein-1 (MCP-1) production after trauma-hemorrhage, that administration of 17ß-estradiol (E2) after trauma-hemorrhage modulates MCP-1 release and reduces remote organ damage, and that salutary effects of E2 are mediated via estrogen receptor (ER)-{alpha}. To test these hypotheses, female B57BL/J6 mice received E2 (50 µg/25 g) or vehicle after trauma-hemorrhage and female 129 Sve ER-ß–/– transgenic mice and ovariectomized wild-type mice received E2 or ER-{alpha} agonist propyl pyrazole triol (50 µg/25 g) after trauma-hemorrhage. Systemic MCP-1 and interleukin-6 and their release by liver, spleen, and lung macrophages were determined by flow cytometry 4 hours after trauma-hemorrhage. Prior Kupffer cell depletion with gadolinium chloride significantly decreased systemic MCP-1 and interleukin-6 after trauma-hemorrhage and was associated with decreased edema/neutrophil infiltration in lung and liver. Kupffer cells were the only macrophages showing significant MCP-1 release, which was markedly reduced by E2 or propyl pyrazole triol in wild-type and in ER-ß–/– mice. Pretreatment of mice with anti-MCP-1 antiserum prevented an increase in myeloperoxidase and edema in lung and liver. These findings suggest that Kupffer cell-derived MCP-1 plays a major role in remote organ dysfunction after trauma-hemorrhage.





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