Kupffer cells and their mediators: the culprits in producing distant organ damage after trauma-hemorrhage.

Abstract

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 17beta-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 microg/25 g) or vehicle after trauma-hemorrhage and female 129 Sve ER-beta-/- transgenic mice and ovariectomized wild-type mice received E2 or ER-alpha agonist propyl pyrazole triol (50 microg/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-beta-/- 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.

• Authors: Frank Hildebrand, William J Hubbard, Mashkoor A Choudhry, Michael Frink, Hans-Christoph Pape, Steven L Kunkel, Irshad H Chaudry
• Journal: The American journal of pathology (Am J Pathol) Vol. 169 Issue 3 Pg. 784-94 (Sep 2006) ISSN: 0002-9440 [Print] United States
• PMID: 16936255 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-Inflammatory Agents
• Antibodies
• Ccl2 protein, mouse
• Chemokine CCL2
• Estrogen Receptor beta
• Interleukin-6
• Phenols
• Pyrazoles
• 4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol
• Estradiol
• Gadolinium
• gadolinium chloride

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Antibodies (immunology, pharmacology)
• Chemokine CCL2 (immunology)
• Estradiol (pharmacology)
• Estrogen Receptor beta (agonists, deficiency, immunology)
• Female
• Gadolinium (pharmacology)
• Hemorrhage (immunology, pathology)
• Interleukin-6 (immunology)
• Kupffer Cells (immunology, pathology)
• Liver (immunology, pathology)
• Lung (immunology, pathology)
• Macrophage Activation (drug effects, immunology)
• Mice
• Mice, Knockout
• Neutrophil Infiltration (drug effects, immunology)
• Phenols
• Pulmonary Edema (immunology, pathology)
• Pyrazoles (pharmacology)
• Spleen (immunology, pathology)
• Wounds and Injuries (immunology, pathology)