Kupffer cells and their mediators: the culprits in producing distant organ damage after trauma-hemorrhage.
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.
Hildebrand
Frank
F
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Volker Hall G094, 1670 University Blvd., Birmingham, AL 35294-0019, USA.
Hubbard
William J
WJ
Choudhry
Mashkoor A
MA
Frink
Michael
M
Pape
Hans-Christoph
HC
Kunkel
Steven L
SL
Chaudry
Irshad H
IH
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000276:immunology; D004958:Estradiol / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000819:agonists / Q000172:deficiency / Q000276:immunology*; D005260:Female; D005682:Gadolinium / Q000494:pharmacology; D006470:Hemorrhage / Q000276:immunology* / Q000473:pathology; D015850:Interleukin-6 / Q000276:immunology; D007728:Kupffer Cells / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D010636:Phenols; D011654:Pulmonary Edema / Q000276:immunology* / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D014947:Wounds and Injuries / Q000276:immunology* / Q000473:pathology
D000893:Anti-Inflammatory Agents; D000906:Antibodies; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D047629:Estrogen Receptor beta; D015850:Interleukin-6; D010636:Phenols; D011720:Pyrazoles; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D004958:Estradiol; D005682:Gadolinium; C038958:gadolinium chloride