title: Murine Kupffer cells are protective in total hepatic ischemia/reperfusion injury with bowel congestion through IL-10.
abstract: Kupffer cells (KCs) are thought to mediate hepatocyte injury via their production of proinflammatory cytokines and reactive oxygen species in response to stress. In this study, we depleted KCs from the liver to examine their role in total warm hepatic ischemia/reperfusion (I/R) injury with bowel congestion. We injected 8-wk-old C57BL/10J mice with liposome-encapsulated clodronate 48 h before 35 min of hepatic ischemia with bowel congestion, followed by 6 or 24 h of reperfusion. KC-depleted animals had a higher mortality rate than diluent-treated animals and a 10-fold elevation in transaminase levels that correlated with increases in centrilobular necrosis. There was extensive LPS binding to the endothelial cells, which correlated with an upregulation of endothelial adhesion molecules in the KC-depleted animals versus diluent-treated animals. There was an increase in the levels of proinflammatory cytokines in KC-depleted animals, and a concomitant decrease in IL-10 levels. When KC-depleted mice were treated with recombinant IL-10, their liver damage profile in response to I/R was similar to diluent-treated animals, and endothelial cell adhesion molecules and proinflammatory cytokine levels decreased. KCs are protective in the liver subjected to total I/R with associated bowel congestion and are not deleterious as previously thought. This protection appears to be due to KC secretion of the potent anti-inflammatory cytokine IL-10.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Ellett
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Evans
authors.forename: Zainab
authors.initials: Z
authors.lastname: Amani
authors.forename: Edward
authors.initials: E
authors.lastname: Balish
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schmidt
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Chavin
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000276:immunology; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D004002:Clodronic Acid / Q000008:administration & dosage; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000502:physiology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D007511:Ischemia / Q000276:immunology / Q000401:mortality / Q000473:pathology; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D008070:Lipopolysaccharides / Q000378:metabolism / Q000633:toxicity; D008081:Liposomes / Q000008:administration & dosage; D016031:Liver Transplantation / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis
chemical_list: D008070:Lipopolysaccharides; D008081:Liposomes; D004002:Clodronic Acid; D016753:Interleukin-10
references.citation: Hepatology. 1996 May;23(5):1239-43
references.pmid: 8621159
references.citation: Immunol Rev. 2008 Dec;226:205-18
references.pmid: 19161426
references.citation: Immunol Lett. 1995 Feb;45(1-2):61-5
references.pmid: 7542627
references.citation: Liver. 2000 Feb;20(1):66-77
references.pmid: 10726963
references.citation: J Leukoc Biol. 1992 Sep;52(3):296-302
references.pmid: 1522388
references.citation: Am J Transplant. 2004 Oct;4(10):1567-73
references.pmid: 15367211
references.citation: J Biol Chem. 2008 Mar 28;283(13):8573-9
references.pmid: 18086675
references.citation: Arch Med Res. 2006 Jul;37(5):576-83
references.pmid: 16740426
references.citation: J Surg Res. 2009 Nov;157(1):e71-8
references.pmid: 19555976
references.citation: J Exp Med. 1994 Jul 1;180(1):95-109
references.pmid: 7911822
references.citation: Transplantation. 2001 Jun 15;71(11):1566-72
references.pmid: 11435966
references.citation: J Hepatol. 1995 Feb;22(2):226-9
references.pmid: 7790711
references.citation: Liver Transpl. 2007 Apr;13(4):558-65
references.pmid: 17394154
references.citation: J Nephrol. 2006 Jan-Feb;19(1):50-6
references.pmid: 16523426
references.citation: Scand J Gastroenterol. 1995 Oct;30(10):1027-35
references.pmid: 8545609
references.citation: Am J Physiol. 1999 Aug;277(2):L310-9
references.pmid: 10444525
references.citation: Hepatology. 1997 Apr;25(4):889-95
references.pmid: 9096593
references.citation: Hepatology. 2000 Apr;31(4):932-6
references.pmid: 10733550
references.citation: Am J Surg. 2008 Jul;196(1):139-48
references.pmid: 18565339
references.citation: Liver Transpl. 2008 Dec;14(12):1737-44
references.pmid: 19025917
references.citation: Exp Mol Pathol. 2007 Dec;83(3):311-26
references.pmid: 17996232
references.citation: Surg Today. 2006;36(5):450-6
references.pmid: 16633752
references.citation: Blood. 1997 Jun 15;89(12):4461-9
references.pmid: 9192770
references.citation: J Surg Res. 2007 Aug;141(2):176-82
references.pmid: 17543989
references.citation: J Am Coll Surg. 1997 Oct;185(4):358-64
references.pmid: 9328384
references.citation: Transplantation. 2008 Jul 27;86(2):286-92
references.pmid: 18645492
references.citation: Hepatology. 2004 Mar;39(3):688-98
references.pmid: 14999687
references.citation: Gastroenterology. 1996 Sep;111(3):736-44
references.pmid: 8780580
references.citation: Injury. 2004 Jan;35(1):35-43
references.pmid: 14728953
references.citation: Hepatogastroenterology. 2003 Sep-Oct;50(53):1587-92
references.pmid: 14571792
references.citation: Hepatology. 2002 Feb;35(2):289-98
references.pmid: 11826401
references.citation: J Leukoc Biol. 2005 May;77(5):626-33
references.pmid: 15860798
references.citation: J Surg Res. 2008 Jun 1;147(1):153-9
references.pmid: 17707862
references.citation: Am J Physiol Regul Integr Comp Physiol. 2002 Aug;283(2):R477-86
references.pmid: 12121861
references.citation: Am J Physiol Gastrointest Liver Physiol. 2000 May;278(5):G734-43
references.pmid: 10801266