Murine Kupffer cells are protective in total hepatic ischemia/reperfusion injury with bowel congestion through IL-10.
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.
Ellett
Justin D
JD
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
Atkinson
Carl
C
Evans
Zachary P
ZP
Amani
Zainab
Z
Balish
Edward
E
Schmidt
Michael G
MG
van Rooijen
Nico
N
Schnellmann
Rick G
RG
Chavin
Kenneth D
KD
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
D008070:Lipopolysaccharides; D008081:Liposomes; D004002:Clodronic Acid; D016753:Interleukin-10
Hepatology. 1996 May;23(5):1239-43
8621159
Immunol Rev. 2008 Dec;226:205-18
19161426
Immunol Lett. 1995 Feb;45(1-2):61-5
7542627
Liver. 2000 Feb;20(1):66-77
10726963
J Leukoc Biol. 1992 Sep;52(3):296-302
1522388
Am J Transplant. 2004 Oct;4(10):1567-73
15367211
J Biol Chem. 2008 Mar 28;283(13):8573-9
18086675
Arch Med Res. 2006 Jul;37(5):576-83
16740426
J Surg Res. 2009 Nov;157(1):e71-8
19555976
J Exp Med. 1994 Jul 1;180(1):95-109
7911822
Transplantation. 2001 Jun 15;71(11):1566-72
11435966
J Hepatol. 1995 Feb;22(2):226-9
7790711
Liver Transpl. 2007 Apr;13(4):558-65
17394154
J Nephrol. 2006 Jan-Feb;19(1):50-6
16523426
Scand J Gastroenterol. 1995 Oct;30(10):1027-35
8545609
Am J Physiol. 1999 Aug;277(2):L310-9
10444525
Hepatology. 1997 Apr;25(4):889-95
9096593
Hepatology. 2000 Apr;31(4):932-6
10733550
Am J Surg. 2008 Jul;196(1):139-48
18565339
Liver Transpl. 2008 Dec;14(12):1737-44
19025917
Exp Mol Pathol. 2007 Dec;83(3):311-26
17996232
Surg Today. 2006;36(5):450-6
16633752
Blood. 1997 Jun 15;89(12):4461-9
9192770
J Surg Res. 2007 Aug;141(2):176-82
17543989
J Am Coll Surg. 1997 Oct;185(4):358-64
9328384
Transplantation. 2008 Jul 27;86(2):286-92
18645492
Hepatology. 2004 Mar;39(3):688-98
14999687
Gastroenterology. 1996 Sep;111(3):736-44
8780580
Injury. 2004 Jan;35(1):35-43
14728953
Hepatogastroenterology. 2003 Sep-Oct;50(53):1587-92
14571792
Hepatology. 2002 Feb;35(2):289-98
11826401
J Leukoc Biol. 2005 May;77(5):626-33
15860798
J Surg Res. 2008 Jun 1;147(1):153-9
17707862
Am J Physiol Regul Integr Comp Physiol. 2002 Aug;283(2):R477-86
12121861
Am J Physiol Gastrointest Liver Physiol. 2000 May;278(5):G734-43
10801266