PMID- 10751350
OWN - NLM
STAT- MEDLINE
DCOM- 20000629
LR  - 20240414
IS  - 0002-9440 (Print)
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Linking)
VI  - 156
IP  - 4
DP  - 2000 Apr
TI  - Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C 
      chemokine receptor 2.
PG  - 1245-52
AB  - Monocyte chemoattractant protein-1 is one of the major C-C chemokines that has 
      been implicated in liver injury. The C-C chemokine receptor, CCR2, has been 
      identified as the primary receptor that mediates monocyte chemoattractant 
      protein-1 (MCP-1) responses in the mouse. Accordingly, the present study 
      addressed the role of CCR2 in mice acutely challenged with acetaminophen (APAP). 
      Mice genetically deficient in CCR2 (CCR2(-/-)) and their wild-type counterparts 
      (CCR2(+/+)) were fasted for 10 hours before receiving an intraperitoneal 
      injection of APAP (300 mg/kg). Liver and serum samples were removed from both 
      groups of mice before and at 24 and 48 hours post APAP. Significantly elevated 
      levels of MCP-1 were detected in liver samples from CCR2(+/+) and CCR2(-/-) mice 
      at 24 hours post-APAP. Although CCR2(+/+) mice exhibited no liver injury at any 
      time after receiving APAP, CCR2(-/-) mice exhibited marked evidence of necrotic 
      and TUNEL-positive cells in the liver, particularly at 24 hours post-APAP. 
      Enzyme-linked immunosorbent assay analysis of liver homogenates from both groups 
      of mice at the 24 hours time point revealed that liver tissue from CCR2(-/-) mice 
      contained significantly greater amounts of immunoreactive IFN-gamma and 
      TNF-alpha. The in vivo immunoneutralization of IFN-gamma or TNF-alpha 
      significantly attenuated APAP-induced liver injury in CCR2(-/-) mice and 
      increased hepatic IL-13 levels. Taken together, these findings demonstrate that 
      CCR2 expression in the liver provides a hepatoprotective effect through its 
      regulation of cytokine generation during APAP challenge.
FAU - Hogaboam, C M
AU  - Hogaboam CM
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, 
      Michigan 48109-0602, USA. hogaboam@path.med.umich.edu
FAU - Bone-Larson, C L
AU  - Bone-Larson CL
FAU - Steinhauser, M L
AU  - Steinhauser ML
FAU - Matsukawa, A
AU  - Matsukawa A
FAU - Gosling, J
AU  - Gosling J
FAU - Boring, L
AU  - Boring L
FAU - Charo, I F
AU  - Charo IF
FAU - Simpson, K J
AU  - Simpson KJ
FAU - Lukacs, N W
AU  - Lukacs NW
FAU - Kunkel, S L
AU  - Kunkel SL
LA  - eng
GR  - R01 AI036302/AI/NIAID NIH HHS/United States
GR  - P50 HL056402/HL/NHLBI NIH HHS/United States
GR  - 1P50HL56402/HL/NHLBI NIH HHS/United States
GR  - P01 HL031963/HL/NHLBI NIH HHS/United States
GR  - R37 HL035276/HL/NHLBI NIH HHS/United States
GR  - 1P50HL60289/HL/NHLBI NIH HHS/United States
GR  - CA66180/CA/NCI NIH HHS/United States
GR  - R29 AI036302/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Antibodies)
RN  - 0 (Ccr2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Immune Sera)
RN  - 0 (Interleukin-13)
RN  - 0 (Receptors, CCR2)
RN  - 0 (Receptors, Chemokine)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 362O9ITL9D (Acetaminophen)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Acetaminophen/*poisoning
MH  - Animals
MH  - Antibodies/immunology
MH  - Apoptosis
MH  - *Chemical and Drug Induced Liver Injury
MH  - Chemokine CCL2/metabolism
MH  - Immune Sera/immunology
MH  - Interferon-gamma/metabolism
MH  - Interleukin-13/immunology/metabolism
MH  - Liver/*drug effects/*metabolism/pathology/physiopathology
MH  - Liver Diseases/pathology
MH  - Mice
MH  - Necrosis
MH  - Receptors, CCR2
MH  - Receptors, Chemokine/*deficiency/metabolism
MH  - Tumor Necrosis Factor-alpha/immunology/metabolism
PMC - PMC1876888
EDAT- 2000/04/07 09:00
MHDA- 2000/07/06 11:00
PMCR- 2000/10/01
CRDT- 2000/04/07 09:00
PHST- 2000/04/07 09:00 [pubmed]
PHST- 2000/07/06 11:00 [medline]
PHST- 2000/04/07 09:00 [entrez]
PHST- 2000/10/01 00:00 [pmc-release]
AID - S0002-9440(10)64995-4 [pii]
AID - 2134 [pii]
AID - 10.1016/S0002-9440(10)64995-4 [doi]
PST - ppublish
SO  - Am J Pathol. 2000 Apr;156(4):1245-52. doi: 10.1016/S0002-9440(10)64995-4.