Novel CXCR2-dependent liver regenerative qualities of ELR-containing CXC chemokines.
Severe acute liver injury due to accidental or intentional acetaminophen overdose presents a major clinical dilemma often requiring liver transplantation. In the present study, liver regeneration after profound liver injury in mice challenged with acetaminophen was facilitated by the exogenous addition of ELR-containing CXC chemokines such as macrophage inflammatory protein-2 (MIP-2), epithelial neutrophil-activating protein-78 (ENA-78), or interleukin 8. Intravenous administration of ELR-CXC chemokines or N-acetyl-cysteine (NAC) immediately after acetaminophen challenge in mice significantly reduced histological and biochemical markers of hepatic injury. However, when the intervention was delayed until 10 h after acetaminophen challenge, only ELR-CXC chemokines significantly reduced liver injury and mouse mortality. The delayed addition of ELR-CXC chemokines to cultured hepatocytes maintained the proliferation of these cells in a CXCR2-dependent fashion after acetaminophen challenge whereas delayed NAC treatment did not. These observations demonstrate that ELR-CXC chemokines represent novel hepatic regenerative factors that exhibit prolonged therapeutic effects after acetaminophen-induced hepatotoxicity.
Hogaboam
C M
CM
Department of Pathology, Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA. hogaboam@path.med.umich.edu
Bone-Larson
C L
CL
Steinhauser
M L
ML
Lukacs
N W
NW
Colletti
L M
LM
Simpson
K J
KJ
Strieter
R M
RM
Kunkel
S L
SL
D000082:Acetaminophen / Q000633:toxicity; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D054426:Chemokine CXCL2; D054365:Chemokine CXCL5; D019743:Chemokines, CXC / Q000494:pharmacology*; D002630:Chemotactic Factors / Q000494:pharmacology; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D016209:Interleukin-8 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D015846:Monokines / Q000494:pharmacology*; D019707:Receptors, Chemokine / Q000502:physiology*; D018123:Receptors, Interleukin / Q000502:physiology*; D023063:Receptors, Interleukin-8B
C486263:CXCL5 protein, human; D054426:Chemokine CXCL2; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D016209:Interleukin-8; D015846:Monokines; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D023063:Receptors, Interleukin-8B; D000082:Acetaminophen; D017228:Hepatocyte Growth Factor; D001219:Aspartate Aminotransferases; D000111:Acetylcysteine