Macrophage inflammatory protein-2 gene therapy attenuates adenovirus- and acetaminophen-mediated hepatic injury.
Profound hepatocellular injury is often a consequence of adenovirus-mediated gene therapy or acetaminophen ingestion. The aim of the present study was to examine the role of a CXC chemokine, macrophage inflammatory protein-2 (MIP-2), in the hepatotoxic response by mice infected with adenovirus and challenged with acetaminophen. CD1 mice that received a replication-defective human type 5 adenovirus vector (Ad70-3) intravenously exhibited hepatic injury that peaked at 24 h after infection. In contrast, mice that received a similar adenovirus vector containing a rodent MIP-2 cDNA insert had no hepatic injury at any time after infection. The combination of Ad70-3 infection and an intraperitoneal challenge with 400 mg/kg of acetaminophen was fatal in 50% of the mice, but only 10% of the AdMIP-2 group receiving acetaminophen were similarly affected. Furthermore, AdMIP-2 mice had significantly lower hepatic injury and serum aminotransaminases compared with the Ad70-3 group. However, AdMIP-2 infection in mice lacking the CXC chemokine receptor that binds MIP-2, CXCR2, did not attenuate any of the markers of liver injury after adenovirus and acetaminophen challenge. AdMIP-2 treatment of CD1 mice was also associated with significantly decreased leukocyte infiltration into the liver and an earlier increase in hepatic 3H-thymidine incorporation compared with the control group. Taken together, these data demonstrate that MIP-2 has a protective role in both adenovirus- and acetaminophen-mediated hepatotoxicity, and suggest that MIP-2 may promote rapid hepatic regeneration following acute hepatic injury.
Hogaboam
C M
CM
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA.
Simpson
K J
KJ
Chensue
S W
SW
Steinhauser
M L
ML
Lukacs
N W
NW
Gauldie
J
J
Strieter
R M
RM
Kunkel
S L
SL
D000082:Acetaminophen / Q000009:adverse effects*; D000208:Acute Disease; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D054426:Chemokine CXCL2; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D015846:Monokines / Q000235:genetics*; D009336:Necrosis; D014162:Transfection / Q000379:methods*
D054426:Chemokine CXCL2; D015846:Monokines; D000082:Acetaminophen