Macrophage inflammatory protein-2 gene therapy attenuates adenovirus- and acetaminophen-mediated hepatic injury

Profound hepatocellular injury is often a consequence of adenovirus-mediate d 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 c hallenged with acetaminophen. CD1 mice that received a replication-defectiv e human type 5 adenovirus Vector (Ad70-3) intravenously exhibited hepatic i njury that peaked at 24 h after infection. fn contrast mice that received a similar adenovirus vector containing a rodent MIP-2 cDNA insert had no hep atic injury at any time after infection. The combination of Ad70-3 infectio n and an intraperitoneal challenge with 400 mg/kg of acetaminophen was fata l in 50% of the mice, but only 10% of the AdMIP-2 group receiving acetamino phen were similarly affected. Furthermore, AdMIP-2 mice had significantly l ower hepatic injury and serum aminotransaminases compared with the Ad70-3 g roup. 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 inj ury after adenovirus and acetaminophen challenge. AdMIP-2 treatment of CD1 mice was also associated with significantly decreased leukocyte infiltratio n into the liver and an earlier increase in hepatic H-3-thymidine incorpora tion compared with the control group. Taken together, these data demonstrat e that MIP-2 has a protective role in both adenovirus- and acetaminophen-me diated hepatotoxicity, and suggest that MIP-2 may promote rapid hepatic reg eneration following acute hepatic injury.