Article
Augmenter of Liver Regeneration attenuates CD4+ T cell recruitment and hepatocellular injury after ischemia-reperfusion of the liver
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Published: | March 21, 2014 |
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Introduction: Augmenter of Liver Regeneration (ALR), a protein synthesized in the liver is suggested to be protective against oxidative stress-induced cell death. Hepatic ischemia-reperfusion (I/R) injury is triggered by reactive oxygen species. CD4+ T cells play a critical role during hepatic I/R. The aim of this study was to analyse the impact of ALR on CD4 T cell migration and I/R injury in vivo.
Material and methods: C57BL6 mice were subjected to warm hepatic ischemia for 90 min. Either recombinant ALR (100 µg/kg) or vehicle were administered to mice prior ischemia. Sham-operated animals served as controls (n=7 each group). Freshly isolated and fluorescence-labelled CD4+ T cells were infused intraarterially, their migration was quantified in hepatic microvessels using intravital microscopy. ALT/AST (plasma) and caspase-3 (tissue) activities were determined as markers of hepatocellular necrotic and apoptotic injury after 60 and 240 min of reperfusion.
Results: Hepatic I/R led to a significant enhancement of CD4+ T cell recruitment in hepatic sinusoids (9.2±0.7/acinus) as compared to the sham-operated mice (2.8±0.2/acinus). The plasma activity of AST and ALT (3938±610 and 1615±457 U/L, respectively) as well as caspase-3 activity in tissue (125.8±4.5 RFU/min/µg protein) were dramatically increased. In ALR-treated group, however, CD4 T cell trafficking in the hepatic microvasculature was attenuated (p<0.05). This effect was associated with a significant reduction of tissue injury (liver enzymes and caspase-3 activity).
Conclusion: Our in vivo data show that ALR has a therapeutic potential against postischemic liver injury. As a mechanism we suggest a direct protective effect of ALR on apoptotic and necrotic death of hepatocytes as well as attenuation of inflammatory cell influx into the postischemic tissue.