Issn Print: 0954-691X
Publication Date: 2006/01/01
Ischemia/reperfusion accelerates the outgrowth of hepatic micrometastases in a highly standardized murine model
JDW van der Bilt; EA te Velde; MW Nijkamp; N Smakman; LM Veenendaal; EE Voest; PJ van Diest; O Kranenburg; R van Hillegersberg; IHM Borel Rinkes
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Excerpt
During liver surgery, hepatic ischemia/reperfusion (I/R) injury often occurs due to vascular clamping. The adverse effects of I/R on hepatocellular damage and postoperative liver function are well documented. The influence on the outgrowth of residual micrometastases is unknown. We investigated the effect of hepatic I/R on the outgrowth of pre-established colorectal micrometastases in a highly standardized murine model and evaluated the putative protective effect of alternative clamping methods. Five days following intrasplenic injection with C26 colon carcinoma cells the vascular structures to the left lobe were clamped for 45 min under hemodynamically stable conditions. Markers of oxidative stress (GSH), liver cell damage (ALT/AST) and tumor growth were assessed over time. Next, we analyzed the effect of ischemic preconditioning, intermittent clamping and selective clamping of the portal vein on hepatocellular damage and tumor growth. I/R induced oxidative stress and hepatocellular damage as measured by decreased liver GSH, a marked increase in liver enzymes and the presence of hepatic necrosis covering 14% of the parenchyma. The outgrowth of micrometastases in occluded liver lobes was accelerated 5–6 fold when compared to non-occluded liver lobes and was associated with the presence of necrotic areas. Both early and late heaptocellular damage were prevented by occluding blood flow intermittently or by portal clamping as indicated by a 96% reduction in liver enzymes and by the absence of necrosis. In addition, accelerated tumor growth was completely prevented by both methods. In contrast, although early liver cell damage was largely prevented (87%), ischemic preconditioning reduced hepatocellular necrosis only by 50% and failed to protect against accelerated tumor growth. Our results identify I/R as a strong stimulus of recurrent intrahepatic tumor growth and indicate that protection against I/R-induced tissue necrosis cross-protects against this phenomenon.
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