[Preconditioning of the liver for protecting the hepatic functional reserve]

Ischemia reperfusion (I/R) injury of the liver is a major cause of post-surgical hepatic failure. The liver produced heat shock protein 72 (HSP72) 24 approximately 48 hours after heat shock preconditioning. We have found that these livers were provided with ischemic tolerance. The animal survival after I/R injury was improved, and the release of hepatic enzymes during reperfusion was significantly suppressed. As one of the mechanisms of this tolerance, the integrity of hepatic mitochondria was well maintained during I/R in the liver after heat shock preconditioning. In addition, the production of denatured proteins during I/R was significantly reduced in the heat shock group. This fact was well corroborated with the theoretical function of HSP72 as a molecular chaperon. Intra-vital microscopy showed that sinusoidal perfusion failure as well as leukocyte stagnation after ischemia were well suppressed. These beneficial effects of heat shock preconditioning on the hepatic microcirculation seemed to be related with the effective suppression of NF-kappaB activation and subsequent TNF-alpha production during I/R injury. We further studied the effects of geranyl-geranylacetone(GGA) in inducing HSP72 protein. Although GGA could not induce HSP72 by itself, GGA of 200mg/kg facilitated the production of HSP72 after heat shock preconditioning. With the preadministration of GGA, the heat stress to induce HSP72 (stress for preconditioning) could be minimized to one third. Although further investigation is necessary before the use of this strategy in the clinical setting of liver surgery, preconditioning and ischemic tolerance is a promising field of surgical research.