Effect of MTP on TNF-α in Perfused Rat Liver after Bacteremia and Ischemia/Reperfusion

Abstract

Introduction.Muramlytripeptide phosphatidylethanolamine (MTP) stimulates synthesis of cytokines by hepatic Kupffer cells. We have shown in a perfused rat liver model that secondary ischemia/reperfusion (I/R) downregulates tumor necrosis factor alpha (TNF-α) expression afterEscherichia coli(EC) bacteremia. Here, we tested the hypothesis that pretreatment with MTP restores cytokine response after sequential bacteremia and I/R.Methods.Thirty-eight livers were studied in eight groups after intraportal injection of 109live EC or normal saline (NS): (1) normoxic EC; (2) EC + I/R (ischemia began 30 min after EC followed by 2 h of reperfusion); (3) normoxic NS controls; and (4) NS + I/R. Four groups of rats received 300 μg/kg of MTP i.v. 24 h prior to liver harvesting: (5) MTP + EC; (6) MTP + EC + I/R; (7) MTP + NS; and (8) MTP + NS + I/R. Bioactive and antigenic TNF-α, PGE2and bacterial clearance were assessed.Results.MTP increased bioactive TNF-α response to EC (MTP + EC vs EC controls: 685 ± 255 U/ml vs 250 ± 180 U/ml,P< 0.02). I/R did not downregulate TNF-α in animals treated with MTP (MTP + NS vs MTP + NS + I/R,P= 0.83). Pretreatment with MTP restored TNF-α after I/R MTP + EC + I/R vs EC + I/R: 671 ± 215 U/ml vs 27 ± 14 U/ml,P< 0.001) to levels similar to those found in the MTP + EC group (MTP + EC + I/R vs MTP + EC: 671 ± 215 U/ml vs 685 ± 255 U/ml,P= 0.75). Finally, bacterial clearance was increased in groups which received MTP.Conclusion. In vivoadministration of MTP increases hepatic TNF-α response to intraportal EC bacteremia by a PGE2independent mechanism. This response is maintained even after subsequent ischemia and reperfusion.