EFFECT OF MTP ON TNF-ALPHA IN PERFUSED-RAT-LIVER AFTER BACTEREMIA ANDISCHEMIA REPERFUSION/

Introduction. Muramlytripeptide phosphatidylethanolamine (MTP) stimula tes synthesis of cytokines by hepatic Kupffer cells. We have shown in a perfused rat liver model that secondary ischemia/reperfusion (I/R) d ownregulates tumor necrosis factor alpha (TNF-alpha) expression after Escherichia coil (EC) bacteremia. Here, we tested the hypothesis that pretreatment with MTP restores cytokine response after sequential bact eremia and I/R. Methods. Thirty-eight livers were studied in eight gro ups after intraportal injection of 10(9) live EC or normal saline (NS) : (1) normoxic EC; (2) EC + I/R (ischemia began 30 min after EC follow ed by 2 h of reperfusion); (3) normoxic NS controls; and (4) NS + IIR. Four groups of rats received 300 mu g/kg of MTP i.v. 24 h prior to li ver harvesting: (5) MTP + EC; (6) MTP + EC + I/R; (7) MTP + NS; and (8 ) MTP + NS + I/R. Bioactive and antigenic TNF-alpha, PGE(2) and bacter ial clearance were assessed. Results. MTP increased bioactive TNF-alph a 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-alpha in animals tr eated with MTP (MTP + NS vs MTP + NS + I/R, P = 0.83). Pretreatment wi th MTP restored TNF-alpha 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 fo und in the MTP + EC group (MTP;EC; I/R vs MTP + EC: 671 +/- 215 U/ml v s 685 +/- 255 U/ml, P = 0.75). Finally, bacterial clearance was increa sed in groups which received MTP. Conclusion. In vivo administration o f MTP increases hepatic TNF-alpha response to intraportal EC bacteremi a by a PGE2 independent mechanism. This response is maintained even af ter subsequent ischemia and reperfusion. (C) 1998 Academic Press.