Effect of MTP on TNF-alpha in perfused rat liver after bacteremia and ischemia/reperfusion.
BACKGROUND
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-alpha) expression after Escherichia 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 10(9) live 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 micrograms 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-alpha, PGE2 and bacterial clearance were assessed.


RESULTS
MTP increased bioactive TNF-alpha 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 treated with MTP (MTP + NS vs MTP + NS +I/R, P = 0.83). Pretreatment with 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 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.


CONCLUSIONS
In vivo administration of MTP increases hepatic TNF-alpha response to intraportal EC bacteremia by a PGE2 independent mechanism. This response is maintained even after subsequent ischemia and reperfusion.
Health Science Division, St. Louis University, Missouri 63110, USA.
R M
RM
Durham
A J
AJ
Lechner
C A
CA
Johanns
Z
Z
Chen
G M
GM
Matuschak
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D016470:Bacteremia / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004927:Escherichia coli Infections; D007155:Immunologic Factors / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010714:Phosphatidylethanolamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D007155:Immunologic Factors; D010714:Phosphatidylethanolamines; D014409:Tumor Necrosis Factor-alpha; C037144:mifamurtide; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D015232:Dinoprostone