New evidence for the role of TNF-alpha in liver ischaemic/reperfusion injury.
BACKGROUND
Tumour necrosis factor-alpha (TNF-alpha) plays a key role in causing ischaemia/reperfusion (I/R) injury. I/R also causes activation of xanthine oxidase and dehydrogenase (XDH + XO) system that, via generated free radicals, causes organ damage. We investigated the effect of ischaemia, reperfusion and non-ischaemic prolonged perfusion (NIP) on TNF-alpha and XDH + XO production in an isolated perfused rat liver model.


METHODS
Rat livers underwent 150 min NIP (control group) or two hours of ischaemia followed by reperfusion (I/R group). TNF-alpha (TNF-alpha mRNA and protein level), XDH + XO production and bile secretion were determined in tissue and effluent at baseline, at 120 min of ischaemia, after 30 min of reperfusion (I/R group) and after 120 and 150 min of prolonged perfusion (control).


RESULTS
Unexpectedly, neither ischaemia nor reperfusion had any effect on TNF-alpha production. TNF-alpha in effluent was 11 +/- 4.8 pg mL(-1) at baseline, 7 +/- 3.2 pg mL(-1) at the end of ischaemia, and 13 +/- 5.3 pg mL(-1) after 30 min of reperfusion. NIP, however, caused a significant increase of TNF-alpha synthesis and release. TNF-alpha effluent level after 120 and 150 min of perfusion was 392 +/- 78.7 pg mL(-1) and 408 +/- 64.3 pg mL(-1), respectively. TNF-alpha mRNA in tissue was also significantly elevated compared to baseline levels (1.31 +/- 0.2 P < 0.001 and 1.38 P < 0.002, respectively). Decrease of liver function (expressed by bile secretion) during I/R and NIP was accompanied by significant XDH + XO elevation.


CONCLUSIONS
This is the first evidence that NIP, and not I/R, is the decisive trigger for TNF-alpha production. This study leads to a better understanding of pathogenesis of liver I/R and perfusion damage.
Department of Cardiac Surgery, Tel-Aviv Sourasky Medical Centre, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
D
D
Pevni
I
I
Frolkis
D
D
Schwartz
I
I
Schwartz
T
T
Chernichovski
A
A
Kramer
Y
Y
Ben-Gal
G
G
Uretzky
I
I
Shapira
A
A
Weinbroum
D000818:Animals; D008099:Liver / Q000098:blood supply*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000209:etiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*; D014968:Xanthine Dehydrogenase / Q000096:biosynthesis*; D014969:Xanthine Oxidase / Q000096:biosynthesis*
D014409:Tumor Necrosis Factor-alpha; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase