Cytokines contribute to early hepatic parenchymal injury and microvasculardysfunction after bilateral hindlimb ischemia

Purpose: Hepatic dysfunction may contribute to death from multiple organ dy sfunction after abdominal aortic surgery. Several factors are likely respon sible, and the purpose of this study was to determine whether the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 (IL-1) are invol ved in initiating this remote hepatic injury. Methods: In a normotensive rat model of 4-hour bilateral hindlimb ischemia/ reperfusion (I/R), we measured systemic TNF-alpha and IL-1 levels throughou t the I/R period. Rats were randomly assigned to either the 3-hour control group, the 3-hour I/R group, or the I/R group with administration of a poly clonal antibody (PAb) to TNF-alpha (I/R + TNF-alpha PAb). Direct evidence o f lethal hepatocyte injury through the labeling of nuclei by propidium iodi de (per 10(-1)mm(3)) and altered microvascular perfusion were assessed by u sing intravital microscopy. Results: Systemic TNF-alpha peaked at 83.97 pg/mL (P <.05, n = 5) at 30 min utes of reperfusion and returned to baseline in 60 to 90 minutes. No signif icant change in systemic IL-1 was detected (P <.05, n = 4). Alanine aminotr ansferase increased 2.5-fold in the I/R group through 3 hours of reperfusio n (P <.05, n = 4), and TNF-alpha PAb did not attenuate this alanine aminotr ansferase increase (P <.05, n = 6). Lethal hepatocyte injury increased by 8 -fold in the I/R group compared with the control group (P <.05, n = 5), whe reas TNF-alpha PAb significantly educed this injury (P <.05, n = 4). No reg ion al differences in injury were noted within the acinus. Total perfusion within the microvascular unit did not drop; however, significant now hetero geneity was observed. The proportion of continuously perfused sinusoids dec lined in the I/R group after 3 hours of reperfusion in both periportal (62. 0 +/- 2.2, P <.05) and, to a lesser, although significant, degree, in the p ericentral regions (73.2 +/- 1.73, P <.05). Conclusion: By scavenging extracellular TNF-alpha with a PAb, rye provide d irect evidence that TNF-alpha contributes to, but is not solely responsible for, early remote hepatocellular injury and microvascular dysfunction. The administration of TNF-alpha PAb, reduced lethal hepatocyte injury in both regions of the acinus and also improved perfusion in the periportal region (76.8 +/- 5.41, P <.05), but not in the pericentral region. This suggests t hat TNF-alpha released during reperfusion mediates early remote hepatocellu lar injury and microvascular dysfunction after a remote ischemic insult.