Sustained tolerance to lipopolysaccharide after liver ischemia-reperfusion injury.
Liver ischemia-reperfusion injury (IR) would be expected to alter the capacity of previously ischemic as well as continuously perfused segments that are exposed to circulating inflammatory mediators to respond to a subsequent infectious insult. IR is reported to induce tolerance to subsequent endotoxin stimulation if the lipopolysaccharide (LPS) challenge is delayed until the late, neutrophil-mediated phase of reperfusion. Whether ischemic or perfused liver is differentially affected and whether LPS-tolerance may be overcome by increasing exposure is unknown. We hypothesized that late tolerance after IR reflects a refractory state in which the liver's expression of pro-inflammatory mediators in response to secondary LPS is limited. Precision-cut tissue culture methodology was used to investigate the capacity of rabbit liver to respond to a spectrum of LPS stimulation 24 h after partial IR. Slices from normal liver showed a dose-dependent response to LPS for tumor necrosis factor (TNF-alpha) expression. Slices from both previously ischemic and continuously perfused lobes retained dose responsiveness for TNF-alpha, although TNF-alpha was significantly decreased at high LPS concentrations compared with normal liver. Ischemic liver sustained this blunted response despite extended exposure to LPS, whereas perfused slices recovered responsiveness to high dose LPS with prolonged stimulation. IR induced interleukin-8 in both ischemic and perfused liver, but secondary LPS stimulation did not augment interleukin-8 expression. Hepatic IR induces a late tolerance to secondary LPS challenge in locally ischemic tissue that cannot be overcome by increasing LPS exposure. Nonischemic liver exposed to the systemic effects of IR injury, however, retains a capacity to respond to LPS with sufficient stimulation.
Langdale
Lorrie A
LA
Department of Surgery, University of Washington and VA-PSHC, Seattle, Washington 98108, USA.
Kajikawa
Osamu
O
Frevert
Charles
C
Liggitt
H Denny
HD
D000818:Animals; D007511:Ischemia / Q000517:prevention & control; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000098:blood supply*; D008102:Liver Circulation / Q000187:drug effects; D009924:Organ Culture Techniques; D011817:Rabbits; D015427:Reperfusion Injury / Q000517:prevention & control*
D008070:Lipopolysaccharides; D007770:L-Lactate Dehydrogenase