Kupffer Cells and PMNs as Cellular Sources That Contribute to Organ Damage During Endotoxin-Enhanced Hepatic IschemiaReferfusion Injury
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Periods of hepatic ischemia (I) followed by reperfusion (RP) have been demonstrated to produce severe injury which can act as a priming event when combined with a secondary insult such as sepsis, to potentiate more severe injury in the host and lead to a multiple organ failure. To better understand the mechanisms involved in the process and to identify possible cellular sources for reactive oxygen, a series of three related investigations were performed: l) male Fisher rats were exposed to 20 min liver ischemia followed by RP (3 hr) and injection of 0.5 mg/kg Salmonella enteritidis endotoxin (ET); 2) rats were treated as above and treated with 2 mg/kg of monoclonal antibody (WT3), which was directed against adhesion molecule of CD18; 3) rats were treated as above and treated with 7 mg/kg of gadolinium chloride (GdCI3), which inactivated Kupffer cells (KCs). As indicated by an increase of plasma alanine aminotransferase (ALT) activities from 870±122 U /L (I/RP only) to 3900±470 U /L at 4 h RP, postischemic liver injury was potentiated by ET. KCs and polymorphonuclear cells (PMNs) were isolated from the digested liver by centrifugal elutriation (CE). Cells isolated from experimental rats showed more spontaneous 0 2- formation than control cells. To clearly identify the cellular source(s) of reactive oxygen in the experimental model, the effect of KC inhibition with GdCl3 and PMN inactivation with WT3 was examined during the early phase of RP (3h). Inactivation of KCs protected the liver by about 50%. In contrast, PMN inhibition did not show any attenuation in liver injury in the early phase. In addition, when KCs and PMNs were challenged by classical stimulators such as phorbol ester (PMA) or opsonized zymosan (OZ), KCs and PMNs were primed for enhanced superoxide production. The following studies suggest that KCs are responsible for oxidant stress during the initial postischemic injury phase.