Activation of Kupffer cells on reperfusion following hypoxia: particle phagocytosis in a low-flow, reflow model

Abstract

Hypoxia is produced selectively in pericentral regions of the liver lobule with a low-flow, reflow perfusion model in which the flow rate is reduced to approximately one-third to one-fourth of normal. This model was used to monitor carbon particle phagocytosis by Kupffer cells during hypoxia and reoxygenation. At normal flow rates, oxygen uptake was 131 mumol.g-1.h-1, pressure was 7.5 cmH2O, and carbon uptake was 150 mg.g-1.h-1. During the low-flow period, oxygen uptake, pressure, and carbon uptake decreased to values of 54 mumol.g-1.h-1, 6.4 cmH2O and 83 mg.g-1.h-1, respectively. Upon reflow, oxygen uptake and pressure increased to 141 mumol.g-1.h-1 and 10.3 cmH2O, respectively. In addition, carbon uptake was elevated approximately threefold to 234 mg.g-1.h-1, indicating activation of Kupffer cells. This activation was prevented by pretreatment with methyl palmitate, a known inhibitor of Kupffer cells. Histological examination revealed significantly more Kupffer cells laden with carbon particles in untreated livers after reflow than in livers from methyl palmitate-treated or untreated rats. Electron microscopic analysis of livers at reflow revealed Kupffer cells with numerous pseudopodia and lamellapodia, reflecting an activated state. These changes were absent in controls or in livers perfused under low-flow conditions. This study demonstrates that Kupffer cells are activated on reoxygenation after hypoxia.