Superoxide Generation by Kupffer Cells and Priming of Neutrophils During Reperfusion After Hepatic Ischemia

Abstract

The objective of this study was to identify the cellular source of the vascular oxidant stress in hepatic ischemia-reperfusion injury in male Fischer rats. Nonparenchymal cells (Kupffer cells, endothelial cells) and neutrophils were isolated from postischemic liver lobes by collagenase-pronase digestion followed by centrifugal elutriation. The spontaneous and stimulated generation of superoxide by these cells were subsequently quantified in vitro. Large Kupffer cells from the postischemic lobes spontaneously generated 300% more superoxide than similar cells from control animals. No difference in spontaneous superoxide formation was found when the small Kupffer cells were compared. No other cells isolated from the postischemic lobes or control liver including neutrophils released any detectable superoxide spontaneously. In contrast, small Kupffer cells and neutrophils from the postischemic liver generated significantly more superoxide after stimulation with phorbol ester or opsonized zymosan than the controls. The considerably higher response with zymosan stimulation compared to phorbol ester indicates a particular priming for a receptor-mediated signal transduction pathway during reperfusion. These studies demonstrate that Kupffer cells are the principal source of the oxidant stress during the initial reperfusion phase after hepatic ischemia. The priming of neutrophils during this time may be an important factor for the later neutrophil-induced injury phase.

Peroxiredoxin-6 protects against mitochondrial dysfunction and liver injury during ischemia-reperfusion in mice

“…The injury resulting from warm hepatic I/R has a biphasic pattern. The early phase involves the production of reactive oxygen species (ROS) by Kupffer cells and hepatocytes and leads to an early oxidant-dependent injury (6,13,35). The late phase is characterized by a robust inflammatory cascade, culminating in the recruitment of neutrophils to the liver (11,32).…”

Distinct contributions of CD4+T cell subsets in hepatic ischemia/reperfusion injury

“…This insult can lead to hepatocellular damage and organ dysfunction through the initiation of a biphasic inflammatory response (14). The initial phase of this response is characterized by activation of Kupffer cells and their subsequent production and release of reactive oxygen species, leading to mild hepatocellular injury (15,16). Activated Kupffer cells also induce activation of redox-sensitive transcription factors such as NF-B, which results in release of many proinflammatory mediators (28,42).…”

Blockade of receptor for advanced glycation end product (RAGE) attenuates ischemia and reperfusion injury to the liver in mice

“…Key roles for endogenous inflammatory cells, such as Kupffer cells, in initiating and sustaining oxidant stress and subsequent potent inflammatory responses have been revealed by extensive investigation in multiple model systems of both cold and warm ischemic injury. [1][2][3][4][5] Generation of reactive oxygen species, at least in part by activated liver macrophages, stimulates a second wave of injury, triggered by influx of neutrophils and other inflammatory cells, especially CD4ϩ T cells and macrophages, into the remnant. Subsequently, release of interleukin, tumor necrosis factor-␣ (TNF-␣), and platelet-activating factor and enhanced expression of cell adhesion molecules, such as intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and chemokines provokes inflammation-mediated liver injury.…”