ROLE OF KUPFFER CELLS IN CHEMICAL TOXICITY

Project Details

Description

Kupffer cells are macrophages that line the hepatic sinusoids.
These cells function to remove foreign and particulate matter
from the portal circulation. In response to tissue injury, Kupffer
cells become activated. They display enhanced biochemical and
functional reactivity and release highly reactive and toxic
mediators. We have been studying the potential role of activated
Kupffer cells and their mediators in chemically induced
hepatotoxicity. For these studies, we focused on the analgesic,
acetaminophen as a model hepatotoxicant. Twenty-four hr
following treatment of rats with acetaminophen, we observed an
infiltration of mononuclear cells into centrilobular regions of the
liver in the absence of necrosis. We hypothesized that these
infiltrated cells consisted of newly recruited and "activated"
macrophages and that they contribute to acetaminophen
hepatotoxicity. In support of this hypothesis, we demonstrated
that Kupffer cells from the livers of acetaminophen treated rats
display morphological and functional characteristics of activated
macrophages. We also showed that macrophage accumulation and
activation in the liver is mediated, in part, by a factor (H-MAF)
released from acetaminophen injured hepatocytes. In addition,
Kupffer cells that accumulate in the liver following
acetaminophen treatment are nonspecifically activated to kill
hepatocytes. Taken together, these data support our model that
activated liver macrophages contribute to hepatotoxicity. It is
the purpose of the present proposal to extend these findings. We
plan to analyze biochemical mechanisms of Kupffer cell
activation following hepatotoxicant treatment. We will also use
the fluorescence activated cell sorter to characterize soluble
immune mediators released by Kupffer cells and hepatocytes, and
to examine the interaction of Kupffer cells with other
inflammatory cells in the liver. These studies should provide
clues on the mechanisms underlying the contribution of Kupffer
cells to chemically-induced hepatotoxicity.
StatusFinished
Effective start/end date12/31/8912/31/12

Funding

  • National Institute of General Medical Sciences: $335,046.00
  • National Institute of General Medical Sciences: $335,046.00
  • National Institute of General Medical Sciences: $344,247.00
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences: $279,806.00
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences: $335,046.00
  • National Institute of General Medical Sciences: $303,503.00
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences: $303,503.00
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences: $303,503.00
  • National Institute of General Medical Sciences: $303,503.00
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences: $33,248.00
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences: $252,857.00
  • National Institute of General Medical Sciences

ASJC

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology
  • Immunology
  • Hepatology

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