Kupffer cells mediate increased anoxic hepatocellular killing from hyperosmolarity by an oxygen- and prostaglandin-independent mechanism.
The purpose of this study was to evaluate the roles of Kupffer cells, prostaglandin biosynthesis, and glycolytic metabolism in accelerated anoxic cell killing by hyperosmolar stress. Isolated rat livers were perfused with anoxic normosmolar Krebs-Heinseleit bicarbonate buffer (KHB) or anoxic hyperosmolar KHB (+40 mM NaCl). Hyperosmolar KHB accelerated LDH release during anoxia in livers from both fed and fasted rats by as much as 3.7-fold. GdCl(3) pretreatment to inactivate Kupffer cells substantially delayed anoxic LDH release during normosmolar perfusions and blocked entirely the hyperosmolarity-induced acceleration of LDH release. Cyclooxygenase inhibition with indomethacin failed to alter LDH release during anoxia in hyperosmolar KHB. Neither GdCl(3) nor hyperosmolarity changed glycolytic flux during hypoxia, and hyperosmolarity did not change basal oxygen uptake. We conclude that accelerated cell killing in hyperosmolar buffer is a Kupffer cell-dependent event that is independent of oxygen-requiring prostaglandin synthesis, changes of glycolytic flux, and activation of cellular ATP demand. Another as yet unidentified Kupffer cell product appears to mediate the effect of hyperosmolarity of anoxic hepatocellular injury.
Oh
K W
KW
Department of Cell Biology and Anatomy, School of Medicine, University of North Carolina at Chapel Hill, CB#7090, 236 Taylor Hall, Chapel Hill, NC 27599-7090, USA.
Currin
R T
RT
Lemasters
J J
JJ
D000818:Animals; D004435:Eating; D005215:Fasting; D005682:Gadolinium / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007728:Kupffer Cells / Q000166:cytology / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010100:Oxygen / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012462:Saline Solution, Hypertonic / Q000494:pharmacology*; D013997:Time Factors
D011453:Prostaglandins; D012462:Saline Solution, Hypertonic; D005682:Gadolinium; D007770:L-Lactate Dehydrogenase; C038958:gadolinium chloride; D010100:Oxygen; D007213:Indomethacin