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Articles in PresS, published online ahead of print January 4, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00358.2001
Submitted on September 7, 2001
Accepted on December 14, 2001
1 Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
2 Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Pathology, University of Pittsburgh, Pittsburgh, PA, USA
3 Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
* To whom correspondence should be addressed. E-mail: finkmp{at}anes.upmc.edu.
Sepsis appears to be associated with an acquired intrinsic derangement in the ability of cells to consume O2. We sought to use an in vitro "reductionist" model system using cultured Caco-2 cells stimulated with pro-inflammatory cytokines to test the hypothesis that cytopathic hypoxia is mediated, at least in part, by depletion of intracellular levels of NAD+/NADH secondary to activation of the nuclear enzyme, poly(ADP-ribose) polymerase (PARP). We measured the consumption of O2 by Caco-2 enterocytes growing on micro-carrier beads after the cells were incubated for 24 h under control conditions or with cytomix, a mixture of TNF-
, IL-1ß, and IFN-
. Immunostimulated cells consumed O2 at about half the rate of control cells, but this effect was largely prevented if pharmacological approaches were employed to scavenge superoxide radical anion, scavenge nitric oxide, scavenge or promote the decomposition of peroxynitrite, or inhibit PARP. The decrease in O2 uptake induced by cytomix was associated with decreased cellular levels of NAD+/NADH. Moreover, both the decrease in cellular NAD+/NADH content and the decrease in O2 uptake induced by cytomix was completely abrogated if liposome-encapsulated NAD+ was added to the cultures during the period of immunostimulation. Empty liposomes also increased O2 uptake by immunostimulated Caco-2 cells, but much less effectively than liposomes containing NAD+. These data are consistent with the view that enterocytes exposed to proinflammatory cytokines consume less O2 due to NAD+/NADH depletion secondary to activation of PARP by peroxynitrite or other oxidants.
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