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Bench-to-bedside review: Cytopathic hypoxia.
1Department of Critical Care Medicine, Watson Chair in Surgery, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, USA. finkmp@anes.upmc.edu
Critical Care (London, England)
|December 21, 2002
Summary
Cytopathic hypoxia impairs cellular respiration during sepsis by depleting nicotinamide adenine dinucleotide (NAD+/NADH) stores. This mitochondrial dysfunction, rather than oxygen delivery issues, is key to sepsis pathophysiology.
Area of Science:
- Biochemistry
- Cellular Respiration
- Pathophysiology
Background:
- Lipopolysaccharide injection in rodents and cytokine incubation of Caco-2 cells impair tissue oxygen consumption.
- This impairment reflects an intrinsic cellular defect, termed 'cytopathic hypoxia', not altered oxygen delivery.
Purpose of the Study:
- To investigate the underlying biochemical mechanisms of cytopathic hypoxia in sepsis.
- To identify the primary cause of impaired cellular respiration during sepsis.
Main Methods:
- Incubation of Caco-2 human enterocyte-like cells with cytomix (tumor necrosis factor, IL-1beta, IFN-gamma).
- Assessment of oxygen consumption rates and cellular energy metabolism.
- Evaluation of potential biochemical pathways including nitric oxide and peroxynitrite inhibition.
Main Results:
- Cytopathic hypoxia is characterized by a decrease in cellular oxygen consumption.
- Depletion of cellular nicotinamide adenine dinucleotide (NAD+/NADH) stores is identified as a critical mechanism.
- Activation of poly(ADP-ribose) polymerase-1 is implicated in NAD+/NADH depletion.
Conclusions:
- Nicotinamide adenine dinucleotide (NAD+/NADH) depletion, driven by poly(ADP-ribose) polymerase-1 activation, is the primary cause of cytopathic hypoxia in sepsis.
- Targeting mitochondrial function and energy production is crucial for future therapeutic strategies in sepsis and multiorgan dysfunction syndrome.