Bench-to-bedside review: Cytopathic hypoxia.
The rate of oxygen consumption by certain tissues is impaired when mice or rats are injected with lipopolysaccharide. A similar change in the rate of oxygen consumption is observed when Caco-2 human enterocyte-like cells are incubated in vitro with cytomix, a cocktail of cytokines containing tumor necrosis factor, IL-1beta, and IFN-gamma. The decrease in the rate of oxygen consumption is not due to a change in oxygen delivery (e.g. on the basis of diminished microvascular perfusion), but rather to an acquired intrinsic defect in cellular respiration, a phenomenon that we have termed 'cytopathic hypoxia'. A number of different biochemical mechanisms have been postulated to account for cytopathic hypoxia in sepsis, including reversible inhibition of cytochrome a,a3 by nitric oxide, and irreversible inhibition of one or more mitochondrial respiratory complexes by peroxynitrite. Recently, however, our laboratory has obtained data to suggest that the most important mechanism underlying the development of cytopathic hypoxia is depletion of cellular stores of nicotinamide adenine dinucleotide (NAD+/NADH) as a result of activation of the enzyme, poly(ADP-ribose) polymerase-1. If cytopathic hypoxia is important in the pathophysiology of established sepsis and multiorgan dysfunction syndrome, then efforts in the future will need to focus on pharmacological interventions designed to preserve normal mitochondrial function and energy production in sepsis.
Fink
Mitchell P
MP
Department of Critical Care Medicine, Watson Chair in Surgery, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, USA. finkmp@anes.upmc.edu
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019069:Cell Respiration; D006801:Humans; D008070:Lipopolysaccharides / Q000009:adverse effects; D028361:Mitochondrial Diseases / Q000378:metabolism / Q000503:physiopathology*; D009243:NAD / Q000378:metabolism; D010085:Oxidative Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism / Q000503:physiopathology*
D008070:Lipopolysaccharides; D009243:NAD; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases