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Bench-to-bedside review: Cytopathic hypoxia.

Fink MP - Crit Care (2002)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Critical Care Medicine, Watson Chair in Surgery, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, USA. finkmp@anes.upmc.edu

ABSTRACT
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.

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Effect of lipopolysaccharide (LPS) on ileal mucosal O2 consumption. Rats in the NS/NS group were injected at T = 0 hours with normal saline (NS) and were treated with NS. Rats in the LPS/NS group were injected with LPS (5 mg/kg) at T = 0 hours and were treated with NS. Rats in the LPS/AG group were challenged with the same dose of LPS and treated with aminoguanidine (30 mg/kg per dose at T = 1, 3 and 6 hours). Ex vivo O2 consumption was measured at T = 8 hours. Adapted from [24] with permission.
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Figure 4: Effect of lipopolysaccharide (LPS) on ileal mucosal O2 consumption. Rats in the NS/NS group were injected at T = 0 hours with normal saline (NS) and were treated with NS. Rats in the LPS/NS group were injected with LPS (5 mg/kg) at T = 0 hours and were treated with NS. Rats in the LPS/AG group were challenged with the same dose of LPS and treated with aminoguanidine (30 mg/kg per dose at T = 1, 3 and 6 hours). Ex vivo O2 consumption was measured at T = 8 hours. Adapted from [24] with permission.

Mentions: The MTT assay reflects the activity of a number of different dehydrogenases, particularly succinate dehydrogenase [22], and is not a direct measure of mitochondrial O2 consumption per se. Several studies have obtained more direct evidence that cellular or mitochondrial respiration is impaired in animals with sepsis or endotoxemia. For example, Kantrow et al. showed that hepatocytes isolated from septic rats consumed significantly less O2 than did hepatocytes from nonseptic control rats [23]. King et al. subsequently sought to determine whether ileal mucosal O2 consumption is impaired in endotoxemic rats [24]. Rats were injected with either LPS or a similar volume of the saline vehicle. Eight hours later, a strip of ileal mucosa was harvested from the animals and mounted in a polaragraphic chamber, and the rate of O2 consumption determined using standard methods. The rate of O2 consumption was significantly lower for mucosal samples from endotoxemic rats as compared with control rats (Fig. 4). If the endotoxemic rats were treated with aminoguanidine to block iNOS activity, then normal ileal mucosal O2 consumption was preserved. These findings thus provide further support for the notion that the development of cytopathic hypoxia in LPS-challenged rats requires iNOS-dependent NO· production.


Bench-to-bedside review: Cytopathic hypoxia.

Fink MP - Crit Care (2002)

Effect of lipopolysaccharide (LPS) on ileal mucosal O2 consumption. Rats in the NS/NS group were injected at T = 0 hours with normal saline (NS) and were treated with NS. Rats in the LPS/NS group were injected with LPS (5 mg/kg) at T = 0 hours and were treated with NS. Rats in the LPS/AG group were challenged with the same dose of LPS and treated with aminoguanidine (30 mg/kg per dose at T = 1, 3 and 6 hours). Ex vivo O2 consumption was measured at T = 8 hours. Adapted from [24] with permission.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC153437&req=5

Figure 4: Effect of lipopolysaccharide (LPS) on ileal mucosal O2 consumption. Rats in the NS/NS group were injected at T = 0 hours with normal saline (NS) and were treated with NS. Rats in the LPS/NS group were injected with LPS (5 mg/kg) at T = 0 hours and were treated with NS. Rats in the LPS/AG group were challenged with the same dose of LPS and treated with aminoguanidine (30 mg/kg per dose at T = 1, 3 and 6 hours). Ex vivo O2 consumption was measured at T = 8 hours. Adapted from [24] with permission.
Mentions: The MTT assay reflects the activity of a number of different dehydrogenases, particularly succinate dehydrogenase [22], and is not a direct measure of mitochondrial O2 consumption per se. Several studies have obtained more direct evidence that cellular or mitochondrial respiration is impaired in animals with sepsis or endotoxemia. For example, Kantrow et al. showed that hepatocytes isolated from septic rats consumed significantly less O2 than did hepatocytes from nonseptic control rats [23]. King et al. subsequently sought to determine whether ileal mucosal O2 consumption is impaired in endotoxemic rats [24]. Rats were injected with either LPS or a similar volume of the saline vehicle. Eight hours later, a strip of ileal mucosa was harvested from the animals and mounted in a polaragraphic chamber, and the rate of O2 consumption determined using standard methods. The rate of O2 consumption was significantly lower for mucosal samples from endotoxemic rats as compared with control rats (Fig. 4). If the endotoxemic rats were treated with aminoguanidine to block iNOS activity, then normal ileal mucosal O2 consumption was preserved. These findings thus provide further support for the notion that the development of cytopathic hypoxia in LPS-challenged rats requires iNOS-dependent NO· production.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Critical Care Medicine, Watson Chair in Surgery, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, USA. finkmp@anes.upmc.edu

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus