Oxygen tension in the bladder epithelium rises in both high and low cardiac output endotoxemic sepsis

Rosser, David; Stidwill, R; Jacobson, D.; Singer, M

doi:10.1152/jappl.1995.79.6.1878

Cited by 103 publications

(46 citation statements)

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“…Although mitochondrial dysfunction and sustained local oxygenation have been described in tissues obtained from experimentally septic mammals (heart, skeletal muscle, and liver) and human subjects with sepsis (skeletal muscle biopsies) (29)(30)(31)(32)(33)(34), less work has been done to test this hypothesis in sepsis-associated AKI. Prior studies have shown that in the first 1-4 hours after intravenous endotoxin exposure, intrarenal oxygen consumption is unchanged despite reduced delivery (35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice

Tran

Tam²,

Bardia³

et al. 2011

J. Clin. Invest.

426

489

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Sepsis-associated acute kidney injury (AKI) is a common and morbid condition that is distinguishable from typical ischemic renal injury by its paucity of tubular cell death. The mechanisms underlying renal dysfunction in individuals with sepsis-associated AKI are therefore less clear. Here we have shown that endotoxemia reduces oxygen delivery to the kidney, without changing tissue oxygen levels, suggesting reduced oxygen consumption by the kidney cells. Tubular mitochondria were swollen, and their function was impaired. Expression profiling showed that oxidative phosphorylation genes were selectively suppressed during sepsis-associated AKI and reactivated when global function was normalized. PPARγ coactivator-1α (PGC-1α), a major regulator of mitochondrial biogenesis and metabolism, not only followed this pattern but was proportionally suppressed with the degree of renal impairment. Furthermore, tubular cells had reduced PGC-1α expression and oxygen consumption in response to TNF-α; however, excess PGC-1α reversed the latter effect. Both global and tubule-specific PGC-1α-knockout mice had normal basal renal function but suffered persistent injury following endotoxemia. Our results demonstrate what we believe to be a novel mechanism for sepsis-associated AKI and suggest that PGC-1α induction may be necessary for recovery from this disorder, identifying a potential new target for future therapeutic studies.

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Section: Discussionmentioning

confidence: 99%

PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice

Tran

Tam²,

Bardia³

et al. 2011

J. Clin. Invest.

426

489

View full text Add to dashboard Cite

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“…During endotoxinemia and sepsis, glycolytic ATP production was increased (5). Apparently, OxPhos was inhibited, although increased tissue oxygen levels suggest cellular availability of O 2 (6), indicating a decrease of oxygen utilization (7,8).…”

mentioning

confidence: 99%

Tumor Necrosis Factor α Inhibits Oxidative Phosphorylation through Tyrosine Phosphorylation at Subunit I of Cytochrome c Oxidase

Samavati

Lee

Mathes

et al. 2008

Journal of Biological Chemistry

174

152

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Mitochondrial oxidative phosphorylation provides most cellular energy. As part of this process, cytochrome c oxidase (CcO) pumps protons across the inner mitochondrial membrane, contributing to the generation of the mitochondrial membrane potential, which is used by ATP synthase to produce ATP. During acute inflammation, as in sepsis, aerobic metabolism appears to malfunction and switches to glycolytic energy production. The pro-inflammatory cytokine tumor necrosis factor ␣ (TNF␣) has been shown to play a central role in inflammation. We hypothesized that TNF␣-triggered cell signaling targets CcO, which is a central enzyme of the aerobic energy metabolism and can be regulated through phosphorylation. Using total bovine and murine hepatocyte homogenates TNF␣ treatment led to an ϳ60% reduction in CcO activity. In contrast, there was no direct effect of TNF␣ on CcO activity using isolated mitochondria and purified CcO, indicating that a TNF␣-triggered intracellular signaling cascade mediates CcO inhibition. CcO isolated after TNF␣ treatment showed tyrosine phosphorylation on CcO catalytic subunit I and was ϳ50 and 70% inhibited at high cytochrome c concentrations in the presence of allosteric activator ADP and inhibitor ATP, respectively. CcO phosphorylation occurs on tyrosine 304 as demonstrated with a phosphoepitope-specific antibody. Furthermore, the mitochondrial membrane potential was decreased in H2.35 cells in response to TNF␣. Concomitantly, cellular ATP was more than 35 and 64% reduced in murine hepatocytes and H2.35 cells. We postulate that an important contributor in TNF␣-mediated pathologies, such as sepsis, is energy paucity, which parallels the poor tissue oxygen extraction and utilization found in such patients. Pro-inflammatory cytokine TNF␣3 exerts a wide range of inflammatory, immune-modulatory, and metabolic effects. TNF␣ is associated with various diseases such as sepsis, atherosclerosis, and hepatic failure and initiates its biological effects by binding to high affinity cell surface receptors (TNF receptor types 1 and 2) (1). Receptor ligation in different types of cells is associated with an increased production of reactive oxygen species (ROS). It is well documented that TNF␣ increases ROS in the mitochondria and that it does so in the cytoplasm in a NADPHdependent fashion. Mitochondria are considered an early target in TNF␣-induced cytotoxicity, because they appear swollen with a reduction in cristae membrane structure in the early course of endotoxinemia and sepsis (2, 3). It was suggested that early mitochondrial dysfunction and inhibition of the oxidative phosphorylation (OxPhos) system play a pivotal role in impaired O 2 utilization during inflammatory processes (2, 4). During endotoxinemia and sepsis, glycolytic ATP production was increased (5). Apparently, OxPhos was inhibited, although increased tissue oxygen levels suggest cellular availability of O 2 (6), indicating a decrease of oxygen utilization (7,8).The formation of the cellular energy carrier ATP is the result of both anaerob...

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“…Direct and indirect evidence exists for the development of cytopathic hypoxia in sepsis (or related inflammatory conditions, such as endotoxemia) in experimental animals. For example, tissue PO 2 has been shown to increase in rats (33) and pigs (42) infused with purified lipopolysaccharide (LPS) and also in human patients with septic shock (5). In an indirect way, these data suggest that the ability of cells to extract O 2 from arterial blood is impaired in these conditions, which are associated with systemic inflammation.…”

mentioning

confidence: 99%

Liposomal NAD⁺prevents diminished O₂consumption by immunostimulated Caco-2 cells

Khan

Delude

Han

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Accumulating data support the view that sepsis is associated with an acquired intrinsic derangement in the ability of cells to consume O 2, a phenomenon that has been termed "cytopathic hypoxia." We sought to use an in vitro "reductionist" model system using cultured cells stimulated with proinflammatory cytokines to test the hypothesis that cytopathic hypoxia is mediated, at least in part, by depletion of intracellular levels of NAD ϩ / NADH secondary to activation of the nuclear enzyme poly-(ADP-ribose) polymerase (PARP). We measured O2 consumption by Caco-2 enterocytes growing on microcarrier beads after cells were incubated for 24 h under control conditions or with cytomix, a mixture of tumor necrosis factor-␣, interleukin-1␤, and interferon-␥. Immunostimulated cells consumed O2 at about one-half the rate of control cells, but this effect was largely prevented if any one of the following pharmacological agents was present during the period of incubation with cytomix: 4,5-dihydroxy-1,3-benzene disulfonic acid, a superoxide radical anion scavenger; 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, a nitric oxide scavenger; 5,10,15,20-HCl, a chemically dissimilar and more potent PARP inhibitor. The decrease in O 2 uptake induced by cytomix was associated with decreased cellular levels of NAD ϩ /NADH. The decrease in cellular NAD ϩ /NADH content and the decrease in O2 uptake induced by cytomix were completely abrogated if liposome-encapsulated NAD ϩ was added to the cultures during immunostimulation. Empty liposomes also increased O2 uptake by immunostimulated Caco-2 cells, but much less effectively than liposomes containing NAD ϩ . These data are consistent with the view that enterocytes exposed to proinflammatory cytokines consume less O2 due to NAD ϩ /NADH depletion secondary to activation of PARP by ONOO Ϫ or other oxidants.poly(ADP-ribose) polymerase; nitric oxide; peroxynitrite; enterocyte; epithelium; intestinal ACCUMULATING DATA SUPPORT the view that sepsis is associated with an acquired intrinsic derangement in the ability of cells to consume O 2 . This phenomenon has been termed "cytopathic hypoxia" (15). Direct and indirect evidence exists for the development of cytopathic hypoxia in sepsis (or related inflammatory conditions, such as endotoxemia) in experimental animals. For example, tissue PO 2 has been shown to increase in rats (33) and pigs (42) infused with purified lipopolysaccharide (LPS) and also in human patients with septic shock (5). In an indirect way, these data suggest that the ability of cells to extract O 2 from arterial blood is impaired in these conditions, which are associated with systemic inflammation. More direct evidence comes from a study performed by Kantrow et al. (22), where it was shown that the rate of O 2 consumption by hepatocytes isolated from septic rats was less than that by liver cells from control rats. More recently, King et al. (25), working in our laboratory, showed that ex vivo O 2 consumption by ileal mucosa was decreased (relative to the norm...

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Oxygen tension in the bladder epithelium rises in both high and low cardiac output endotoxemic sepsis

Cited by 103 publications

References 0 publications

PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice

PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice

Tumor Necrosis Factor α Inhibits Oxidative Phosphorylation through Tyrosine Phosphorylation at Subunit I of Cytochrome c Oxidase

Liposomal NAD⁺prevents diminished O₂consumption by immunostimulated Caco-2 cells

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Oxygen tension in the bladder epithelium rises in both high and low cardiac output endotoxemic sepsis

Cited by 103 publications

References 0 publications

PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice

PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice

Tumor Necrosis Factor α Inhibits Oxidative Phosphorylation through Tyrosine Phosphorylation at Subunit I of Cytochrome c Oxidase

Liposomal NAD+prevents diminished O2consumption by immunostimulated Caco-2 cells

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Liposomal NAD⁺prevents diminished O₂consumption by immunostimulated Caco-2 cells