Modulation of serum cytokine levels by a novel superoxide dismutase mimetic, M40401, in an Escherichia coli model of septic shock: Correlation with preserved circulating catecholamines*

Macarthur, Heather; Couri, Daniel; Wilken, Gerald H.; Westfall, Thomas C.; Lechner, Andrew J.; Matuschak, George M.; Chen, Zhoumou; Salvemini, Daniela

doi:10.1097/00003246-200301000-00037

Cited by 54 publications

(41 citation statements)

References 39 publications

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“…In combination, these findings with two selective inhibitors of superoxide anion support the central role of this mediator in the pathogenesis of tissue injury related to several different stimuli, including bacterial sepsis. Although superoxide anion contributes to important components in host defense, this and a previous study show that, even with infection, inhibition of superoxide may have beneficial effects if the infectious challenge is sufficiently severe (23). This benefit may, in part, relate to the inhibitory effect that superoxide anion may have on catecholamines and vascular tone (13,26,50).…”

Section: Discussionmentioning

confidence: 56%

“…Control animals received diluent only. The dose of M40401 chosen for the present study was based on published results in a rat model similar to ours, as well as on dose-response studies that we conducted with highly lethal E. coli challenge (23). Both in published studies (7) and in pilot experiments that we performed, M40401 did not result in lethality in sham-challenged controls.…”

Section: M40401 Experimentsmentioning

confidence: 89%

“…Based on the potential role of superoxide anion in the inflammatory injury associated with sepsis, both exogenous SOD preparations and SOD mimetics (SODm) have been proposed as adjunctive treatment for this potentially lethal condition (1,5,6,14,15,17,19,20,23,30,35,36,38,39,41,47,48). However, recent studies with other anti-inflammatory agents in sepsis suggest that the severity of sepsis, as reflected by control mortality rate, could have an important influence on agents directed against superoxide anion (10).…”

mentioning

confidence: 99%

“…Both M40401 and a similar compound, M40403, inhibit superoxide anion-mediated tissue injury related to ischemia-reperfusion, endotoxin, and other inflammatory stimuli (8,9,24,37). Recent studies have also shown that M40401 increases endogenous serum catecholamine levels and IL-10 levels, decreases serum TNF and IL-1 levels, and improves arterial blood pressure and survival in rats challenged with highly lethal (i.e., 83% control mortality rate) intravenous (IV) Escherichia coli challenge (23). In the experiments reported here, animals were randomized to be challenged with doses of IV E. coli designed to produce high-or low-control mortality rates, following which they were treated with M40401 or placebo.…”

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confidence: 99%

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Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model

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Macarthur³

et al. 2004

Journal of Applied Physiology

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of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model. J Appl Physiol 97: 1349 -1357, 2004. First published May 28, 2004 10.1152 10. /japplphysiol.01161.2003 analysis showed that selective inhibitors of five different host inflammatory mediators administered for sepsis, although beneficial with severe sepsis and high-control mortality rates, were ineffective or harmful with less severe sepsis. We hypothesized that severity of sepsis would also influence inhibition of superoxide anion, another inflammatory mediator. To test this, 6-h infusions of M40401, a selective SOD mimetic, or placebo were given to antibiotic-treated rats (n ϭ 547) starting 3 h after challenge with differing doses of intravenous Escherichia coli designed to produce low-or high-control mortality rates. There was a positive and significant (P ϭ 0.0008) relationship between the efficacy of M40401 on survival rate and control mortality rates. M40401 increased or decreased the log (odds ratio of survival) (means Ϯ SE), dependent on whether control mortality rates were greater or less than the median (66%) (ϩ0.19 Ϯ 0.12 vs. Ϫ0.25 Ϯ 0.10, P ϭ 0.01). In a subset of animals examined (n ϭ 152) at 9 h after E. coli challenge, M40401 increased (mean effect Ϯ SE compared with control) mean arterial blood pressure (8 Ϯ 5 mmHg) and decreased platelets (Ϫ37 Ϯ 22 cells ϫ 10 3 /ml) with high-control mortality rates but had opposing effects on each parameter (Ϫ3 Ϯ 3 mmHg and 28 Ϯ 19 cells ϫ 10 3 /ml, respectively) with low rates (P Յ 0.05 for the differing effects of M40401 on each parameter with high-vs. low-control mortality rates). A metaregression analysis of published preclinical sepsis studies testing SOD preparations and SOD mimetics showed that most (16 of 18) had control mortality rates Ͼ66%. However, across experiments from published studies, these agents were less beneficial as control mortality rate decreased (P ϭ 0.03) in a relationship not altered (P ϭ not significant) by other variables associated with septic challenge or regimen of treatment and which was similar, compared with experiments with M40401 (P ϭ not significant). Thus, in these preclinical sepsis models, possibly related to divergent effects on vascular function, inhibition of superoxide anion improved survival with more severe sepsis and high-control mortality rates but was less effective or harmful with less severe sepsis. Extrapolated clinically, inhibition of superoxide anion may be most efficacious in septic patients with severe sepsis and a high risk of death. septic shock; treatments; superoxide dismutase mimetic; M40401

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Section: Discussionmentioning

confidence: 56%

Section: M40401 Experimentsmentioning

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model

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Macarthur³

et al. 2004

Journal of Applied Physiology

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“…The former pathway, however, is unlikely since we were unable to demonstrate a clear-cut removal of proinflammatory cytokines nor a suppression of excessive NO production, as documented by the absence of an effect on plasma nitrate/nitrite levels. In addition, reactive nitrogen/ oxygen species were recently reported to be capable of inducing vascular hyporeactivity and vasodilatory hypotension [30][31][32]. Nevertheless, as haemofiltration failed to affect surrogate markers of sepsis-induced oxidative/ nitrosative stress, it seems conceivable to speculate that the better hemodynamic stability was not related to changes in these downstream pathways.…”

Section: Discussionmentioning

confidence: 99%

High versus standard-volume haemofiltration in hyperdynamic porcine peritonitis: effects beyond haemodynamics?

et al. 2008

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Objective: The role of haemofiltration as an adjunctive treatment of sepsis remains a contentious issue. To address the role of dose and to explore the biological effects of haemofiltration we compared the effects of standard and high-volume haemofiltration (HVHF) in a peritonitis-induced model of porcine septic shock. Design and setting: Randomized, controlled experimental study. Subjects: Twenty-one anesthetized and mechanically ventilated pigs. Interventions: After 12 h of hyperdynamic peritonitis, animals were randomized to receive either supportive treatment (Control, n = 7) or standard haemofiltration (HF 35 ml/ kg per h, n = 7) or HVHF (100 ml/kg per hour, n = 7). Measurements and results: Systemic and hepatosplanchnic haemodynamics, oxygen exchange, energy metabolism (lactate/pyruvate, ketone body ratios), ileal and renal cortex microcirculation and systemic inflammation (TNF-a, IL-6), nitrosative/oxidative stress (TBARS, nitrates, GSH/GSSG) and endothelial/coagulation dysfunction (von Willebrand factor, asymmetric dimethylarginine, platelet count) were assessed before, 12, 18, and 22 h of peritonitis. Although fewer haemofiltration-treated animals required noradrenaline support (86, 43 and 29% animals in the control, HF and HVHF groups, respectively), neither of haemofiltration doses reversed hyperdynamic circulation, lung dysfunction and ameliorated alterations in gut and kidney microvascular perfusion. Both HF and HVHF failed to attenuate sepsisinduced alterations in surrogate markers of cellular energetics, nitrosative/oxidative stress, endothelial injury or systemic inflammation. Conclusions: In this porcine model of septic shock early HVHF proved superior in preventing the development of septic hypotension. However, neither of haemofiltration doses was capable of reversing the progressive disturbances in microvascular, metabolic, endothelial and lung function, at least within the timeframe of the study and severity of the model.

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Bioinspired copper single‐atom nanozyme as a superoxide dismutase‐like antioxidant for sepsis treatment

et al. 2022

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Sepsis is a systemic inflammatory response syndrome with high morbidity and mortality mediated by infection-caused oxidative stress. Early antioxidant intervention by removing excessively produced reactive oxygen and nitrogen species (RONS) is beneficial to the prevention and treatment of sepsis. However, traditional antioxidants have failed to improve patient outcomes due to insufficient activity and sustainability. Herein, by mimicking the electronic and structural characteristics of natural Cu-only superoxide dismutase (SOD5), a single-atom nanozyme (SAzyme) featuring coordinately unsaturated and atomically dispersed Cu-N 4 site was synthesized for effective sepsis treatment. The de novo-designed Cu-SAzyme exhibits a superior SOD-like activity to efficiently eliminate O 2•− , which is the source of multiple RONS, thus blocking the free radical chain reaction and subsequent inflammatory response in the early stage of sepsis. Moreover, the Cu-SAzyme effectively harnessed systemic inflammation and multi-organ injuries in sepsis animal models. These findings indicate that the developed Cu-SAzyme possesses great potential as therapeutic nanomedicines for the treatment of sepsis.

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Modulation of serum cytokine levels by a novel superoxide dismutase mimetic, M40401, in an Escherichia coli model of septic shock: Correlation with preserved circulating catecholamines*

Cited by 54 publications

References 39 publications

Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model

Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model

High versus standard-volume haemofiltration in hyperdynamic porcine peritonitis: effects beyond haemodynamics?

Bioinspired copper single‐atom nanozyme as a superoxide dismutase‐like antioxidant for sepsis treatment

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