Animal Models of sepsis: setting the stage

Buras, Jon A.; Holzmann, Bernhard; Sitkovsky, Michail V.

doi:10.1038/nrd1854

Cited by 719 publications

(642 citation statements)

References 100 publications

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“…Ampicillin/sulbactam is a bactericidal antibiotic used against abdominal infections that cause septic peritonitis; for example, it is administered prophylactically before elective colorectal surgery. CLP is the most clinically relevant model of septic peritonitis, because of inflammatory responses to both the polymicrobial infections induced by cecal puncture and the ischemic tissue injury resulting from cecal ligation (8). Ampicillin/sulbactam treatment of CLP rats temporarily increases inflammation, as indicated by elevated serum interleukin-6 concentration (44).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Wilson

2013

Antioxidants & Redox Signaling

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Significance: Evidence is emerging that parenteral administration of high-dose vitamin C may warrant development as an adjuvant therapy for patients with sepsis. Recent Advances: Sepsis increases risk of death and disability, but its treatment consists only of supportive therapies because no specific therapy is available. The characteristics of severe sepsis include ascorbate (reduced vitamin C) depletion, excessive protein nitration in microvascular endothelial cells, and microvascular dysfunction composed of refractive vasodilation, endothelial barrier dysfunction, and disseminated intravascular coagulation. Parenteral administration of ascorbate prevents or even reverses these pathological changes and thereby decreases hypotension, edema, multiorgan failure, and death in animal models of sepsis. Critical Issues: Dehydroascorbic acid appears to be as effective as ascorbate for protection against microvascular dysfunction, organ failure, and death when injected in sepsis models, but information about pharmacodynamics and safety in human subjects is only available for ascorbate. Although the plasma ascorbate concentration in critically ill and septic patients is normalized by repletion protocols that use high doses of parenteral ascorbate, and such doses are tolerated well by most healthy subjects, whether such large amounts of the vitamin trigger adverse effects in patients is uncertain. Future Directions: Further study of sepsis models may determine if high concentrations of ascorbate in interstitial fluid have pro-oxidant and bacteriostatic actions that also modify disease progression. However, the ascorbate depletion observed in septic patients receiving standard care and the therapeutic mechanisms established in models are sufficient evidence to support clinical trials of parenteral ascorbate as an adjuvant therapy for sepsis.

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Section: Introductionmentioning

confidence: 99%

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Wilson

2013

Antioxidants & Redox Signaling

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“…iNOS contributed to the disturbances in gastrointestinal motility in early and late endotoxemia, while TNF-α primarily contributed to the disturbances in late endotoxemia. However, sepsis in clinical settings is far more complicated than in this animal model which utilizes the administration of LPS (23). Although we believe that our findings provide important insights into the mechanism of sepsis-induced gastrointestinal motility disturbances, great care should be taken when attempting to extrapolate our results to sepsis-induced gastrointestinal complications in patients.…”

Section: Discussionmentioning

confidence: 86%

Inducible nitric oxide synthase and tumor necrosis factor-alpha in delayed gastric emptying and gastrointestinal transit induced by lipopolysaccharide in mice

Inada¹,

Hamano²,

Yamada³

et al. 2006

Braz J Med Biol Res

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Gastrointestinal motility disturbances during endotoxemia are probably caused by lipopolysaccharide (LPS)-induced factors: candidates include nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1ß, and interleukin-6. Flow cytometry was used to determine the effects of LPS and these factors on gastric emptying (evaluated indirectly by determining percent gastric retention; %GR) and gastrointestinal transit (GIT) in male BALB/c mice (23-28 g). NO (300 µg/mouse, N = 8) and TNF-α (2 µg/mouse, N = 7) increased (P < 0.01) GR and delayed GIT, mimicking the effect of LPS (50 µg/mouse). During early endotoxemia (1.5 h after LPS), inhibition of inducible NO synthase (iNOS) by a selective inhibitor, 1400 W (150 µg/mouse, N = 11), but not antibody neutralization of TNF-α (200 µg/mouse, N = 11), reversed the increase of GR (%GR 78.8 ± 3.3 vs 47.2 ± 7.5%) and the delay of GIT (geometric center 3.7 ± 0.4 vs 5.6 ± 0.2). During late endotoxemia (8 h after LPS), both iNOS inhibition (N = 9) and TNF-α neutralization (N = 9) reversed the increase of GR (%GR 33.7 ± 2.0 vs 19.1 ± 2.6% (1400 W) and 20.1 ± 2.0% (anti-TNF-α)), but only TNF-α neutralization reversed the delay of GIT (geometric center 3.9 ± 0.4 vs 5.9 ± 0.2). These findings suggest that iNOS, but not TNF-α, is associated with delayed gastric emptying and GIT during early endotoxemia and that during late endotoxemia, both factors are associated with delayed gastric emptying, but only TNF-α is associated with delayed GIT. Correspondence

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“…For these reasons, we recommend that in vivo research into the nociceptin system during sepsis employs the use of a longer term polymicrobial model of sepsis. Our future plan is to evaluate a model which induces sepsis via intraperitoneal injection of a faecal slurry as this has been proposed as a more reliable and reproducible model than CLP [4]. …”

Section: Discussionmentioning

confidence: 99%

“…We want to establish an animal model of sepsis that is suitable to evaluate both gene expression changes in NOP and pp/N/OFQ mRNA, and the effects of nociceptin system modulation on survival. The CLP model has been criticized because of its variability within and between studies [2,4]. Hence we hypothesized that LPSinduced sepsis would be a suitable and reproducible model in which to study these potential changes, because by using the same dose and serotype of LPS for each experiment, the inherent variability should be reduced.…”

Section: Introductionmentioning

confidence: 99%

Exploring LPS-induced sepsis in rats and mice as a model to study potential protective effects of the nociceptin/orphanin FQ system

et al. 2014

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The nociceptin receptor (NOP) and its ligand (N/OFQ) have been shown to exert a modulatory effect on immune cells during sepsis. We evaluated the suitability of an experimental Lipopolysaccharide (LPS)-induced sepsis model for studying changes in the nociceptin system. C57BL/6 mice BALB/c mice and Wistar rats were inoculated with different doses of LPS with or without a nociceptin receptor antagonist (UFP-101 or SB-612111). In C57BL/6 mice LPS 0.85 mg/kg injection produced no septic response whereas 1.2 mg/kg produced a profound response within 5 hours. In BALB/c mice, LPS 4 mg/kg produced no response whereas 7 mg/kg resulted in a profound response within 24 hours. In Wistar rats 15 mg/kg LPS caused no septic response in 6/10 animals whereas 25 mg/kg resulted in marked lethargy before 24 hours. Splenic interleukin-1β mRNA in BALB/c mice, and serum TNF-α concentrations in Wistar rats increased after LPS injection in a dosedependent manner, but were undetectable in control animals, indicating that LPS had stimulated an inflammatory reaction. IL-1β and TNF-α concentrations in LPS-treated animals were unaffected by administration of a NOP antagonist. Similarly NOP antagonists had no effect on survival or expression of mRNA for NOP or ppN/OFQ (the N/OFQ precursor) in a variety of tissues. In these animal models, the dose-response curve for LPS was too steep to allow use in survival studies and no changes in the N/OFQ system occurred within 24 hours. We conclude that LPS-inoculation in rodents is an unsuitable model for studying possible changes in the NOP-N/OFQ system in sepsis. Highlights• We assessed the responses to different doses of lipopolysaccharide (LPS) in C57BL/6 mice, BALB/c mice and Wistar rats.• No symptoms of illness were observed at 24 hours with lower doses of LPS • Higher doses of LPS produced pronounced lethargy before 24 hours.• LPS administration had no effect on the gene expression of the nociceptin/orphanin FQ (N/OFQ) receptor NOP and the N/OFQ receptor precursor ppN/OFQ.• This model is not suitable to study the effects of nociceptin on septic responses 3 IntroductionThe nociceptin system comprises the nociceptin receptor (NOP) and its 17 amino acid peptide ligand N/OFQ, which is cleaved from a precursor protein pre-pro nociceptin (ppN/OFQ) [7]. This system has been linked to many aspects of inflammation and sepsis [10] and has been shown to modulate the cellular response to inflammatory stimuli in animals and humans [12]; in a rat caecal ligation and puncture (CLP) experimental model of sepsis, the administration of exogenous N/OFQ increased mortality whilst NOP receptor blockade significantly reduced mortality [3]. We want to establish an animal model of sepsis that is suitable to evaluate both gene expression changes in NOP and pp/N/OFQ mRNA, and the effects of nociceptin system modulation on survival. The CLP model has been criticized because of its variability within and between studies [2, 4]. Hence we hypothesized that LPSinduced sepsis would be a suitable and reproducible mode...

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Animal Models of sepsis: setting the stage

Cited by 719 publications

References 100 publications

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Inducible nitric oxide synthase and tumor necrosis factor-alpha in delayed gastric emptying and gastrointestinal transit induced by lipopolysaccharide in mice

Exploring LPS-induced sepsis in rats and mice as a model to study potential protective effects of the nociceptin/orphanin FQ system

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