Animal models of sepsis

Fink, Mitchell P

doi:10.4161/viru.26083

Cited by 391Sepsis Diagnosis and TreatmentInflammation biomarkers and pathwaysAnimal testing and alternatives

Animal models of sepsis

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Fink, Mitchell P·2014·Virulence

DOI 10.4161/viru.26083PMC PMC3916368

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Abstract

Sepsis remains a common, serious, and heterogeneous clinical entity that is difficult to define adequately. Despite its importance as a public health problem, efforts to develop and gain regulatory approval for a specific therapeutic agent for the adjuvant treatment of sepsis have been remarkably unsuccessful. One step in the critical pathway for the development of a new agent for adjuvant treatment of sepsis is evaluation in an appropriate animal model of the human condition. Unfortunately, the animal models that have been used for this purpose have often yielded misleading findings. It is likely that there are multiple reasons for the discrepancies between the results obtained in tests of pharmacological agents in animal models of sepsis and the outcomes of human clinical trials. One of important reason may be that the changes in gene expression, which are triggered by trauma or infection, are different in mice, a commonly used species for preclinical testing, and humans. Additionally, many species, including mice and baboons, are remarkably resistant to the toxic effects of bacterial lipopolysaccharide, whereas humans are exquisitely sensitive. New approaches toward the use of animals for sepsis research are being investigated. But, at present, results from preclinical studies of new therapeutic agents for sepsis must be viewed with a degree of skepticism.

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High doses of endotoxin in blood cause a 'cytokine storm', septic shock and death, via activating TLR4, RAGE and caspases.
“High doses of endotoxin in blood (endotoxemia) cause a ‘cytokine storm’, septic shock and death, via activating TLR4, RAGE and caspases [16, 18, 20, 21].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [16]
Endotoxin is released by bacteria and its toxicity is due to the host's inflammatory over-reaction rather than an intrinsic toxicity to animal cells.
“we now know that (i) endotoxin is released by bacteria and (ii) the toxicity of endotoxin is due to the host’s inflammatory over-reaction to it, rather than an intrinsic toxicity to animal cells [3, 16, 18].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [16]
Humans are orders of magnitude more sensitive to endotoxin than other mammals, such as mice.
“Humans are orders of magnitude more sensitive to endotoxin than other mammals, such as mice [16].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [16]

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Effects of recombinant dimeric TNF receptor on human inflammatory responses following intravenous endotoxin administration
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Treatment of Severe Systemic Inflammatory Response Syndrome and Sepsis With a Novel Bradykinin Antagonist, Deltibant (CP-0127) Results of a Randomized, Double-blind, Placebo-Controlled Trial
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Confirmatory platelet-activating factor receptor antagonist trial in patients with severe Gram-negative bacterial sepsis
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CDP571, a humanized antibody to human tumor necrosis factor-alpha
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Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial*
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Effect of Pentoxifylline in Severe Sepsis
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RODENT MODELS OF INTRA-ABDOMINAL INFECTION
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A Controlled Trial of HA-1A in a Canine Model of Gram-negative Septic Shock
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Characterization of a Hyperdynamic Murine Model of Resuscitated Sepsis Using Echocardiography
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Hemopexin down-regulates LPS-induced proinflammatory cytokines from macrophages
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Interleukin 10 reduces mortality from severe peritonitis in mice
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BCG-induced enhancement of endotoxin sensitivity in C3H/HeJ mice. I. In vivo studies.
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Anti-inflammatory response is associated with mortality and severity of infection in sepsis
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Delayed Treatment with Recombinant Human Tissue Factor Pathway Inhibitor Improves Survival in Rabbits with Gram‐Negative Peritonitis
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Endotoxin-binding and -neutralizing properties of recombinant bactericidal/permeability-increasing protein and monoclonal antibodies HA-1A and E5
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Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb, multicenter, randomized, placebo-controlled, clinical trial*
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Phase II multicenter clinical study of the platelet-activating factor receptor antagonist BB-882 in the treatment of sepsis
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Lipid A Receptor TLR4-Mediated Signaling Pathways
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Safety and efficacy of affinity-purified, anti–tumor necrosis factor-α, ovine fab for injection (CytoFab) in severe sepsis*
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A Phase 2 Randomized, Double-Blind, Placebo–Controlled Study of the Safety and Efficacy of Talactoferrin in Patients With Severe Sepsis*
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Molgramostim (GM-CSF) Associated With Antibiotic Treatment in Nontraumatic Abdominal Sepsis
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The activity of tissue factor pathway inhibitor in experimental models of superantigen-induced shock and polymicrobial intra-abdominal sepsis
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Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: Results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial
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Genetic Factors in Leucocyte Responses to Endotoxin: Further Studies in Mice
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EXOGENOUS PLATELET-ACTIVATING FACTOR ACETYLHYDROLASE REDUCES MORTALITY IN MICE WITH SYSTEMIC INFLAMMATORY RESPONSE SYNDROME AND SEPSIS
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Effectiveness of Steroid/Antibiotic Treatment in Primates Administered LD100 Escherichia coli
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DECREASED ORGAN FAILURE IN PATIENTS WITH SEVERE SIRS AND SEPTIC SHOCK TREATED WITH THE PLATELET-ACTIVATING FACTOR ANTAGONIST TCV-309: A PROSPECTIVE, MULTICENTER, DOUBLE-BLIND, RANDOMIZED PHASE II TRIAL
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A Double-Blind Placebo-Controlled Study of an Infusion of Lexipafant (Platelet-Activating Factor Receptor Antagonist) in Patients with Severe Sepsis
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A Critical Role of Leukotriene B4 in Neutrophil Migration to Infectious Focus in Cecal Ligation and Puncture Sepsis
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Of men, not mice
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Scavenger Receptor Class A Plays a Central Role in Mediating Mortality and the Development of the Pro-Inflammatory Phenotype in Polymicrobial Sepsis
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An antagonist of platelet-activating factor suppresses endotoxin-induced tumor necrosis factor and mortality in mice pretreated with carrageenan
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TREATMENT WITH THE PLATELET-ACTIVATING FACTOR ANTAGONIST TCV-309 IN PATIENTS WITH SEVERE SYSTEMIC INFLAMMATORY RESPONSE SYNDROME: A PROSPECTIVE, MULTI-CENTER, DOUBLEBLIND, RANDOMIZED PHASE II TRIAL;
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TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling
Ciesielska, A., Matyjek, M., & Kwiatkowska, K. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03656-y · Cited by 1,420 · see citing works
The Neutrophil's Role During Health and Disease.
Liew, P., & Kubes, P. (2019) · Physiological Reviews · doi:10.1152/physrev.00012.2018 · Cited by 1,032 · see citing works
The endotoxin hypothesis of neurodegeneration
Brown, G. C. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1564-7 · Cited by 457 · see citing works
The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill
Friedrich, O., Reid, M. B., den Berghe, G. V., Vanhorebeek, I., Hermans, G., Rich, M. M., & Larsson, L. (2015) · Physiological Reviews · doi:10.1152/physrev.00028.2014 · Cited by 394 · see citing works
Ceria–Zirconia Nanoparticles as an Enhanced Multi‐Antioxidant for Sepsis Treatment
Soh, M., Kang, D., Jeong, H., Kim, D., Kim, D. Y., Yang, W., Song, C., Baik, S., Choi, I., Ki, S., et al. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201704904 · Cited by 371 · see citing works
Imaging robust microglial activation after lipopolysaccharide administration in humans with PET
Sandiego, C. M., Gallezot, J.-D., Pittman, B., Nabulsi, N., Lim, K., Lin, S.-F., Matuskey, D., Lee, J.-Y., O’Connor, K. C., Huang, Y., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1511003112 · Cited by 356 · see citing works
Current Murine Models of Sepsis
Lewis, A., Seymour, C. W., & Rosengart, M. R. (2016) · Surgical Infections · doi:10.1089/sur.2016.021 · Cited by 299 · see citing works
Sepsis: Inflammation Is a Necessary Evil
Nedeva, C., Menassa, J., & Puthalakath, H. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00108 · Cited by 304 · see citing works
Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases
Wagner, K. M., McReynolds, C. B., Schmidt, W. K., & Hammock, B. D. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.06.006 · Cited by 279 · see citing works
Strategies to improve drug development for sepsis
Fink, M. P., & Warren, H. S. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4368 · Cited by 242 · see citing works
Self-citation
The role of mitochondria in sepsis-induced cardiomyopathy
Stanzani, G., Duchen, M. R., & Singer, M. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.10.011 · Cited by 195 · see citing works
Blood platelets and sepsis pathophysiology: A new therapeutic prospect in critical ill patients?
Dewitte, A., Lepreux, S., Villeneuve, J., Rigothier, C., Combe, C., Ouattara, A., & Ripoche, J. (2017) · Annals of Intensive Care · doi:10.1186/s13613-017-0337-7 · Cited by 194 · see citing works
On the translocation of bacteria and their lipopolysaccharides between blood and peripheral locations in chronic, inflammatory diseases: the central roles of LPS and LPS-induced cell death
Kell, D. B., & Pretorius, E. (2015) · Integrative Biology · doi:10.1039/c5ib00158g · Cited by 160 · see citing works
Murine Models of Sepsis and Trauma: Can We Bridge the Gap?
Stortz, J. A., Raymond, S. L., Mira, J. C., Moldawer, L., Mohr, A. M., & Efron, P. (2017) · ILAR journal · doi:10.1093/ilar/ilx007 · Cited by 150 · see citing works
Like Cures Like: Pharmacological Activity of Anti-Inflammatory Lipopolysaccharides From Gut Microbiome
Lin, T.-L., Shu, C.-C., Chen, Y.-M., Lu, J.-J., Wu, T.-S., Lai, W.-F., Tzeng, C.-M., Lai, H.-C., & Lu, C.-C. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00554 · Cited by 143 · see citing works
The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases
Weinbaum, S., Cancel, L. M., Fu, B. M., & Tarbell, J. M. (2020) · Cardiovascular Engineering and Technology · doi:10.1007/s13239-020-00485-9 · Cited by 150 · see citing works
Abandon the Mouse Research Ship? Not Just Yet!
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Prompt Administration of Antibiotics and Fluids in the Treatment of Sepsis: A Murine Trial*
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Authors: Fink, M. P.
Affiliations: University of California, Los Angeles (US)
Corresponding author: Fink, Mitchell P
Venue: Virulence
Publisher: Informa UK Limited
Published: 2013-08-19
Volume: 5
Issue: 1
Pages: 143-153
ISSN: 2150-5594 (ISSN-L)
2150-5608
DOI: 10.4161/viru.26083
PMC: PMC3916368
OpenAlex: W2065468254
Cited by: 391
References: 125
Citations by year: 2026: 19 · 2025: 22 · 2024: 31 · 2023: 35 · 2022: 31 · 2021: 38 · 2020: 40 · 2019: 46 · 2018: 44 · 2017: 32 · 2016: 21 · 2015: 17 · 2014: 12 · 2013: 3
FWCI: 2.08
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc
Locations: Virulence (publishedVersion, cc-by-nc)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Keywords: sepsis, animal models of sepsis, preclinical drug testing, translational research, lipopolysaccharide toxicity
MeSH terms: Animals, Disease Models, Animal, Humans, Lipopolysaccharides, Monkey Diseases, Papio, Sheep, Sheep Diseases, Sepsis, Mice

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