Development and characterization of a fecal-induced peritonitis model of murine sepsis: results from a multi-laboratory study and iterative modification of experimental conditions

被引：5

作者：

Sharma, Neha ^{[1
,2
]}

Chwastek, Damian J. ^{[3
]}

Dwivedi, Dhruva ^{[1
,4
]}

Schlechte, Jared ^{[5
,6
]}

Yu, Ian-Ling ^{[5
,6
]}

McDonald, Braedon ^{[5
,6
]}

Arora, Jaskirat ^{[1
,2
]}

Cani, Erblin ^{[1
,2
]}

Eng, Mikaela ^{[1
,2
]}

Engelberts, Doreen ^{[3
]}

Kuhar, Eva K. ^{[3
]}

Medeiros, Sarah L. ^{[1
,2
]}

Bourque, Stephane ^{[7
]}

Cepinskas, Gediminas E. ^{[8
,9
]}

Gill, Sean ^{[8
,10
]}

Jahandideh, Forough F. ^{[3
]}

Macala, Kimberly ^{[7
,11
]}

Panahi, Sareh ^{[7
]}

Pape, Cynthia ^{[8
]}

Sontag, David ^{[12
]}

Sunohara-Neilson, Janet A. ^{[13
]}

Fergusson, Dean E. ^{[14
,15
]}

Fox-Robichaud, Alison C. ^{[1
,4
]}

Liaw, Patricia M. ^{[1
,4
]}

Lalu, Manoj A. ^{[3
,15
,16
]}

Mendelson, Asher ^{[12
]}

机构：

[1] Thrombosis & Atherosclerosis Res Inst, Hamilton, ON, Canada

[2] McMaster Univ, Dept Med Sci, Hamilton, ON, Canada

[3] Ottawa Hosp Res Inst, Regenerat Med Program, Ottawa, ON, Canada

[4] McMaster Univ, Dept Med, Hamilton, ON, Canada

[5] Univ Calgary, Snyder Inst Chron Dis, Cumming Sch Med, Calgary, AB, Canada

[6] Univ Calgary, Cumming Sch Med, Dept Crit Care Med, Calgary, AB, Canada

[7] Univ Alberta, Dept Anesthesiol & Pain Med, Edmonton, AB, Canada

[8] Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON, Canada

[9] Western Univ, Schulich Sch Med & Dent, Dept Med Biophys, London, ON, Canada

[10] Western Univ, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON, Canada

[11] Univ Alberta, Royal Alexandra Hosp, Dept Crit Care Med, Edmonton, AB, Canada

[12] Univ Manitoba, Rady Fac Hlth Sci, Hlth Sci Ctr Winnipeg, Dept Med,Sect Crit Care Med, Rm GF-234,820 Sherbrook St, Winnipeg, MB R3A 1R9, Canada

[13] Western Univ, Anim Care & Vet Serv, London, ON, Canada

[14] Univ Ottawa, Fac Med, Ottawa, ON, Canada

[15] Ottawa Hosp Res Inst, Clin Epidemiol Program, Blueprint Translat Grp, POB 201B,501 Smyth Rd, Ottawa, ON K1H 8L6, Canada

[16] Ottawa Hosp, Dept Anesthesiol & Pain Med, Ottawa, ON, Canada

来源：

INTENSIVE CARE MEDICINE EXPERIMENTAL | 2023年 / 11卷 / 01期

关键词：

Sepsis; Preclinical sepsis; Animal models of sepsis; Fecal-induced peritonitis; National Preclinical Sepsis Platform; Multi-laboratory; Preclinical reproducibility; TRIALS; MORTALITY;

D O I：

10.1186/s40635-023-00533-3

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

BackgroundPreclinical sepsis models have been criticized for their inability to recapitulate human sepsis and suffer from methodological shortcomings that limit external validity and reproducibility. The National Preclinical Sepsis Platform (NPSP) is a consortium of basic science researchers, veterinarians, and stakeholders in Canada undertaking standardized multi-laboratory sepsis research to increase the efficacy and efficiency of bench-to-bedside translation. In this study, we aimed to develop and characterize a 72-h fecal-induced peritonitis (FIP) model of murine sepsis conducted in two independent laboratories. The experimental protocol was optimized by sequentially modifying dose of fecal slurry and timing of antibiotics in an iterative fashion, and then repeating the experimental series at site 1 and site 2.ResultsEscalating doses of fecal slurry (0.5-2.5 mg/g) resulted in increased disease severity, as assessed by the modified Murine Sepsis Score (MSS). However, the MSS was poorly associated with progression to death during the experiments, and mice were found dead without elevated MSS scores. Administration of early antibiotics within 4 h of inoculation rescued the animals from sepsis compared with late administration of antibiotics after 12 h, as evidenced by 100% survival and reduced bacterial load in peritoneum and blood in the early antibiotic group. Site 1 and site 2 had statistically significant differences in mortality (60% vs 88%; p < 0.05) for the same dose of fecal slurry (0.75 mg/g) and marked differences in body temperature between groups.ConclusionsWe demonstrate a systematic approach to optimizing a 72-h FIP model of murine sepsis for use in multi-laboratory studies. Alterations to experimental conditions, such as dose of fecal slurry and timing of antibiotics, have clear impact on outcomes. Differences in mortality between sites despite rigorous standardization warrants further investigations to better understand inter-laboratory variation and methodological design in preclinical studies.

引用

页数：17

共 3 条

[1] Development and characterization of a fecal-induced peritonitis model of murine sepsis: results from a multi-laboratory study and iterative modification of experimental conditions
Neha Sharma
Damian Chwastek
Dhruva J. Dwivedi
Jared Schlechte
Ian-Ling Yu
Braedon McDonald
Jaskirat Arora
Erblin Cani
Mikaela Eng
Doreen Engelberts
Eva Kuhar
Sarah K. Medeiros
Stephane L. Bourque
Gediminas Cepinskas
Sean E. Gill
Forough Jahandideh
Kimberly F. Macala
Sareh Panahi
Cynthia Pape
David Sontag
Janet Sunohara-Neilson
Dean A. Fergusson
Alison E. Fox-Robichaud
Patricia C. Liaw
Manoj M. Lalu
Asher A. Mendelson
Intensive Care Medicine Experimental, 11
[2] Impact of age on the host response to sepsis in a murine model of fecal-induced peritonitis
Sharma, Neha
Chen, Alex
Heinen, Leah
Liu, Ruth
Dwivedi, Dhruva J.
Zhou, Ji
Lalu, Manoj M.
Mendelson, Asher A.
McDonald, Braedon
Kretz, Colin A.
Fox-Robichaud, Alison E.
Liaw, Patricia C.
INTENSIVE CARE MEDICINE EXPERIMENTAL, 2024, 12 (01)
[3] Impact of age on the host response to sepsis in a murine model of fecal-induced peritonitis
Neha Sharma
Alex Chen
Leah Heinen
Ruth Liu
Dhruva J. Dwivedi
Ji Zhou
Manoj M. Lalu
Asher A. Mendelson
Braedon McDonald
Colin A. Kretz
Alison E. Fox-Robichaud
Patricia C. Liaw
Intensive Care Medicine Experimental, 12

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