Browsing by Author "Cepinskas, Gediminas"

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    Development and characterization of a fecal-induced peritonitis model of murine sepsis: results from a multi-laboratory study and iterative modification of experimental conditions
    (2023-07-17) Sharma, Neha; Chwastek, Damian; Dwivedi, Dhruva J.; Schlechte, Jared; Yu, Ian-Ling; McDonald, Braedon; Arora, Jaskirat; Cani, Erblin; Eng, Mikaela; Engelberts, Doreen; Kuhar, Eva; Medeiros, Sarah K.; Bourque, Stephane L.; Cepinskas, Gediminas; Gill, Sean E.; Jahandideh, Forough; Macala, Kimberly F.; Panahi, Sareh; Pape, Cynthia; Sontag, David; Sunohara-Neilson, Janet; Fergusson, Dean A.; Fox-Robichaud, Alison E.; Liaw, Patricia C.; Lalu, Manoj M.; Mendelson, Asher A.
    Abstract Background Preclinical 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. Results Escalating 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. Conclusions We 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.
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    National Preclinical Sepsis Platform: developing a framework for accelerating innovation in Canadian sepsis research
    (2021-03-19) Mendelson, Asher A; Lansdell, Casey; Fox-Robichaud, Alison E; Liaw, Patricia; Arora, Jaskirat; Cailhier, Jean-François; Cepinskas, Gediminas; Charbonney, Emmanuel; dos Santos, Claudia; Dwivedi, Dhruva; Ellis, Christopher G; Fergusson, Dean; Fiest, Kirsten; Gill, Sean E; Hendrick, Kathryn; Hunniford, Victoria T; Kowalewska, Paulina M; Krewulak, Karla; Lehmann, Christian; Macala, Kimberly; Marshall, John C; Mawdsley, Laura; McDonald, Braedon; McDonald, Ellen; Medeiros, Sarah K; Muniz, Valdirene S; Osuchowski, Marcin; Presseau, Justin; Sharma, Neha; Sohrabipour, Sahar; Sunohara-Neilson, Janet; Vázquez-Grande, Gloria; Veldhuizen, Ruud A W; Welsh, Donald; Winston, Brent W; Zarychanski, Ryan; Zhang, Haibo; Zhou, Juan; Lalu, Manoj M
    Abstract Despite decades of preclinical research, no experimentally derived therapies for sepsis have been successfully adopted into routine clinical practice. Factors that contribute to this crisis of translation include poor representation by preclinical models of the complex human condition of sepsis, bias in preclinical studies, as well as limitations of single-laboratory methodology. To overcome some of these shortcomings, multicentre preclinical studies—defined as a research experiment conducted in two or more research laboratories with a common protocol and analysis—are expected to maximize transparency, improve reproducibility, and enhance generalizability. The ultimate objective is to increase the efficiency and efficacy of bench-to-bedside translation for preclinical sepsis research and improve outcomes for patients with life-threatening infection. To this end, we organized the first meeting of the National Preclinical Sepsis Platform (NPSP). This multicentre preclinical  research collaboration of Canadian sepsis researchers and stakeholders was established to study the pathophysiology of sepsis and accelerate movement of promising therapeutics into early phase clinical trials. Integrated knowledge translation and shared decision-making were emphasized to ensure the goals of the platform align with clinical researchers and patient partners. 29 participants from 10 independent labs attended and discussed four main topics: (1) objectives of the platform; (2) animal models of sepsis; (3) multicentre methodology and (4) outcomes for evaluation. A PIRO model (predisposition, insult, response, organ dysfunction) for experimental design was proposed to strengthen linkages with interdisciplinary researchers and key stakeholders. This platform represents an important resource for maximizing translational impact of preclinical sepsis research.