Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis

Osuchowski, Marcin F.; Ayala, Alfred; Bahrami, Soheyl; Bauer, Michael; Boros, Mihály; Cavaillon, Jean‐Marc; Chaudry, Irshad H.; Coopersmith, Craig M.; Deutschman, Clifford S.; Drechsler, Susanne; Efron, Philip A.; Frostell, Claes; Fritsch, Gerhard; Goździk, Waldemar; Hellman, Judith; Huber‐Lang, Markus; Inoue, Shigeaki; Knapp, Sylvia; Kozlov, Andrey V.; Libert, Claude; Marshall, John C.; Moldawer, Lyle L.; Radermacher, Peter; Redl, Heinz; Remick, Daniel G.; Singer, Mervyn; Thiemermann, Christoph; Wang, Ping; Wiersinga, W. Joost; Xiao, Xianzhong; Zingarelli, Basilia

doi:10.1007/s15010-018-1183-8

Cited by 59 publications

(67 citation statements)

References 22 publications

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“…Furthermore, as the goal is often to study short-term survival, animal models have been designed such that only a minority of animals survive the insult. These limitations have been addressed in a recent expert consensus initiative for improving animal modeling in sepsis, which aims to improve the translation of preclinical findings 84 .…”

Section: Additional Areas Of Focusmentioning

confidence: 99%

Understanding and Enhancing Sepsis Survivorship. Priorities for Research and Practice

Prescott

Iwashyna

Blackwood

et al. 2019

Am J Respir Crit Care Med

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111

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An estimated 14.1 million patients survive sepsis hospitalization each year. Many survivors experience poor long-term outcomes, including new or exacerbated neuropsychological impairment, functional disability, and heightened vulnerability to further health deterioration, including recurrent infection, cardiovascular events, and acute renal failure. However, current guidelines and interventional trials have focused on shorter-term survival, so there is little data on how to best promote longer-term recovery. To address this unmet need, a Colloquium on "Understanding and Enhancing Sepsis Survivorship" was held in February 2018, sponsored by the International Sepsis Forum. The goals of the Colloquium were to identify (1) gaps and limitations of current research, (2) shorter-term research priorities, and (3) longer-term research priorities for understanding and enhancing sepsis survivorship, informed by review of the literature and expert opinion. A total of 26 experts from 8 countries participated. The top three short-term priorities were to better leverage existing databases for research, to develop and disseminate educational resources on post-sepsis morbidity, and to build deep connections with sepsis survivors to define and achieve research priorities. The top longer-term priorities were to link mechanisms to long-term outcomes through large cohort studies with deep phenotyping, build a harmonized global sepsis registry from which patients could be enrolled into cohort studies or interventional trials, and to complete detailed longitudinal follow-up to characterize the heterogeneity of recovery experiences across sepsis survivors. This Perspective reports on the Colloquium discussions, the rationale for the research priorities, and current initiatives addressing these priorities.

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Section: Additional Areas Of Focusmentioning

confidence: 99%

Understanding and Enhancing Sepsis Survivorship. Priorities for Research and Practice

Prescott

Iwashyna

Blackwood

et al. 2019

Am J Respir Crit Care Med

Self Cite

111

View full text Add to dashboard Cite

show abstract

“…at 26°C [15]. Importantly, recent guidelines for preclinical studies in sepsis research [32,33] and cerebrovascular research [34][35][36], with the emphasis to improve reproducibility and translational impact, neglected the impact of ambient temperature on pathogenesis of inflammatory diseases or did not consider that their recommended lower baseline limit for housing temperatures of small rodents causes chronic 'cold' stress [37,38]. Furthermore, ignoring the role of ambient temperature on basal physiological responsiveness in small animals frequently used in preclinical sepsis models leads to far-reaching repercussions of profound misinterpretation: Time course of body temperature lowering and development of hypothermia is used for prognosis prediction while mice are under chronic cold stress for mice [39][40][41][42][43].…”

Section: Discussionmentioning

confidence: 99%

Impact of Ambient Temperature on Inflammation-induced Encephalopathy in Endotoxemic Mice—Role of Phosphoinositide 3-Kinase Gamma

Lang

Ndongson-Dongmo

Lajqi

et al. 2020

Preprint

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Background: Sepsis-associated encephalopathy (SAE) is an early and frequent event of infection-induced systemic inflammatory response syndrome. Phosphoinositide 3-kinase γ (PI3Kγ) is linked to neuroinflammation and inflammation-related microglial activity. In homeotherms, variations in ambient temperature (Ta) outside the thermoneutral zone lead to thermoregulatory responses, mainly driven by a gradually increasing sympathetic activity, and may affect disease severity. We hypothesized that thermoregulatory response to hypothermia (reduced Ta) aggravates SAE in PI3Kγ-dependent manner.Methods: Experiments were performed in wild-type, PI3Kγ knockout, and PI3Kγ kinase-dead mice, which were kept at neutral (30±0.5°C) or moderately lowered (26±0.5°C) Ta. Mice were exposed to lipopolysaccharide (LPS, 10 μg/g, from Escherichia coli serotype 055:B5, single intraperitoneal injection) - evoked systemic inflammatory response (SIR) and monitored 24 hours for thermoregulatory response and blood–brain barrier integrity. Primary microglial cells and brain tissue derived from treated mice were analyzed for inflammatory responses and related cell functions. Comparisons between groups were made with one-way or two-way analysis of variance, as appropriate. Post hoc comparisons were made with the Holm–Sidak test or t-tests with Bonferroni’s correction for adjustments of multiple comparisons. Data not following normal distribution was tested with Kruskal-Wallis test followed by Dunn’s multiple comparisons test.Results: We show that a moderate reduction of ambient temperature triggers enhanced hypothermia of mice undergoing LPS-induced systemic inflammation by aggravated SAE. PI3Kγ deficiency enhances blood–brain barrier injury and upregulation of matrix metalloproteinases (MMPs) as well as an impaired microglial phagocytic activity.Conclusions: Thermoregulatory adaptation in response to ambient temperatures below the thermoneutral range exacerbates LPS-induced blood–brain barrier injury and neuroinflammation. PI3Kγ serves a protective role in suppressing release of MMPs, maintaining microglial motility and reinforcing phagocytosis leading to improved brain tissue integrity. Thus, preclinical research targeting severe brain inflammation responses is seriously biased when basic physiological prerequisites of mammal species such as preferred ambient temperature are ignored.

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“…Mice were observed every 12 h during the 7‐day period and survival rates were recorded. All procedures follow the recommendations of the international expert consensus initiative for minimum quality threshold in preclinical sepsis studies (MQTiPSS) …”

Section: Methodsmentioning

confidence: 99%

Preexisting malignancy abrogates the beneficial effects of CXCR4 blockade during sepsis

Zhang

Chihade

Xie

et al. 2020

Journal of Leukocyte Biology

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Patients with cancer are at an increased risk of developing and dying from sepsis. We previously reported that blockade of the chemokine receptor CXCR4 resulted in decreased CD4+ T cell exhaustion and improved survival in a model of polymicrobial sepsis in previously healthy mice. Here, we sought to determine whether CXCR4 blockade could improve mortality and immune dysregulation during sepsis complicated with malignancy. Results in animals inoculated with a lung cancer cell line and subjected to CLP 3 weeks later indicated that CXCR4 was up‐regulated on naïve and central memory T cells following sepsis. Of note, and in contrast to results in previously healthy mice, CXCR4 blockade failed to improve survival in cancer septic animals; instead, it actually significantly worsened survival. In the setting of cancer, CXCR4 blockade failed to result in T cell egress from the bone marrow, reverse lymphopenia in the spleen, or reverse T cell exhaustion. Mechanistically, elevated expression of CD69 on naïve T cells in the bone marrow of cancer septic animals was associated with their inability to egress from the bone marrow in the setting of CXCR4 blockade. In conclusion, these results illuminate the differential impact of CXCR4 blockade on sepsis pathophysiology in the setting of cancer and highlight the need for personalized therapy during sepsis.

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Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis

Cited by 59 publications

References 22 publications

Understanding and Enhancing Sepsis Survivorship. Priorities for Research and Practice

Understanding and Enhancing Sepsis Survivorship. Priorities for Research and Practice

Impact of Ambient Temperature on Inflammation-induced Encephalopathy in Endotoxemic Mice—Role of Phosphoinositide 3-Kinase Gamma

Preexisting malignancy abrogates the beneficial effects of CXCR4 blockade during sepsis

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