Rapid onset of severe septic shock in the pregnant mouse†

Zöllner, Julia; Lambden, Simon; Nasri, Noor Mohd; Leiper, James; Johnson, Mark R.

doi:10.1093/biolre/ioy193

Cited by 6 publications

(7 citation statements)

References 29 publications

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“…Previously, we reported that the administration of the bacterial wall component, lipopolysaccharide (LPS), to pregnant mice resulted in marked hypotension, but had no effect in non-pregnant mice [3]. We extended these findings using caecal ligation and puncture (CLP), showing that pregnant mice had a more marked hypotensive response and a higher mortality [4]. Earlier, in a mouse model of inflammation-induced preterm labour (PTL) based on an intrauterine injection of LPS, Elovitz and Mrinalini reported that progesterone (P4) supplementation, in the form of 17-alpha hydroxyprogesterone caproate , was associated with a dose dependent increase in maternal mortality of between 50-75% [5].…”

Section: Introductionmentioning

confidence: 90%

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LPS-Induced Hypotension in Pregnancy: The Effect of Progesterone Supplementation

Zöllner

Howe

Edey

et al. 2020

Shock

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Our previous work has shown that pregnancy exacerbates the hypotensive response to both infection and LPS. The high levels of progesterone (P4) associated with pregnancy have been suggested to be responsible for the pregnancy-induced changes in the cardiovascular response to infection. Here, we test the hypothesis that P4 supplementation exacerbates the hypotensive response of the maternal cardiovascular to LPS. Female CD1 mice had radiotelemetry probes implanted to measure haemodynamic function non-invasively and were time-mated. From day 14 of pregnancy, mice received either 10mg of P4 or vehicle alone per day and on day 16, intraperitoneal LPS (10µg of serotype 0111:B4) was injected. In two identically treated cohorts of mice, tissue and serum (for RNA, protein studies) were collected at 6 and 12 hours. Administration of LPS resulted in a fall in blood pressure in vehicle treated, but not P4 supplemented mice. This occurred with similar changes in the circulating levels of cytokines, vasoactive factors and in both circulating and tissue inflammatory cell numbers, but with reduced left ventricular expression of cytokines in P4-supplemented mice. However, left ventricular expression of markers of cardiac dysfunction and apoptosis were similar. This study demonstrates that P4 supplementation prevented LPS-induced hypotension in pregnant mice in association with reduced myocardial inflammatory cytokine gene expression. These observations suggest that rather than being detrimental, P4 supplementation has a protective effect on the maternal cardiovascular response to sepsis.

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Section: Introductionmentioning

confidence: 90%

“…Macrophage numbers were studied in uterus and placenta only. The detailed methods have been described previous[4] and the antibodies used listed in Supplementary table 1, http://links.lww.com/SHK/A861. Multiplex Assay: Mouse cytokine/chemokine or angiogenesis/growth factor magnetic bead panel (Merck Millipore) were used according to manufacturer's protocol.…”

mentioning

confidence: 99%

LPS-Induced Hypotension in Pregnancy: The Effect of Progesterone Supplementation

Zöllner

Howe

Edey

et al. 2020

Shock

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“…[ 27 ]. A maternal septic response with increased maternal mortality in mice, however, is not detected until very high doses of LPS (10 to 40 mg/kg) are given [ 29 ]. Our mouse model is similar to a late pregnancy MIR model, by not causing overt maternal morbidity or mortality.…”

Section: Discussionmentioning

confidence: 99%

Inflammation-induced alterations in maternal-fetal Heme Oxygenase (HO) are associated with sustained innate immune cell dysregulation in mouse offspring

et al. 2021

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Heme oxygenase-1 (HO-1) is an evolutionarily conserved stress response enzyme and important in pregnancy maintenance, fetal and neonatal outcomes, and a variety of pathologic conditions. Here, we investigated the effects of an exposure to systemic inflammation late in gestation [embryonic day (E)15.5] on wild-type (Wt) and HO-1 heterozygous (Het, HO-1+/-) mothers, fetuses, and offspring. We show that alterations in fetal liver and spleen HO homeostasis during inflammation late in gestation can lead to a sustained dysregulation of innate immune cell populations and intracellular myeloid HO-1 expression in the spleen through young adolescence [postnatal day 25] in mice.

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“…This model showed again that pregnancy was associated with a more marked hypotensive response and greater mortality [51]. In the group’s latest study, the administration of a broad-spectrum antibiotic and a vascular smooth muscle specific inhibitor of nitric oxide synthesis was associated with improved outcomes [52]. Hypotheses attributing these to the unique nature of the obstetric immune and cardiovascular milieu are prevalent but are yet to be validated.…”

Section: Maternal Sepsismentioning

confidence: 99%

“…Using animal models, researchers have developed experiments to reduce systemic inflammation as it is thought excessive immune cell trafficking may contribute to maternal morbidity in sepsis, rather than ineffective bacterial clearance. Using a murine model of polymicrobial sepsis in pregnancy, C-C chemokine receptor type 2 (CCR2), which is a monocyte chemoattractant receptor, knockout mice have reduced inflammatory cell trafficking, but increased bacteraemia and worse survival [52]. The same group have also shown that pregnancy in the mouse is associated with a more marked hypotensive response to LPS [51].…”

Section: Maternal Sepsismentioning

confidence: 99%

Sepsis: Precision-Based Medicine for Pregnancy and the Puerperium

Greer

Shah

Sriskandan

et al. 2019

IJMS

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Sepsis contributes significantly to global morbidity and mortality, particularly in vulnerable populations. Pregnant and recently pregnant women are particularly prone to rapid progression to sepsis and septic shock, with 11% of maternal deaths worldwide being attributed to sepsis. The impact on the neonate is considerable, with 1 million neonatal deaths annually attributed to maternal infection or sepsis. Pregnancy specific physiological and immunological adaptations are likely to contribute to a greater impact of infection, but current approaches to the management of sepsis are based on those developed for the non-pregnant population. Pregnancy-specific strategies are required to optimise recognition and management of these patients. We review current knowledge of the physiology and immunology of pregnancy and propose areas of research, which may advance the development of pregnancy-specific diagnostic and therapeutic approaches to optimise the care of pregnant women and their babies.

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Rapid onset of severe septic shock in the pregnant mouse†

Cited by 6 publications

References 29 publications

LPS-Induced Hypotension in Pregnancy: The Effect of Progesterone Supplementation

LPS-Induced Hypotension in Pregnancy: The Effect of Progesterone Supplementation

Inflammation-induced alterations in maternal-fetal Heme Oxygenase (HO) are associated with sustained innate immune cell dysregulation in mouse offspring

Sepsis: Precision-Based Medicine for Pregnancy and the Puerperium

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