Ultrasound-Guided Intrauterine Injection of Lipopolysaccharide as a Novel Model of Preterm Birth in the Mouse

Rinaldi, Sara F.; Makieva, Sofia; Frew, Lorraine; Wade, James B.; Thomson, Adrian; Moran, Carmel M.; Norman, Jane E.; Stock, Sarah

doi:10.1016/j.ajpath.2015.01.009

Cited by 33 publications

(42 citation statements)

References 23 publications

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“…In mice, systemic inflammation can cause progesterone withdrawal due to the regression of the corpus luteum, triggering preterm birth (109). Localized intrauterine inflammation can be induced in mice by injecting agents into the uterine horn between the gestational sacs (88). Most commonly, this has been done by mini-laparotomy to expose the uterine horns (96); however, such procedure could induce adverse pregnancy outcomes due to a rapid localized inflammatory response that surrounds the incision area.…”

Section: Animal Modelsmentioning

confidence: 99%

“…Most commonly, this has been done by mini-laparotomy to expose the uterine horns (96); however, such procedure could induce adverse pregnancy outcomes due to a rapid localized inflammatory response that surrounds the incision area. In the last few years, new less-invasive techniques have been developed, including ultrasound-guided intraamniotic and intrauterine injection of TLR, thus minimizing the effects of surgery (88). Similarly, ultrasound-guided intraamniotic injection has been used in a variety of species.…”

Section: Animal Modelsmentioning

confidence: 99%

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Immunobiology of Acute Chorioamnionitis

2020

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Acute chorioamnionitis is characterized by neutrophilic infiltration and inflammation at the maternal fetal interface. It is a relatively common complication of pregnancy and can have devastating consequences including preterm labor, maternal infections, fetal infection/inflammation, fetal lung, brain, and gastrointestinal tract injury. In this review, we will discuss current understanding of the pathogenesis, immunobiology, and mechanisms of this condition. Most commonly, acute chorioamnionitis is a result of ascending infection with relatively low-virulence organisms such as the Ureaplasma species. Furthermore, recent vaginal microbiome studies suggest that there is a link between vaginal dysbiosis, vaginal inflammation, and ascending infection. Although less common, microorganisms invading the maternal-fetal interface via hematogenous route (e.g., Zika virus, Cytomegalovirus, and Listeria) can cause placental villitis and severe fetal inflammation and injury. We will provide an overview of the knowledge gleaned from different animal models of acute chorioamnionitis and the role of different immune cells in different maternal-fetal compartments. Lastly, we will discuss how infectious agents can break the maternal tolerance of fetal allograft during pregnancy and highlight the novel future therapeutic approaches.

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Section: Animal Modelsmentioning

confidence: 99%

Section: Animal Modelsmentioning

confidence: 99%

Immunobiology of Acute Chorioamnionitis

2020

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“…Specifically, in nonhuman primates, administration of a TLR4 antagonist before LPS challenge inhibited uterine contractility and reduced proinflammatory cytokine production [86]. In mice, TLR4 stimulation induces PTB [87], whereas its blockade reduced LPS-induced PTB [88,89]. Moreover, TLR4 mutant mice are protected from LPS-induced PTB [88,90].…”

Section: Innate Immune Response Receptorsmentioning

confidence: 99%

Inflammation and preterm birth

Cappelletti

Bella

Ferrazzi

et al. 2015

Journal of Leukocyte Biology

243

200

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Preterm birth is the leading cause of neonatal morbidity and mortality. Although the underlying causes of pregnancy-associated complication are numerous, it is well established that infection and inflammation represent a highly significant risk factor in preterm birth. However, despite the clinical and public health significance, infectious agents, molecular trigger(s), and immune pathways underlying the pathogenesis of preterm birth remain underdefined and represent a major gap in knowledge. Here, we provide an overview of recent clinical and animal model data focused on the interplay between infection-driven inflammation and induction of preterm birth. Furthermore, here, we highlight the critical gaps in knowledge that warrant future investigations into the interplay between immune responses and induction of preterm birth.

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“…The timing and frequency of injections also differs throughout studies; we administered a single injection at day 17 of gestation (because LPS injection at this time point leads to preterm delivery (26)), whereas Scharfe and colleagues gave a single injection between days 10 and 14 of gestation. Interestingly, it may be worth noting that despite their findings of fetal resorption, the systemic inflammation that is seen in studies using LPS-induced sPTB models (26) was not observed after administration of fetal DNA. It is possible that the human fetal DNA used could not induce sufficient inflammation to cause sPTB or that the fetal resorption observed was mediated by a pathway induced by injection between days 10 and 14 of gestation, but with a different outcome when stimuli were not introduced until day 17.…”

Section: Discussionmentioning

confidence: 94%

“…Placental DNA was chosen as a stimulus because cff-DNA (using a placental explant method) does not yield enough DNA for the in-vivo studies. Our in-vivo ultrasound guided intra-uterine model of sPTB was chosen because it is minimally invasive, allows for a more precisely targeted injection, and because LPS-injected animals have previously shown high rates of sPTB (26). We hypothesised that this model is more physiologically relevant than the intra-peritoneal injection of stimuli used in previous studies, which found that neither CpG nor mouse placental DNA induced adverse pregnancy outcomes in wildtype mice (27)(28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

Evaluating the Role of Cell-free Fetal DNA in Inflammation and Spontaneous Preterm Birth

van

MacPherson

Davidson

et al. 2017

Preprint

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Preterm birth is the leading cause of neonatal mortality. While spontaneous preterm birth (sPTB) is the cause of over 70% of PTB, the pathogenesis behind sPTB remains unclear. Cellfree fetal DNA (cff-DNA) originates from the placenta and is increased in women who develop PTB. It has been demonstrated that fetal DNA is hypomethylated and is pro-inflammatory. The pro-inflammatory properties of placental-derived DNA, the effects of placental inflammation on the production of cff-DNA, and its significance in the pathogenesis of PTB are unknown.Using a human placental explant model, we analysed the effect of lipopolysaccharide (LPS) stimulation on cff-DNA production, and used the cff-DNA generated by these explants to examine the methylation profile and in-vitro pro-inflammatory properties of cff-DNA. LPS caused significant production of TNF-α from placental explants, but did not significantly increase the cff-DNA production. Placental-derived cff-DNA, was found to have a small proportion of unmethylated CpG motifs, but was more similar to adult DNA than to more highly unmethylated E-coli DNA. However, cff-DNA did not elicit production of inflammatory cytokines (IL-6, IL-8, TNF-α and CXCL10) by peripheral blood mononuclear cells from pregnant women. Furthermore, in contrast to LPS, intra-uterine injections of mouse placental DNA did not decrease time to delivery in an in-vivo mouse PTB model compared to control animals.This study demonstrates that placental inflammation does not increase the production of cff-DNA in placental explants, and cff-DNA alone is not sufficient to elicit an inflammatory response in human PBMC cultures ex-vivo. It also shows that mouse placental DNA does not cause PTB in-vivo. This suggests that cff-DNA might be predominantly an effect of parturition and not a principal causative agent.

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Ultrasound-Guided Intrauterine Injection of Lipopolysaccharide as a Novel Model of Preterm Birth in the Mouse

Cited by 33 publications

References 23 publications

Immunobiology of Acute Chorioamnionitis

Immunobiology of Acute Chorioamnionitis

Inflammation and preterm birth

Evaluating the Role of Cell-free Fetal DNA in Inflammation and Spontaneous Preterm Birth

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