Mice Deficient in Surfactant Protein A (SP-A) and SP-D or in TLR2 Manifest Delayed Parturition and Decreased Expression of Inflammatory and Contractile Genes

Montalbano, Alina P.; Hawgood, Samuel; Mendelson, Carole R.

doi:10.1210/en.2012-1797

Cited by 78 publications

(90 citation statements)

References 82 publications

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“…The majority of the pregnant mice (~84%) delivered 1 to 2 days late or had to be sacrificed at 22.5 dpc because of a failure to deliver spontaneously ( Figure 1A). Thus, a pronounced and statistically significant delay in the time to parturition was observed in SRC-1/-2 dhet females bred to genotypically matched (6,15). To determine whether a deficiency of SRC-1/-2 affected the activation of inflammatory signaling pathways, the proinflammatory transcription factors, NF-κB p65 and p50, were analyzed in myometrial cytoplasmic and nuclear fractions by immunoblotting.…”

Section: Src-1/src-2 Double Deficiency In Mice Results In Delayed Labormentioning

confidence: 99%

“…Near term, increased uterine stretch (12,13) and factors produced by the developing fetus (6,(14)(15)(16) may provide inflammatory stimuli. Previously, we (6) and others (17) suggested that the fetus may provide a signal via pulmonary surfactant, a developmentally regulated, glycerophospholipid-rich lipoprotein produced by pulmonary alveolar type II cells and secreted into AF in increased amounts during late gestation (11).…”

Section: Introductionmentioning

confidence: 99%

“…injection of SP-A caused preterm delivery of fetuses within 6 to 24 hours (6). In mice, targeted deletion of the genes encoding SP-A and the related C-type lectin, SP-D, caused a modest but significant parturition delay and prevented induction of "contractile" genes, oxytocin receptor (Oxtr) and connexin-43 (Cx43, also known as gap junction protein 1 [Gja1]), in myometrium (15). While these findings were compelling, both parents were double KO (dKO) for SP-A and SP-D.…”

Section: Introductionmentioning

confidence: 99%

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Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition

Gao¹,

Rabbitt²,

Condon³

et al. 2015

J. Clin. Invest.

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115

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Section: Src-1/src-2 Double Deficiency In Mice Results In Delayed Labormentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition

Gao¹,

Rabbitt²,

Condon³

et al. 2015

J. Clin. Invest.

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115

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“…The Mendelson group further demonstrated that SP-A promotes parturition by shuttling amniotic fluid macrophages to the myometrium and increasing uterine IL-1β levels. A subsequent study reported that parturition is delayed by an average of 12 hours in the second pregnancies of SP-A-deficient mice (12). However, as both mother and fetuses lacked SP-A, these experiments did not reveal whether fetal SP-A is indeed a signal for parturition.…”

Section: Does the Fetus Have A Say In Gestational Length?mentioning

confidence: 87%

“…Importantly, fetal SRC-1/-2 deficiency led to longer delays in parturition than loss of SP-A alone, indicating that SRC-1 and SRC-2 have other targets that regulate the onset of parturition (12). Because mice completely lacking SRC-1 or SRC-2 die at birth due to respiratory distress and alveolar collapse, Gao and colleagues examined expression of enzymes that catalyze metabolic reactions required for lung development and found that expression of lysophosphatidylcholine acyl transferase 1 (LPCAT1), an enzyme that is responsible for synthesis of surfactant phospho- Figure 1.…”

Section: Remaining Questions and Future Directionsmentioning

confidence: 99%

Fetal-to-maternal signaling to initiate parturition

Reinl¹,

England²

2015

J. Clin. Invest.

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C o m m e n t a r y 2 5 6 9 jci.org Volume 125 Number 7July 2015 Fetal-to-maternal signaling to initiate parturition Erin L. Reinl and Sarah K. EnglandDepartment of Obstetrics and Gynecology -Basic Science Division, Washington University School of Medicine, St. Louis, Missouri, USA. Maternal control of gestational lengthWorldwide, 12% of babies are born preterm (<37 completed weeks of gestation), putting them at increased risk of mortality or lifelong disability. In fact, according to the World Health Organization, preterm birth is the leading cause of death in children under five years of age (1). Unfortunately, the ability to intervene to delay parturition (delivery) is limited. For example, tocolytics, which are used to acutely inhibit uterine contractions, are ineffective for long-term pregnancy maintenance. The successful development of effective interventions requires a more complete understanding of the molecular mechanisms that transition the uterus from a quiescent, noncontractile state during gestation to a highly activated, contractile state during parturition. The transition to activation and parturition is widely accepted as an inflammatory process (reviewed by Shynlova et al., ref. 2). Toward term, myometrial smooth muscle cells (MSMCs) produce chemo kines, such as CCL-2, that attract leukocytes into the myometrium (3). These leukocytes then produce a multitude of cyto kines (e.g., IL-8, TNF-α, IL-6, and IL-1β), thereby activating a feed-forward inflammation pathway (4). Within the MSMCs, cytokines activate the proinflammatory transcription factor NF-κB, which induces expression of several genes that promote parturition. These include receptors for the contraction inducers (uterotonins) oxytocin (5) and prostaglandin F 2 α (PGF 2 α) (6) and the prostaglandin synthase enzyme cyclooxygenase-2 (7). Additionally, NF-κB and mechanical stretch induce expression of the gap junction protein connexin-43 (8) and structural and contractile proteins (9, 10), known collectively as contractionassociated proteins (CAPs). The increased expression of CAPs enhances the sensitivity of the uterus to uterotonins, resulting in forceful and synchronous contractions. Coinciding with the increased NF-κB signaling at term is the downregulation of the antiinflammatory hormone progesterone, which is key for pregnancy maintenance. By lifting the effects of progesterone, either by a reduction in circulating progesterone via luteolysis (rodents) or by a functional withdrawal (humans), labor contractions can initiate. The importance of both progesterone withdrawal and inflammatory signaling is shown by the guaranteed induction of labor by treatment with the antiprogestin RU486 or by intrauterine injection of the endotoxin LPS. Does the fetus have a say in gestational length?In addition to the well-accepted role of the mother's physiology in triggering parturition, a signal from the growing fetus has long been thought to induce the cascade of events required for parturition. Previous work from Carole Mendelson's group (11) demonst...

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Targeting Toll‐like receptor‐4 to tackle preterm birth and fetal inflammatory injury

et al. 2020

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Every year, 15 million pregnancies end prematurely, resulting in more than 1 million infant deaths and long-term health consequences for many children. The physiological processes of labour and birth involve essential roles for immune cells and proinflammatory cytokines in gestational tissues. There is compelling evidence that the mechanisms underlying spontaneous preterm birth are initiated when a premature and excessive inflammatory response is triggered by infection or other causes. Exposure to pro-inflammatory mediators is emerging as a major factor in the 'fetal inflammatory response syndrome' that often accompanies preterm birth, where unscheduled effects in fetal tissues interfere with normal development and predispose to neonatal morbidity. Toll-like receptors (TLRs) are critical upstream gatekeepers of inflammatory activation. TLR4 is prominently involved through its ability to sense and integrate signals from a range of microbial and endogenous triggers to provoke and perpetuate inflammation. Preclinical studies have identified TLR4 as an attractive pharmacological target to promote uterine quiescence and protect the fetus from inflammatory injury. Novel smallmolecule inhibitors of TLR4 signalling, specifically the non-opioid receptor antagonists (+)-naloxone and (+)-naltrexone, are proving highly effective in animal models for preventing preterm birth induced by bacterial mimetic LPS, heat-killed Escherichia coli, or the TLR4-dependent pro-inflammatory lipid, platelet-activating factor (PAF). Here, we summarise the rationale for targeting TLR4 as a master regulator of inflammation in fetal and gestational tissues, and the potential utility of TLR4 antagonists as candidates for preventative and therapeutic application in preterm delivery and fetal inflammatory injury.

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Mice Deficient in Surfactant Protein A (SP-A) and SP-D or in TLR2 Manifest Delayed Parturition and Decreased Expression of Inflammatory and Contractile Genes

Cited by 78 publications

References 82 publications

Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition

Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition

Fetal-to-maternal signaling to initiate parturition

Targeting Toll‐like receptor‐4 to tackle preterm birth and fetal inflammatory injury

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