RESUMEN
An increase in telomere shortening in gestational tissues has been proposed as a mechanism involved in the timing for the initiation of parturition. An increase in very short telomeres with increasing gestational age has been observed in mice; this study sought to explore this phenomenon in human pregnancies. Specifically, this study addressed the hypothesis that prior to labor, the quantity of very short telomeres (<3 kilobase (kb) lengths) increases in human placental tissue as term gestation approaches. The primary outcome was the quantity of very short telomeres present in placental tissue. Quantitative measurements of very short telomeres were performed using real-time polymerase chain reaction (qPCR) adaptation of the telomere restriction fragment technique. Placental tissue from 69 pregnant individuals were included. Mean gestational age was 39.1 weeks (term) and 36.2 weeks (preterm). For term versus preterm placentas, the observed increase in very short telomeres were as follows: 500 bp telomeres increased by 1.67-fold (p < 0.03); 1 kb telomeres increased 1.67-fold (p < 0.08); and 3 kb telomeres increased 5.20-fold (p < 0.001). This study confirms a significant increase in very short telomeres in human placental tissue at term; thereby supporting the hypothesis that telomere shortening at term contributes to the mechanism that determine the length of pregnancy thereby leading to onset of parturition.
Asunto(s)
Placenta , Acortamiento del Telómero , Animales , Femenino , Edad Gestacional , Humanos , Lactante , Ratones , Embarazo , Tercer Trimestre del Embarazo , Telómero/genéticaRESUMEN
Telomeres are nucleoprotein complexes located at the distal ends of chromosomes. In adults, progressive telomere shortening occurs throughout the lifetime and is thought to contribute to progressive aging, physiological senescence, multiorgan dysfunction, and ultimately, death. As discussed in this review, multiple lines of evidence provide support for the biological plausibility that a telomere-based clock mechanism also determines the length of gestation, leading to the onset of labor (parturition). After telomere expansion at the beginning of pregnancy, the telomere lengths in the gestational tissues (ie, the placenta and fetal membranes) progressively shorten throughout the remainder of pregnancy. The rate of telomere shortening can be accelerated by conditions that affect the mother and result in oxidative stress. Preterm births in the United States are associated with multiple risk factors that are linked with increased oxidative stress. Antioxidant vitamins (ie, vitamins E and C) mitigate the effects of oxidative stress and delay or prevent telomere shortening. Clinical trials with vitamins E and C and with multivitamins started during the periconception period have been associated with reduced rates of preterm births. In the United States, African-American women have a 2-3-fold higher rate of preterm birth. African-American women have multiple risk factors for premature birth, all of which are distinct and potentially additive with regard to epigenetic telomere shortening. The "weathering effect" is the hypothesis to explain the increased rates of chronic illness, disabilities, and early death observed in African-Americans. With regard to pregnancy, accelerated weathering with the associated telomere shortening in the gestational tissues would not only explain the preterm birth disparity but could also explain why highly educated, affluent African-American women continue to have an increased rate of preterm birth. These studies suggest that the racial disparities in preterm birth are potentially mediated by telomere shortening produced by lifetime or even generational exposure to the effects of systemic racism and socioeconomic marginalization. In conclusion, this review presents multiple lines of evidence supporting a novel hypothesis regarding the biological clock mechanism that determines the length of pregnancy, and it opens the possibility of new approaches to prevent or reduce the rate of spontaneous preterm birth.
Asunto(s)
Trabajo de Parto Prematuro , Nacimiento Prematuro , Adulto , Femenino , Humanos , Recién Nacido , Estrés Oxidativo , Embarazo , Nacimiento Prematuro/epidemiología , Telómero , VitaminasRESUMEN
Cell-free fetal DNA in the maternal circulation has been associated with the onset of labor at term. Moreover, clinical studies have suggested that cell-free fetal DNA has value to predict pregnancy complications such as spontaneous preterm labor leading to preterm birth. However, a mechanistic link between cell-free fetal DNA and preterm labor and birth has not been established. Herein, using an allogeneic mouse model in which a paternal green fluorescent protein (GFP) can be tracked in the fetuses, we established that cell-free fetal DNA (Egfp) concentrations were higher in late gestation compared to mid-pregnancy and were maintained at increased levels during the onset of labor at term, followed by a rapid decrease after birth. A positive correlation between cell-free fetal DNA concentrations and the number of GFP-positive pups was also observed. The increase in cell-free fetal DNA concentrations prior to labor at term was not linked to a surge in any specific cytokine/chemokine; yet, specific chemokines (i.e., CCL2, CCL7, and CXCL2) increased as gestation progressed and maintained elevated levels in the postpartum period. In addition, cell-free fetal DNA concentrations increased prior to systemic inflammation-induced preterm birth, which was associated with a strong cytokine response in the maternal circulation. However, cell-free fetal DNA concentrations were not increased prior to intra-amniotic inflammation-induced preterm birth, but in this model, a mild inflammatory response was observed in the maternal circulation. Collectively, these findings suggest that an elevation in cell-free fetal DNA concentrations in the maternal circulation precedes the physiological process of labor at term and the pathological process of preterm labor linked with systemic inflammation, but not that associated with intra-amniotic inflammation.
Asunto(s)
Ácidos Nucleicos Libres de Células/sangre , Trabajo de Parto/sangre , Trabajo de Parto Prematuro/sangre , Nacimiento Prematuro/sangre , Nacimiento a Término/sangre , Animales , Quimiocinas/sangre , Citocinas/sangre , Femenino , Ratones , Parto/sangre , EmbarazoRESUMEN
These experiments aimed to understand the relationship between interleukin 10 (IL10), the IL10 receptor subunits, and progesterone (P4) at the time of parturition. We hypothesized that there is a biologic connection between IL10 and P4, supporting an immunomodulatory mechanism for the onset of labor. Using samples from control and P4-treated pregnant mice, we assessed the production of IL10 and its receptor subunits (IL10Rα and IL10Rß) in gestational tissues. After preliminary studies, P4-treated pregnant mice were compared with controls to assess for differences in IL10 and IL10 receptor subunit expression throughout gestation. To investigate the contribution of the P4 receptor at the onset of labor, we performed timed studies on pregnant mice after treatment with RU486. Samples collected included placentas, placentation sites, and maternal livers. IL10, IL10Rα, and IL10Rß levels were measured in homogenized tissue using ELISA assays; the cytokine results were normalized for homogenate protein concentration. Control mice delivered on gd 18-19, and P4 treatment prevented parturition to beyond gd 20, as expected. In treated mice, P4 not only prevented the anticipated nadir of IL10 at term, but maintained elevated levels of IL10 through gd 20 (p < 0.05). P4 also reversed the anticipated decrease of the IL10Rα, which was increased in P4-treated mice (p < 0.05). Treatment with RU486 did not modulate the expression of IL10 or IL10Rα, but showed a significant decrease in the level of IL10Rß (p < 0.05). Progesterone functions at least in part through the IL10 signaling pathway to prolong gestation.
Asunto(s)
Subunidad alfa del Receptor de Interleucina-10/metabolismo , Subunidad beta del Receptor de Interleucina-10/metabolismo , Interleucina-10/metabolismo , Parto/metabolismo , Progesterona/metabolismo , Animales , Femenino , Ratones Endogámicos C57BL , Parto/efectos de los fármacos , Placenta/efectos de los fármacos , Placenta/metabolismo , Embarazo , Progesterona/administración & dosificación , Útero/efectos de los fármacos , Útero/metabolismoRESUMEN
BACKGROUND: The biologic mechanism(s) regulating the length of gestation are currently poorly understood. After peaking at the blastocyst stage, the average telomere lengths have been reported to shorten during the remainder of gestation in the placenta and fetal membranes in both human and mouse pregnancies, thereby providing a potential countdown biologic clock. These previous studies have reported changes in the average telomere lengths, whereas it has now been shown that the shortest telomeres, not the average telomere lengths, are the mediators of telomere dysfunction which limits cellular survival and results in aging. OBJECTIVE: These studies sought to assess for the first time a significant increase in short telomeres in the fetal membrane and placental tissue near the end of pregnancy in the mouse. STUDY DESIGN: Placental and fetal membrane tissues were harvested from timed-pregnant CD-1 mice on gestational days 14-18 prior to the onset of parturition. Telomere lengths were determined for 30 DNA samples (5 each for gestational days 14, 16, and 18 from placentas and fetal membranes) using a commercial high-throughput quantitative fluorescence in situ hybridization technique. Quantitative measurements of representative short telomeres (ie, 3 kb and 5 kb telomere fragments) were performed for 29-30 DNA samples (4-7 each for gestational days 14, 15, 16, 17, and 18 from placentas, fetal membranes, and maternal liver) using a real-time quantitative polymerase chain reaction modification of the classic telomere restriction fragment technique. RESULTS: The median telomere lengths of fetal membrane tissue decreased from gestational days 14-18 (18,705-16,364 kb) and were significantly shorter than telomeres in placental tissue (P < .05). Representative histograms for the distribution of telomere lengths in mouse fetal membranes (as shown in the Figure) confirm a curve skewed to the left (toward shorter telomere lengths).The relative quantity of the representative short telomeres (ie, 3 kb and 5 kb fragments) increased significantly as gestation progressed in both placenta and fetal membrane tissue. In gestational day 18 fetal membranes, the relative quantity of 3 kb and 5 kb telomeres increased 5.5-fold and 9.3-fold compared with gestational day 14 tissues (P < .05). In placental tissue the relative quantity of 3 kb and 5 kb telomeres increased 9.3-fold and 7.8-fold compared with gestational day 14 tissues (P < .05). Studies performed using adult liver tissue demonstrated little variation of the representative short telomeres and no significant difference between the nonpregnant and pregnant samples. CONCLUSION: These mouse studies have demonstrated that the distribution of telomere lengths in fetal membrane and placental tissues are skewed toward shorter lengths and that the quantity of representative short telomeres increase significantly prior to parturition. The telomere gestational clock is a novel hypothesis supported by several preliminary mouse studies and interesting associations in human pregnancies between maternal conditions and telomere lengths. (eg, stress, education, pollution, neighborhood quality, and race). As such, the current hypothesis generating study provides a foundation for future research regarding the potential role for a telomere-based biologic clock that determines gestational length in human and other mammalian pregnancies.
Asunto(s)
Membranas Extraembrionarias/patología , Edad Gestacional , Placenta/patología , Acortamiento del Telómero , Animales , Femenino , Hibridación Fluorescente in Situ , Ratones , EmbarazoRESUMEN
INTRODUCTION: Cell-free "fetal" DNA is released from the placenta. Because the fetal membranes also arise from the trophectoderm layer of the blastocyst, these studies sought to test the hypothesis that the membranes also release cell-free DNA (cfDNA). METHODS: Fetal membranes were harvested from pregnant CD-1 mice and cultured in 12-well plates containing media alone or with staurosporine and thapsigargin (apoptosis stimulators), Q-VD-OPh (caspase inhibitor), Trolox (vitamin E analog), and lipopolysaccharide and tumor necrosis factor α (TNFα; inflammatory mediators). The cfDNA in the media was extracted, quantified, and normalized for tissue weight. Media was used for a lactate dehydrogenase (LDH) assay. Membrane homogenates were used to assess activated caspase levels and the expression of DNA fragmentation factor B (DFFB) and BAX proteins. 5-Methylcytosine was assessed using a 5-mC DNA enzyme-linked immunosorbent assay. The cfDNA was used to stimulate interleukin 6 (IL6) release by J774A.1 mouse macrophage cells. RESULTS: Increased cfDNA release at 6 and 21 hours occurred in parallel with increasing LDH levels. The cfDNA concentrations were significantly suppressed by Q-VD-OPh and Trolox and increased by thapsigargin and TNFα. Increased caspase activity was suppressed by Q-VD-OPh and increased by TNFα, thapsigargin, and staurosporine. The expression of BAX and DFFB proteins significantly increased by 21 hours. 5-Methylcytosine levels were significantly lower in fetal membranes and placentas and below detectable in the cfDNA released by the explants. The cfDNA-stimulated IL6 release by macrophage cells was suppressed by chloroquine, a Toll-like receptor 9 (TLR9) inhibitor. CONCLUSIONS: These studies have confirmed cfDNA release by the mouse fetal membranes; cfDNA was markedly hypomethylated and a robust stimulator of TLR9.
Asunto(s)
Ácidos Nucleicos Libres de Células/metabolismo , Membranas Extraembrionarias/metabolismo , Tapsigargina/farmacología , 5-Metilcitosina/análisis , Clorometilcetonas de Aminoácidos/farmacología , Animales , Apoptosis/efectos de los fármacos , Inhibidores de Caspasas/farmacología , Ácidos Nucleicos Libres de Células/aislamiento & purificación , Medios de Cultivo Condicionados/química , Membranas Extraembrionarias/química , Femenino , Ratones , Placenta/química , Embarazo , Quinolinas/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: The fetal fraction of cell-free DNA (cfDNA) in maternal plasma is decreased in obese women. The underlying mechanism is not well understood. The amount of cfDNA released from the placenta has not been directly examined in maternal obesity. OBJECTIVE: We sought to quantify release of cfDNA from the placenta and fetal membranes in maternal diet-induced obesity using explant cultures in an established mouse model. STUDY DESIGN: C57BL6/J females were fed either 60% high-fat diet or 10% fat-matched control diet for 14 weeks prepregnancy and throughout gestation. Placentas and fetal membranes were collected on e18 and randomly allocated to time 0-, 1-, or 6-hour culture times. The CfDNA was isolated from culture media, quantified, and normalized to tissue weight. RESULTS: Placentas from obese dams released significantly less cfDNA compared to those of lean dams at time 0 (45.8 ± 4.3 ng/mg vs 65.6 ± 7.9 ng/mg, P = .02). Absolute cfDNA levels increased with longer placental culture, with no significant differences between obese and lean dams at 1 and 6 hours. Membranes released significantly less cfDNA than did placentas at every time point. CONCLUSIONS: Maternal obesity is associated with decreased release of cfDNA from the placenta compared to lean controls immediately after tissue harvest. This may provide an alternative explanation for the lower fetal fraction of cfDNA noted in maternal obesity.
Asunto(s)
Ácidos Nucleicos Libres de Células/metabolismo , Dieta Alta en Grasa , Desarrollo Fetal/fisiología , Obesidad Materna/metabolismo , Placenta/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Ratones , EmbarazoRESUMEN
INTRODUCTION: While there is evidence for a relationship between cell-free fetal DNA (cffDNA) and parturition, questions remain regarding whether cffDNA could trigger a pro-inflammatory response on the pathway to parturition. We hypothesized that placental and/or fetal DNA stimulates toll-like receptor 9 (TLR9) leading to secretion of pro-inflammatory cytokines by macrophage cells. METHODS: Four in vitro DNA stimulation studies were performed using RAW 264.7 mouse peritoneal macrophage cells incubated in media containing the following DNA particles: an oligodeoxynucleotide (ODN2395), intact genomic DNA (from mouse placentas, fetuses and adult liver), mouse DNA complexed with DOTAP (a cationic liposome forming compound), and telomere-depleted mouse DNA. Interleukin 6 (IL6) secretion was measured in the media by enzyme-linked immunosorbent assay; and the cell pellet was homogenized for protein content (picograms IL6/mg protein). RESULTS: Robust IL6 secretion was observed in response to ODN2395 (a CpG-rich TLR9 agonist), mouse DNA-DOTAP complexes, and telomere-depleted mouse DNA in concentrations of 5 to 15 µg/mL. In contrast, ODN A151 (containing telomere sequence motifs), intact genomic mouse DNA, and restriction enzyme-digested DNA had no effect on IL6 secretion. The IL6 response was significantly inhibited by chloroquine (10 µg/mL), thereby confirming the important role for TLR9 in the response by macrophage cells. CONCLUSIONS: DNA derived from mouse placentas and fetuses, and depleted of telomeric sequences, stimulates a robust pro-inflammatory response by macrophage cells, thereby supporting the hypothesis that cffDNA is able to stimulate an innate immune response that could trigger the onset of parturition. These findings are of clinical importance, as we search for effective treatment/prevention of preterm parturition.
Asunto(s)
ADN/metabolismo , Inflamación/metabolismo , Parto , Placenta/metabolismo , Receptor Toll-Like 9/metabolismo , Animales , Femenino , Feto , Interleucina-6/metabolismo , Macrófagos/metabolismo , Ratones , Embarazo , Células RAW 264.7 , Telómero/metabolismoAsunto(s)
Ácidos Nucleicos Libres de Células , Nacimiento a Término , Humanos , Inflamación , Trabajo de PartoRESUMEN
Although suggested that "fetal" cell-free DNA (cfDNA) is derived from trophoblast cells, the exact origin is unclear. The studies in this report sought to demonstrate that placental tissue releases cfDNA in parallel with cell death, that the size range of cfDNA is similar to that found in maternal plasma, and that the cfDNA fragments are able to stimulate a proinflammatory cytokine response. Placentas were harvested from near term pregnant CD-1 mice and cultured in DMEM/Ham's F12/FBS media in 8% or 21% O2. After centrifugation to remove cells and cellular debris, the cfDNA was extracted from the media and quantified by DNA spectrophotometry. The cfDNA fragments were sized using a 1.5% TAE gel. Cell death was quantified by lactate dehydrogenase assay; and tissue homogenates were used to quantify caspase activity and BAX expression. Cultured RAW-264.7 macrophage cells were used to determine IL6 stimulation by cfDNA. The cfDNA levels released in 8% O2 (placental normoxia) were not significantly different from explants cultured in 21% O2 (placental hyperoxia). The cfDNA fragments ranged in size from < 100 -< 400 bp. The cfDNA release increased when cultured with LPS, whereas it decreased with trolox (vitamin E analog). Explant release of cfDNA increased in parallel with cell death. The cfDNA release and cell death of trophoblast appears to involve components of the apoptosis signaling pathway as suggested by LPS enhancement of placental caspase activity, suppression of cfDNA release by a pan-caspase inhibitor and the trend toward increased Bax protein expression. Studies with cultured macrophage cells confirmed the ability of cfDNA to stimulate an IL6 response. In summary, these studies have confirmed the ability of placental tissue to release significant amounts of cfDNA, a phenomenon that appears to be mediated, at least in part, by apoptosis; and that the cfDNA released by the placental explants is able to stimulate a significant proinflammatory response. Thus, these studies provide support for the hypothesis that cell-free fetal DNA released by placental tissue potentially plays a mechanistically important role during the events leading to the onset of parturition.
Asunto(s)
Lipopolisacáridos/farmacología , Placenta/metabolismo , Animales , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-6/metabolismo , Ratones , Embarazo , Células RAW 264.7 , Proteína X Asociada a bcl-2/metabolismoRESUMEN
PROBLEM: Influenza infection severity may be mediated by estradiol and/or progesterone. METHOD OF STUDY: An exploratory study was designed to evaluate 17-ß-estradiol and progesterone on influenza infection and examine immune-mediated response in a mouse model. Inoculation with placebo or mouse-adapted H1N1 influenza virus occurred. Treatment groups included 17-ß-estradiol, progesterone, ovariectomy, and pregnancy. Mice were assessed for morbidity and mortality. Toll-like receptor gene studies and airspace cell differentials were performed. RESULTS: Onset of morbidity was earlier and morbidity duration greater for progesterone. Absence of morbidity/mortality and overall survival was greater for 17-ß-estradiol. Airspace cell differentials suggest improved immune cell recruitment for 17-ß-estradiol. Pregnant mouse data demonstrate significant mortality during the period of increased progesterone. Select immune cell markers demonstrate patterns of regulation that may promote proper immune response to influenza infection for 17-ß-estradiol. CONCLUSION: Estradiol may play a protective and progesterone a detrimental role in the pathophysiology of influenza infection.
Asunto(s)
Estradiol/metabolismo , Virus de la Influenza A/inmunología , Gripe Humana/inmunología , Linfocitos/inmunología , Infecciones por Orthomyxoviridae/inmunología , Progesterona/metabolismo , Animales , Movimiento Celular , Modelos Animales de Enfermedad , Estradiol/administración & dosificación , Femenino , Humanos , Inmunidad , Inmunomodulación , Ratones , Ratones Endogámicos , Ovariectomía , Embarazo , Progesterona/administración & dosificación , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMEN
In mammals, there exists a strong correlation between the average life span (in years) and the length of gestation (in days), suggesting that the same biologic clock mechanisms control both of these physiologic events. Life span is determined by a complex sequence of events leading to organismal senescence, and ultimately death. Although multiple biochemical and cellular phenomena are believed to be involved, progressive telomere shortening due to oxidative stress and loss during DNA replication is believed to be an important determinant contributing to aging, senescence, and adult death. We hypothesize that similar biochemical and cellular phenomena occur in the placenta and fetal membranes resulting in their aging during gestation, their senescence at term, and their apoptotic death resulting in the release of an inflammatory mediator in the form of fetal cell-free DNA. This article reviews the evidence supporting this "telomere gestational clock" hypothesis which proposes that progressive telomere shortening in gestational tissue (especially the placenta and fetal membranes) leads to apoptosis and fetal cell-free DNA release, thereby stimulating the proinflammatory signaling cascade that drives the progression of parturition.
Asunto(s)
Muerte , Longevidad/fisiología , Parto/fisiología , Embarazo/fisiología , Telómero/metabolismo , Envejecimiento/fisiología , Animales , Relojes Biológicos/fisiología , Senescencia Celular/fisiología , Femenino , HumanosRESUMEN
AIM: The effect of hormone levels on the stimulation of Toll-like receptor 5 (TLR5) in the bladder is unknown. We aimed to study the effect of estradiol and progesterone on TLR5 expression and function in human bladder epithelial cells. METHODS: After growing to near confluence, T24 human urinary bladder (HUB) cells were incubated in hormone-free (HF) media for 72 hours. Human urinary bladder cells were then incubated in (1) HF media, (2) estradiol media, (3) progesterone media, or (4) media containing estradiol and progesterone at physiologic concentrations. Following flagellin exposure, cells and media were collected. Toll-like receptor 5 expression and stimulated cytokine release were analyzed using enzyme-linked immunosorbent assays. Results were normalized with cellular protein assays. A TLR5 antagonist was used to confirm that stimulation from flagellin was mediated by TLR5 signaling. RESULTS: Cultured HUB cells express TLR5 protein. Estradiol and progesterone environments suppress TLR5 expression compared to HF environment. The function of TLR5 was measured by interleukin 6 (IL-6) and monocyte chemoattractant protein 1 production after flagellin exposure. Interleukin 6 production was 75% higher in the estradiol than progesterone environment. The progesterone environment produced IL-6 levels twice that observed in HF and combined estrogen-progesterone environments. Interestingly, higher TLR5 expression was associated with lower IL-6 production. CONCLUSION: Our study demonstrated that TLR5 expression and functional activity as measured by IL-6 are modulated by hormones. The increase in TLR5-associated IL-6 may play a role in increasing the rate of symptomatic urinary tract infection. Likewise, low TLR5 functional activity may dampen the response of the innate immune system, thereby lessening the likelihood of a symptomatic bladder infection.
Asunto(s)
Estradiol/farmacología , Progesterona/farmacología , Receptor Toll-Like 5/metabolismo , Vejiga Urinaria/metabolismo , Línea Celular , Quimiocina CCL2/metabolismo , Flagelina/farmacología , Humanos , Interleucina-6/metabolismo , Vejiga Urinaria/efectos de los fármacosRESUMEN
Multiple previous reports have provided compelling support for the premise that spontaneous parturition is mediated by activation of inflammation-related signaling pathways leading to increased secretion of cytokines and chemokines, the influx of neutrophils and macrophages into the pregnant uterus, increased production of uterine activation proteins (eg, connexin-43, cyclo-oxygenase-2, oxytocin receptors, etc), activation of matrix metalloproteinases, and the release of uterotonins leading to cervical ripening, membrane rupture, and myometrial contractions. The missing link has been the fetal/placental signal that triggers these proinflammatory events in the absence of microbial invasion and intrauterine infection. This article reviews the biomedical literature regarding the increase in cell-free fetal DNA (cffDNA), which is released during apoptosis in the placenta and fetal membranes at term, the ability of apoptosis modified vertebrate DNA to stimulate toll-like receptor-9 (TLR9) leading to increased release of cytokines and chemokines, and the potential "fail-safe" role for the anti-inflammatory cytokine IL-10. This article also reviews the literature supporting the key role that telomere loss plays in regard to increasing the ability of vertebrate (including placental) DNA to stimulate TLR9, and in regard to signaling the onset of apoptosis in the placenta and fetal membranes, thereby providing a biologic clock that determines the length of gestation and the timing for the onset of parturition. In summary, this literature review provides a strong rationale for future research to test the hypothesis that telomere loss and increased cffDNA levels trigger the proinflammatory events leading to the spontaneous onset of parturition in mammals: the "cffDNA/telomere hypothesis."
Asunto(s)
Apoptosis , ADN/genética , Membranas Extraembrionarias/metabolismo , Inicio del Trabajo de Parto/genética , Parto/genética , Placenta/metabolismo , Telómero/genética , Animales , ADN/inmunología , ADN/metabolismo , Membranas Extraembrionarias/inmunología , Membranas Extraembrionarias/patología , Femenino , Humanos , Inflamación/genética , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-10/metabolismo , Inicio del Trabajo de Parto/inmunología , Parto/inmunología , Placenta/inmunología , Placenta/patología , Embarazo , Transducción de Señal , Telómero/inmunología , Telómero/metabolismo , Receptor Toll-Like 9/metabolismoRESUMEN
The timing of birth is a critical determinant of perinatal outcome. Despite intensive research, the molecular mechanisms responsible for the onset of labor both at term and preterm remain unclear. It is likely that a "parturition cascade" exists that triggers labor at term, that preterm labor results from mechanisms that either prematurely stimulate or short-circuit this cascade, and that these mechanisms involve the activation of proinflammatory pathways within the uterus. It has long been postulated that the fetoplacental unit is in control of the timing of birth through a "placental clock." We suggest that it is not a placental clock that regulates the timing of birth, but rather a "decidual clock." Here, we review the evidence in support of the endometrium/decidua as the organ primarily responsible for the timing of birth and discuss the molecular mechanisms that prime this decidual clock.
Asunto(s)
Relojes Biológicos/fisiología , Decidua/fisiología , Parto/fisiología , Animales , Femenino , Predisposición Genética a la Enfermedad/genética , Edad Gestacional , Humanos , Embarazo , Nacimiento Prematuro/genética , Prostaglandinas/fisiología , Útero/fisiologíaRESUMEN
Influenza is a major health problem worldwide. Both seasonal influenza and pandemics take a major toll on the health and economy of our country. The present review focuses on the virology and complex immunology of this RNA virus in general and in relation to pregnancy. The goal is to attempt to explain the increased morbidity and mortality seen in infection during pregnancy. We discuss elements of innate and adaptive immunity as well as placental cellular responses to infection. In addition, we delineate findings in animal models as well as human disease. Increased knowledge of maternal and fetal immunologic responses to influenza is needed. However, enhanced understanding of nonimmune, pregnancy-specific factors influencing direct interaction of the virus with host cells is also important for the development of more effective prevention and treatment options in the future.
Asunto(s)
Sistema Inmunológico/inmunología , Gripe Humana/inmunología , Orthomyxoviridae/inmunología , Complicaciones Infecciosas del Embarazo/inmunología , Inmunidad Adaptativa , Animales , Modelos Animales de Enfermedad , Femenino , Interacciones Huésped-Patógeno , Humanos , Sistema Inmunológico/virología , Inmunidad Innata , Inmunización , Vacunas contra la Influenza/uso terapéutico , Gripe Humana/mortalidad , Gripe Humana/prevención & control , Gripe Humana/virología , Orthomyxoviridae/patogenicidad , Embarazo , Complicaciones Infecciosas del Embarazo/mortalidad , Complicaciones Infecciosas del Embarazo/prevención & control , Complicaciones Infecciosas del Embarazo/virología , Pronóstico , Factores de RiesgoRESUMEN
Phospholipid scramblases (PLSCR), stimulated by proinflammatory cytokines, are thought to mediate the loss of lipid asymmetry in cell membranes, allowing for specific reactions in the coagulation cascade. The PLSCR may therefore provide a link between inflammation, coagulation, and, because thrombin is a uterotonic, preterm birth (PTB). To explore the relationship between PLSCR expression and inflammation-related PTB, we utilized reverse transcriptase-polymerase chain reaction and Western blot studies to quantify messenger RNA (mRNA) and protein expression for the 4 PLSCR homologues (PLSCR 1-4). Uteri from day 15 pregnant mice were harvested at several time points after intrauterine lipopolysaccharide (LPS) injection (or normal saline, for controls). Expression of mRNA in all 4 Plscr isoforms was demonstrated. Lipopolysaccharide treatment resulted in increased expression of PLSCR-1 and a decrease in Plscr4 mRNA, thereby demonstrating modulation of PLSCR-1 and PLSCR-4 in LPS-induced PTB. Additionally, protein expression was confirmed for all except PLSCR-4, with increased expression of PLSCR-1 after LPS treatment.
Asunto(s)
Lipopolisacáridos/administración & dosificación , Proteínas de Transferencia de Fosfolípidos/genética , Nacimiento Prematuro/etiología , Nacimiento Prematuro/metabolismo , Útero/metabolismo , Animales , Western Blotting , Femenino , Expresión Génica , Inflamación/complicaciones , Isoenzimas/análisis , Isoenzimas/genética , Ratones , Proteínas de Transferencia de Fosfolípidos/análisis , Embarazo , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Útero/química , Útero/efectos de los fármacosRESUMEN
Preterm delivery (PTD) has been associated with inflammation along with activation of the coagulation pathway. These studies sought to characterize the expression of several coagulation pathway genes including plasminogen activator inhibitor 1 (PAI-1), tissue factor (TF), protease-activated receptor 1 (Par1), protease-activated receptor 2 (Par2), fibrinogen-like protein 2 (Fgl2), and thrombomodulin (TM) during lipopolysaccharide (LPS)-induced PTD in day 15 pregnant CD-1 mice. Western blot studies confirmed protein expression for PAI-1, Par1, Par2, Fgl2, and TM in the mouse uterus. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) confirmed increased PAI-1 messenger RNA (mRNA) in the uteri, lung, kidney, and liver tissues at 2 to 6 hours after LPS injection. In contrast, TF expression significantly decreased by 12 hours in uterine tissue; whereas, its expression was unchanged in the other maternal tissues. The uterine mRNA for Par1, Par2, Fgl2, and TM remained stable. In summary, these studies have confirmed expression of coagulation pathway genes within the pregnant uterus; some of which are modulated during LPS-induced PTD.