The signals that lead to the initiation of parturition have remained a mystery. We postulate that in humans and other mammals, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, and spontaneous labor is initiated or facilitated by a concerted series of biochemical events that negatively impact PR function. In recent studies, we have obtained compelling evidence to suggest that the fetus signals the initiation of labor by secretion into amniotic fluid of major lung surfactant protein, SP-A. SP-A expression is developmentally regulated in fetal lung and is secreted into amniotic fluid in high concentrations near term (after 17 days postcoitum [dpc] in the mouse). We found that injection of exogenous SP-A into mouse amniotic fluid at 15 dpc caused preterm labor. SP-A activated amniotic fluid macrophages in vitro to express nuclear factor kappaB (NF-kappaB) and interleukin-1beta (IL-1beta). These macrophages, which are of fetal origin, migrate to the pregnant uterus causing an inflammatory response and increased uterine NF-kappaB activity. We suggest that the increase in NF-kappaB within the maternal uterus both directly increases expression of genes that promote uterine contractility and negatively impacts the capacity of the PR to maintain uterine quiescence, contributing to the onset of labor. Our findings, therefore, indicate that SP-A secreted into amniotic fluid by the maturing fetal lung serves as a hormone of parturition.
"In summary, we propose that throughout pregnancy the uterine myocyte must monitor, tolerate and adapt to intrinsic and extrinsic uterotonic stimuli , . We propose that the pregnant uterine myocyte utilizes physiological and uterotonic events as signals indicating the need to activate the potential tocolytic enzyme CASP3 in order to maintain myocyte quiescence. "
[Show abstract][Hide abstract] ABSTRACT: We have previously proposed that uterine caspase-3 may modulate uterine contractility in a gestationally regulated fashion. The objective of this study was to determine the mechanism by which uterine caspase-3 is activated and consequently controlled in the pregnant uterus across gestation. Utilizing the mouse uterus as our gestational model we examined the intrinsic and extrinsic apoptotic signaling pathways and the endoplasmic reticulum stress response as potential activators of uterine caspase-3 at the transcriptional and translational level. Our study revealed robust activation of the uterine myocyte endoplasmic reticulum stress response and its adaptive unfolded protein response during pregnancy coinciding respectively with increased uterine caspase-3 activity and its withdrawal to term. In contrast the intrinsic and extrinsic apoptotic signaling pathways remained inactive across gestation. We speculate that physiological stimuli experienced by the pregnant uterus likely potentiates the uterine myocyte endoplasmic reticulum stress response resulting in elevated caspase-3 activation, which is isolated to the pregnant mouse myometrium. However as term approaches, activation of an elevated adaptive unfolded protein response acts to limit the endoplasmic reticulum stress response inhibiting caspase-3 resulting in its decline towards term. We speculate that these events have the capacity to regulate gestational length in a caspase-3 dependent manner.
PLoS ONE 09/2013; 8(9):e75152. DOI:10.1371/journal.pone.0075152 · 3.23 Impact Factor
"It is unclear what the causes the initiation of labor in humans and other catarrhine primates because circulating levels of progesterone do not decrease before the onset of labor. Several mechanisms have been proposed including the functional withdrawal of progesterone , , the increase of surfactant production , and the increase in levels of corticotropin releasing hormone . However, further work is required to confirm the causal role of these proposed mechanisms. "
[Show abstract][Hide abstract] ABSTRACT: Preterm birth is a leading cause of perinatal mortality, yet the evolutionary history of this obstetrical syndrome is largely unknown in nonhuman primate species.
We examined the length of gestation during pregnancies that occurred in a captive chimpanzee colony by inspecting veterinary and behavioral records spanning a total of thirty years. Upon examination of these records we were able to confidently estimate gestation length for 93 of the 97 (96%) pregnancies recorded at the colony. In total, 78 singleton gestations resulted in live birth, and from these pregnancies we estimated the mean gestation length of normal chimpanzee pregnancies to be 228 days, a finding consistent with other published reports. We also calculated that the range of gestation in normal chimpanzee pregnancies is approximately forty days. Of the remaining fifteen pregnancies, only one of the offspring survived, suggesting viability for chimpanzees requires a gestation of approximately 200 days. These fifteen pregnancies constitute spontaneous abortions and preterm deliveries, for which the upper gestational age limit was defined as 2 SD from the mean length of gestation (208 days).
The present study documents that preterm birth occurred within our study population of captive chimpanzees. As in humans, pregnancy loss is not uncommon in chimpanzees, In addition, our findings indicate that both humans and chimpanzees show a similar range of normal variation in gestation length, suggesting this was the case at the time of their last common ancestor (LCA). Nevertheless, our data suggest that whereas chimpanzees' normal gestation length is ∼20-30 days after reaching viability, humans' normal gestation length is approximately 50 days beyond the estimated date of viability without medical intervention. Future research using a comparative evolutionary framework should help to clarify the extent to which mechanisms at work in normal and preterm parturition are shared in these species.
PLoS ONE 09/2011; 6(9):e24509. DOI:10.1371/journal.pone.0024509 · 3.23 Impact Factor
"In vitro studies in mice demonstrate increased transcriptional activities of NF-κβ, in response to inflammatory cytokines such as IL-1β produced by fetal macrophages. Activation of fetal macrophages is believed to be due to secretion into the AF of major lung surfactant protein A and the final effect of these activities is supression of the PR.66 "
[Show abstract][Hide abstract] ABSTRACT: Preterm birth is the major cause of perinatal morbidity and mortality in the developed world, and spontaneous preterm labor is the commonest cause of preterm birth. Interventions to treat women in spontaneous preterm labor have not reduced the incidence of preterm births but this may be due to increased risk factors, inclusion of births at the limits of viability, and an increase in the use of elective preterm birth. The role of antibiotics remains unproven. In the largest of the randomized controlled trials, evaluating the use of antibiotics for the prevention of preterm births in women in spontaneous preterm labor, antibiotics against anaerobes and bacterial vaginosis-related organisms were not included, and no objective evidence of abnormal genital tract flora was obtained. Atosiban and nifedipine are the main tocolytic agents used to treat women in spontaneous preterm labor, but atosiban is the tocolytic agent with the fewest maternal - fetal side effects. A well conducted randomized controlled trial comparing atosiban with nifedipine for their effectiveness and safety is needed.
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