New insights into the molecular endocrinology of parturition.
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.
Mendelson
Carole R
CR
Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA. cmende@biochem.swmed.edu
Condon
Jennifer C
JC
D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D005260:Female; D005333:Fetus / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D007375:Interleukin-1 / Q000378:metabolism; D008168:Lung / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D007752:Obstetric Labor, Premature / Q000209:etiology / Q000503:physiopathology; D036801:Parturition / Q000502:physiology*; D011247:Pregnancy; D037662:Pulmonary Surfactant-Associated Protein A / Q000502:physiology; D015398:Signal Transduction
D007375:Interleukin-1; D016328:NF-kappa B; D037662:Pulmonary Surfactant-Associated Protein A