Fetal membranes (amniochorion) provide the structural framework and perform mechanical and protective functions during pregnancy. A progressive p38 mitogen-activated protein kinase (MAPK)-mediated senescence (mechanism of aging) occurs in fetal membranes. It is correlated with fetal growth and is accelerated at term due to increased oxidative stress (OS) in the intrauterine cavity. Senescence of fetal tissues causes inflammation that can promote labor; thus, membranes play a critical role in pregnancy and parturition. Throughout gestation, membranes maintain homeostasis by repairing themselves when cells are shed and the matrix is degraded. This remodeling process creates gaps and microfractures. At the cellular level, it remains unclear how the membranes' pluripotent amnion epithelial and mesenchymal cells repair the damaged sites. Since remodeling is essential for maintaining membrane homeostasis and preventing adverse pregnancy outcomes, understanding this process is critical. We have determined that injury to amnion epithelial cells (AEC) forces AEC proliferation and cell migration to rebuild injured sites, which is a normal physiologic response. Pilot data suggest that OS- and p38 MAPK-mediated senescence cause epithelial mesenchymal transition (EMT) and prevent tissue remodeling through increased production of TGF?. We also determined that TGF? plays dual functions: 1) induction of senescence by autophosphorylation of p38MAPK and 2) induction of EMT transcription factors to facilitate cellular and mechanical membrane disruption. These effects were reversed by progesterone (P4). We hypothesize that balanced tissue remodeling maintains fetal membrane homeostasis during pregnancy, but TGF? increase due to overwhelming OS at term or in response to infection and inflammation (TNF?) at preterm causes an irreversible state of p38MAPK-mediated senescence and EMT that can promote membrane damage. Additionally, we hypothesize that during pregnancy, TGF?-mediated transitions are balanced by progesterone (P4). We will test our hypotheses using 2 specific aims:
Aim 1 ?To determine if LPS (infection) and TNF? (inflammation) can cause TGF? -TAB1-p38MAPK signaling pathways, leading to EMT in AEC.
Aim 2 ?To determine the regulatory role of P4 in LPS and TNF?-mediated TGF? production and its ability to reduce EMT. Maintenance of membrane homeostasis by TGF?-P4 during normal conditions and its disruption by infection/inflammation promoting EMT may provide a novel pathway to preterm parturition mediated by membrane disruption.
Fetal membranes, which help maintain the structure of the uterus and protect the fetus during pregnancy, grow along with the fetus through a well-regulated cellular remodeling process. During normal pregnancy, a growth factor (transforming growth factor beta) and the hormone progesterone work together to balance this remodeling process until term, when inflammation overrides remodeling to promote labor; however, during preterm labor, oxidative stress in response to infection and inflammation can disrupt this delicate balance, forcing the fetal membrane epithelial cells to transition to more inflammatory mesenchymal cells through a process called EMT and leading to preterm labor. Understanding the molecular and cellular mechanisms of this transition in response to infection and inflammation may provide a better understanding of preterm birth pathways and interventions that can be explored in future research.
