Paracrine control of the maternal-fetal interface critical for pregnancy wellness - PROJECT SUMMARY/ABSTRACT Preterm (<37 completed weeks of gestation) birth (PTB) causes the majority of neonatal mortality and morbidity. Around 50% of PTBs are associated with preterm premature (i.e., pre-labor) weakening and rupture of the fetal membranes (FM: amnion-chorion-decidua parietalis) (pPROM). Infection/inflammation and decidual bleeding are major drivers of pPROM. Development of therapies to prevent pPROM and PTB are confounded by gaps in understanding how pregnancy is maintained in the face of inflammatory and bleeding challenges at the FM. The proposed research builds on our previous work examining the mechanisms by which inflammatory stimuli increase risk for pPROM by weakening the FM, and our demonstration that progesterone (P4) prevents inflammation- induced FM weakening. Using our ex-vivo FM explant model, we found that inflammatory stimuli weaken FM by inducing granulocyte-macrophage colony-stimulating factor (GM-CSF) production by decidual stromal (DS) cells. Our studies suggest GM-CSF is a critical intermediate in both inflammation- and bleeding-induced FM weakening. Importantly, we found that P4 prevents GM-CSF production by DS cells. Recently we found that GM-CSF, in addition initiating a cascade of events which cause FM weakening, induces P4 production within the FM. Based on those data, we hypothesize that a locally-acting, paracrine, negative-feedback system exists within the FM, whereby GM-CSF produced in response to localized inflammatory and bleeding stimuli induces P4 production by adjacent chorion cytotrophoblast (CTB) cells. The P4, in turn, inhibits GM-CSF production by the DS cells and GM-CSF- induced FM weakening. This hypothesis is supported by our recent finding that blocking P4 production or action each independently weakens the FM. Thus, locally produced and locally acting P4 is essential for maintaining the structural integrity of the FM. This novel and groundbreaking hypothesis will be tested by achieving two Specific Aims: 1) identify the signaling pathway by which GM-CSF increases P4 production by CTB cells and whether this P4 production declines in association with FM weakening at term and pPROM, and 2) determine the mechanism by which P4 exerts anti-inflammatory activity in DS cells. Achieving the Specific Aims will provide more substantive understanding of P4 function at the human maternal-fetal interface to maintain human pregnancy and prevent pPROM. Understanding this process is important for development of effective therapies to prevent, or at least decrease, the risk for pPROM-induced preterm birth.
