John T Hardy1, Irina A Buhimschi1, Megan E McCarthy1, Guomao Zhao1, Christine A Laky1, Lydia L Shook1, Catalin S Buhimschi1. 1. Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210.
Abstract
CONTEXT: Microbial invasion of the amniotic fluid (AF) cavity stimulates an inflammatory response that involves activin-A, a pleiotropic mediator member of the TGFβ superfamily involved in connective tissue remodeling. The role of AF follistatin, a natural inhibitor of activin-A, in inflammation-induced preterm birth (PTB), has yet to be determined. OBJECTIVE: The objective of the study was to investigate the relationships between AF activin-A and follistatin in physiological gestation and in pregnancies complicated by PTB and to evaluate a possible role played by the activin-A-follistatin balance in processes leading to PTB and preterm premature rupture of membranes (PPROM). STUDY DESIGN: The AF levels of total activin-A and follistatin were immunoassayed in 168 women with a normal pregnancy outcome or PTB with and without intraamniotic inflammation or PPROM. The impact of the activin-A-follistatin imbalance on PTB terminal effector pathways (prostaglandins [prostaglandin E2, prostaglandin F2α] and matrix metalloproteinases [MMP-1, MMP-2, MMP-3, and MMP-9]) was investigated in an amniochorion explant system challenged with lipopolysaccharide (LPS) to mimic inflammation. RESULTS: AF follistatin and the activin-A to follistatin ratio varied with gestational age, both decreasing toward term (P < .001). Activin-A was up-regulated in AF infection (>2-fold elevation in activin-A to follistatin ratio) correlating directly with severity of inflammation (both P < .001). Activin-A increased prostaglandins, MMP-1, and MMP-9 released by amniochorion (P < .05) to LPS-equivalent levels. Follistatin effectively blunted the prostaglandin response to activin-A and LPS and that of MMPs after activin-A but not after LPS challenge. CONCLUSION: Activin-A and follistatin are part of the complex inflammatory response of the gestational sac to infection and modulate effector pathways leading to PTB. The activin-A to follistatin ratio may play a role in determining the clinical phenotype of PTB as preterm labor or PPROM.
CONTEXT: Microbial invasion of the amniotic fluid (AF) cavity stimulates an inflammatory response that involves activin-A, a pleiotropic mediator member of the TGFβ superfamily involved in connective tissue remodeling. The role of AFfollistatin, a natural inhibitor of activin-A, in inflammation-induced preterm birth (PTB), has yet to be determined. OBJECTIVE: The objective of the study was to investigate the relationships between AF activin-A and follistatin in physiological gestation and in pregnancies complicated by PTB and to evaluate a possible role played by the activin-A-follistatin balance in processes leading to PTB and preterm premature rupture of membranes (PPROM). STUDY DESIGN: The AF levels of total activin-A and follistatin were immunoassayed in 168 women with a normal pregnancy outcome or PTB with and without intraamniotic inflammation or PPROM. The impact of the activin-A-follistatin imbalance on PTB terminal effector pathways (prostaglandins [prostaglandin E2, prostaglandin F2α] and matrix metalloproteinases [MMP-1, MMP-2, MMP-3, and MMP-9]) was investigated in an amniochorion explant system challenged with lipopolysaccharide (LPS) to mimic inflammation. RESULTS:AFfollistatin and the activin-A to follistatin ratio varied with gestational age, both decreasing toward term (P < .001). Activin-A was up-regulated in AF infection (>2-fold elevation in activin-A to follistatin ratio) correlating directly with severity of inflammation (both P < .001). Activin-A increased prostaglandins, MMP-1, and MMP-9 released by amniochorion (P < .05) to LPS-equivalent levels. Follistatin effectively blunted the prostaglandin response to activin-A and LPS and that of MMPs after activin-A but not after LPS challenge. CONCLUSION: Activin-A and follistatin are part of the complex inflammatory response of the gestational sac to infection and modulate effector pathways leading to PTB. The activin-A to follistatin ratio may play a role in determining the clinical phenotype of PTB as preterm labor or PPROM.
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