Margaret A Baumbusch1, Catalin S Buhimschi2, Emily A Oliver2, Guomao Zhao3, Stephen Thung2, Kara Rood2, Irina A Buhimschi4. 1. Department of Ob./Gyn. & Reproductive Sciences, Yale University School of Medicine, United States. 2. Department of Obstetrics & Gynecology, The Ohio State University College of Medicine, Columbus, OH 43210, United States. 3. Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43215, United States. 4. Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43215, United States; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43215, United States. Electronic address: irina.buhimschi@nationwidechildrens.org.
Abstract
BACKGROUND: High Mobility Group Box-1 (HMGB1) is considered a prototype alarmin molecule. Upon its extracellular release, HMGB1 engages pattern recognition receptors and the Receptor for Advanced Glycation End-products (RAGE) followed by an outpouring of inflammatory cytokines, including interleukin (IL)-6. METHODS: We assayed the amniotic fluid (AF) levels of HMGB1 and IL-6 in 255 women that either had a normal pregnancy outcome or delivered preterm. Immunohistochemistry on fetal membranes was used for cellular localization and validation of immunoassay findings. HMGB1 also was analyzed in amniochorion tissue explants subjected to endotoxin. RESULTS: AF HMGB1 levels are not gestational age regulated but are increased in women with intra-amniotic inflammation and preterm birth. The likely source is the damaged amniochorion, as demonstrated by immunohistochemistry and explant experiments. CONCLUSIONS: Our research supports a role for HMGB1 in the inflammatory response leading to preterm birth. As a delayed phase cytokine, in utero exposure to elevated AF HMGB1 levels may have an impact on the newborn beyond the time of birth.
BACKGROUND:High Mobility Group Box-1 (HMGB1) is considered a prototype alarmin molecule. Upon its extracellular release, HMGB1 engages pattern recognition receptors and the Receptor for Advanced Glycation End-products (RAGE) followed by an outpouring of inflammatory cytokines, including interleukin (IL)-6. METHODS: We assayed the amniotic fluid (AF) levels of HMGB1 and IL-6 in 255 women that either had a normal pregnancy outcome or delivered preterm. Immunohistochemistry on fetal membranes was used for cellular localization and validation of immunoassay findings. HMGB1 also was analyzed in amniochorion tissue explants subjected to endotoxin. RESULTS:AFHMGB1 levels are not gestational age regulated but are increased in women with intra-amniotic inflammation and preterm birth. The likely source is the damaged amniochorion, as demonstrated by immunohistochemistry and explant experiments. CONCLUSIONS: Our research supports a role for HMGB1 in the inflammatory response leading to preterm birth. As a delayed phase cytokine, in utero exposure to elevated AFHMGB1 levels may have an impact on the newborn beyond the time of birth.
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