The Role And Mechanism Of HMGB1 And Its Receptors In Chorioamnionitis

Objective: Bacteria reaching the amniotic cavity cause Chorioamnionitis(CAM)and inflammatory infiltrates in the placental membranes.CAM is associated with an increased risk of spontaneous preterm birth.CAM including clinical chorioamnionitis and histological chorioamnionitis(HCA).HCA clinical signs often appear in the late stage of intrauterine infection.Most cases are subclinical infection without clinical symptom.Histological examination of the placenta is essential for correct diagnosis of histological.Indeed,premature delivery and neonatal sepsis are reported to be associated with HCA.HCA has long been known to be a risk factor for maternal and neonatal morbidity and mortality.There is no specific and noninvasive method for HCA diagnosis,A series of damage-associated intracellular proteins(also known as alarmins)are released as a result of the host's response to microbial pathogens.One of these alarmins,high mobility group box-1(HMGB1)is characterized as an important endogenous mediator of cellular injury.High mobility group box 1(HMGB1),a highly conserved,ubiquitous protein present in the nuclei and cytoplasm of nearly all cell types,is a necessary and sufficient mediator of inflammation during sterile and infection-associated responses.Under the physiology condition,HMGB1 located in nuclear.Nuclear HMGB1 is engaged in many DNA activityassociated events,including DNA replication,repair,recombination,transcription,and genomic stability.In response to exogenous microbial products,nature immune cells actively release HMGB1 into the extracellular space.In addition,HMGB1 can be passively released by dead cells and injury cells.HMGB1 can interact with different r eceptors,such as tolllike receptor 4(TLR4),and receptor for advanced glycation end products(RAGE).The aim of this study was to investigate the serum levels of high mobility group box-1(HMGB1)in pregnancies with histological chorioamnionitis(HCA)-associated preterm labor(PTL)with intact membranes or preterm premature rupture of membranes(PPROM)and Early-onset neonatal sepsis(EONS),to access the role andmechanisms of serum HMGB1 in HCA and HCA-associated PTL and EONS.Methods: 27 cases of Term labor and 147 cases Premature parturient were collected in Central Maternity Hospital,2015 March to 2016 March.(1)Clinical pathological data for all patients was collected;(2)Extraction of elbow vein blood during first stage of labor;(3)Exam the serum level of HMGB1?s TLR4 and s RAGE.(4)Histological examination of the placenta.(5)Relationship between serum level of HMGB1?s TLR4 and s RAGE and HCA was analyzed.Analyzed the relationship between serum level of HMGB1?s TLR4 and s RAGE and EONS.The expression and location of HMGB1 was analyzed using immunohistochemical staining to explore the relationship between placental epithelial cells cytoplasm HMGB1 with HCA and premature delivery.Result: 1.Matrix serum HMGB1 and its soluble receptor could act as a predictor of HCA biomarkers.(1)The level of PTL and PPROM serum HMGB1 and s TLR4 is significant higher than term labor.The level of serum s RAGE between PTL and PPROM and term labor has no significant different;(2)The level of serum HMGB1 and s TLR4 of PTL and PPROM with HCA is significant higher than that of PTL and PPROM without HCA HMGB1.There is no significant different of RAGE between PTL and PPROM with and without HCA HMGB1.(3)There is a positive correlation between serum HMGB1 and s TLR4,and negative correlation between serum HMGB1 and s RAGE;(4)Logistic analysis shows serum matrix HMGB1?WBC and CRP are risk factor of HCA.(5)The model predictive of HCA with HMGB1?WBC?CRP and constant terms is better than the model without HMGB1.2.Matrix serum HMGB1 and its soluble receptor could act as a predictor of EONS biomarkers.(1)EONS Matrix serum HMGB1 is significant higher than that of no EONS.EONS Matrix serum s TLR4 is significant lower than that of no EONS.(2)Logistic analysis shows matrix serum HMGB1 is risk factor of EONS,s TLR4 is protective factor of EONS.(3)The model predictive of ENOS with HMGB1?s TLR4 is better than the model without HMGB1.3.Discuss of the source of HMGB1 of HCA:(1)The expression of HMGB1 in placental cell nucleus is negative correlation with HCA stage.(2)The expression of HMGB1 in placental cell cytoplasm is positive correlation with HCA stage.(3)The expression of HMGB1 in placental cell nucleus is negative correlation with that in placental cell cytoplasm.(4)The expression of serum HMGB1 in HMGB1 low placental cell nucleus expression group is significantly higher that of HMGB1 high placental cell nucleus expression group.(5)The expression of serum HMGB1 and s TLR4 in negative expression of cytoplasm HMGB1 is significant lower in that of negative expression of positive HMGB1.Conclusions: 1.HMGB1 and s TLR4 could be predictive biomarkers of HCA related premature delivery.2.Matrix serum HMGB1 is risk factor of EONS,Matrix serum s TLR4 is protective factor of EONS.Matrix serum HMGB1 could be a predictive biomarker of EONS.3.HCA serum HMGB1 maybe partly secret by placental cel.