Proteomic Study of Fetal Membrane: Inflammation-Triggered Proteolysis of Extracellular Matrix May Present a Pathogenic Pathway for Spontaneous Preterm Birth.

Jing Pan,Xiujuan Tian,Nanbert Zhong,Honglei Huang

doi:10.3389/fphys.2020.00800

Abstract

IntroductionSpontaneous preterm birth (sPTB), which predominantly presents as spontaneous preterm labor (sPTL) or prelabor premature rupture of membranes (PPROM), is a syndrome that accounts for 5–10% of live births annually. The long-term morbidity in surviving preterm infants is significantly higher than that in full-term neonates. The causes of sPTB are complex and not fully understood. Human placenta, the maternal and fetal interface, is an environmental core of fetal intrauterine life, mediates fetal oxygen exchange, nutrient uptake, and waste elimination and functions as an immune-defense organ. In this study, the molecular signature of preterm birth placenta was assessed and compared to full-term placenta by proteomic profiling.Materials and MethodsFour groups of fetal membranes (the amniochorionic membranes), with five cases in each group in the discovery study and 30 cases in each group for validation, were included: groups A: sPTL; B: PPROM; C: full-term birth (FTB); and D: full-term premature rupture of membrane (PROM). Fetal membranes were dissected and used for proteome quantification study. Maxquant and Perseus were used for protein quantitation and statistical analysis. Both fetal membranes and placental villi samples were used to validate proteomic discovery.ResultsProteomics analysis of fetal membranes identified 2,800 proteins across four groups. Sixty-two proteins show statistical differences between the preterm and full-term groups. Among these differentially expressed proteins are (1) proteins involved in inflammation (HPGD), T cell activation (PTPRC), macrophage activation (CAPG, CD14, and CD163), (2) cell adhesion (ICAM and ITGAM), (3) proteolysis (CTSG, ELANE, and MMP9), (4) antioxidant (MPO), (5) extracellular matrix (ECM) proteins (APMAP, COL4A1, LAMA2, LMNB1, LMNB2, FBLN2, and CSRP1) and (6) metabolism of glycolysis (PKM and ADPGK), fatty acid synthesis (ACOX1 and ACSL3), and energy biosynthesis (ATP6AP1 and CYBB).ConclusionOur molecular signature study of preterm fetal membranes revealed inflammation as a major event, which is inconsistent with previous findings. Proteolysis may play an important role in fetal membrane rupture. Extracellular matrix s have been altered in preterm fetal membranes due to proteolysis. Metabolism was also altered in preterm fetal membranes. The molecular changes in the fetal membranes provided a significant molecular signature for PPROM in preterm syndrome.

Highlights

Spontaneous preterm birth, which predominantly presents as spontaneous preterm labor or prelabor premature rupture of membranes (PPROM), is a syndrome that accounts for 5–10% of live births annually
A retrospective study was designed to investigate the pathological alteration of protein expression with a pre-banked birth cohort of 20 placentas, which were grouped as (A): spontaneous preterm labor, defined as a non-medical and/or non-selective spontaneous birth delivered between 20+1 and 36+6 gestational week (GW) in which regular contractions of the uterus result in changes in the cervix before 37 weeks of pregnancy, (B): prelabor premature rupture of membranes (PPROM) that occurred between 20+1 and 36+6 GW, (C): full-term birth (FTB) between 39+1 and 40+6 GW, and (D): full-term premature rupture of membrane (PROM)
Protein differential expression was defined by the criteria of p < 0.01, fold change (FC) ≥ 2, and permutation-based false discovery rate (FDR) 0.05, with which, 62 (38 upregulated and 24 down-regulated) proteins were identified to be differentially expressed (Tables 2a,b)

Summary

Introduction

Spontaneous preterm birth (sPTB), which predominantly presents as spontaneous preterm labor (sPTL) or prelabor premature rupture of membranes (PPROM), is a syndrome that accounts for 5–10% of live births annually. The longterm morbidity in surviving preterm infants is significantly higher than that in full-term neonates. China has about 1.17 million preterm infants birth every year (World Health Organization [WHO], 2018). It has been demonstrated that pregnancy at 40 years of age and older is strongly associated with preterm birth and other disorders of pregnancy (Fuchs et al, 2018). The brain, lung, liver, and other organs are not fully developed, and there is a high incidence of brain injury, neonatal respiratory distress syndrome, bilirubin encephalopathy, and multiple organ failure (Fraser et al, 2004; Bhutani and Wong, 2013; Paton et al, 2017). It is estimated by the WHO that preterm birth is the most common cause of children’s death under the age of 5 years (World Health Organization [WHO], 2018). Preterm birth brings a great economic burden to families, communities, and societies

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