Dataset Information

Increased Neutrophil Activation and Plasma DNA Levels in Patients with Pre-Eclampsia.

ABSTRACT: Pre-eclampsia (PE) is a chronic inflammatory disease in pregnancy, which is associated with enhanced blood coagulation and high thrombotic risk. To date, the mechanisms underlying such an association are not fully understood. Previous studies reported high levels of plasma deoxyribonucleic acid (DNA) in PE women, but the cellular source of the circulation DNA remains unknown. In this study, we tested the hypothesis that activated neutrophils undergoing cell death, also called NETosis, may be responsible for the elevated plasma DNA levels in PE women. We analysed plasma samples from non-pregnant, normal pregnant and PE women and found high levels of double-stranded DNA, myeloperoxidase (an abundant neutrophil granular enzyme) and histones (the major nucleosome proteins) in PE-derived samples, indicating increased NETosis in the maternal circulation. The high plasma DNA levels positively correlated with enhanced blood coagulation in PE women. When isolated neutrophils from normal individuals were incubated with PE-derived plasma, an elevated NETosis-stimulating activity was detected. Further experiments showed that endothelial micro-particles, but not soluble proteins, in the plasma were primarily responsible for the NETosis-stimulating activity in PE women. These results indicate that circulating micro-particles from damaged maternal endothelium are a potent stimulator for neutrophil activation and NETosis in PE women. Given the pro-coagulant and pro-thrombotic nature of granular and nuclear contents from neutrophils, enhanced systemic NETosis may represent an important mechanism underlying the hyper-coagulability and increased thrombotic risk in PE.

SUBMITTER: Hu Y

PROVIDER: S-EPMC6567982 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Increased Neutrophil Activation and Plasma DNA Levels in Patients with Pre-Eclampsia.

Hu Yae Y Li Hui H Yan Ruhong R Wang Can C Wang Yun Y Zhang Ce C Liu Meng M Zhou Tiantian T Zhu Weipei W Zhang Hong H Dong Ningzheng N Wu Qingyu Q

Thrombosis and haemostasis 20181119 12

Pre-eclampsia (PE) is a chronic inflammatory disease in pregnancy, which is associated with enhanced blood coagulation and high thrombotic risk. To date, the mechanisms underlying such an association are not fully understood. Previous studies reported high levels of plasma deoxyribonucleic acid (DNA) in PE women, but the cellular source of the circulation DNA remains unknown. In this study, we tested the hypothesis that activated neutrophils undergoing cell death, also called NETosis, may be res ...[more]

PMID: 30453347

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Project description:Systemic lupus erythematosus (SLE) is associated with increased risk of adverse pregnancy outcomes, including pre-eclampsia, particularly in association with antiphospholipid antibody syndrome (APS). While significant placental abnormalities are expected in pre-eclampsia, less is known about how lupus activity and APS in pregnancy affect the placenta. We describe placental pathology from a population of lupus pregnancies, several of which were complicated by APS-related thromboses, in which pre-eclampsia and other complications developed. We performed standard histopathological placental review and quantified neutrophils and neutrophil extracellular traps (NETs) in the intervillous space, given the recognised association of NETs with lupus, APS and pre-eclampsia.Pre-eclampsia, SLE and control placentas were scored for histological features, and neutrophils were quantified on H&E and immunohistochemical staining for the granular protein myeloperoxidase. NETs were identified by extracellular myeloperoxidase staining in the setting of decondensed nuclei. Non-parametric analysis was used to evaluate differences in netting and intact neutrophils between groups, with Kruskal-Wallis testing for associations between histological findings and neutrophils.Placentas were evaluated from 35 pregnancies: 10 controls, 11 pre-eclampsia, 4 SLE+pre-eclampsia and 10 SLE, including one complicated by catastrophic APS and one complicated by hepatic and splenic vein thromboses during pregnancy. Intrauterine growth restriction and oligohydramnios were observed in lupus cases but not controls. Significantly more NETs were found infiltrating placental intervillous spaces in pre-eclampsia, SLE+pre-eclampsia and all 10 SLE non-pre-eclampsia cases. The ratio of NETs to total neutrophils was significantly increased in all case groups compared with controls. When present, NETs were associated with maternal vasculitis, laminar decidual necrosis, maternal-fetal interface haemorrhage and non-occlusive fetal thrombotic vasculopathy.In this pilot study of placental tissue from lupus pregnancies, outcomes were more complicated, particularly if associated with APS. Placental tissue revealed marked inflammatory and vascular changes that were essentially indistinguishable from placental tissue of pre-eclampsia pregnancies.

Project description:BackgroundPre-eclampsia is the most common complication occurring during pregnancy. In the majority of cases, it is concurrent with other pathologies in a comorbid manner (frequent co-occurrences in patients), such as diabetes mellitus, gestational diabetes and obesity. Providing bronchial asthma, pulmonary tuberculosis, certain neurodegenerative diseases and cancers as examples, we have shown previously that pairs of inversely comorbid pathologies (rare co-occurrences in patients) are more closely related to each other at the molecular genetic level compared with randomly generated pairs of diseases. Data in the literature concerning the causes of pre-eclampsia are abundant. However, the key mechanisms triggering this disease that are initiated by other pathological processes are thus far unknown. The aim of this work was to analyse the characteristic features of genetic networks that describe interactions between comorbid diseases, using pre-eclampsia as a case in point.ResultsThe use of ANDSystem, Pathway Studio and STRING computer tools based on text-mining and database-mining approaches allowed us to reconstruct associative networks, representing molecular genetic interactions between genes, associated concurrently with comorbid disease pairs, including pre-eclampsia, diabetes mellitus, gestational diabetes and obesity. It was found that these associative networks statistically differed in the number of genes and interactions between them from those built for randomly chosen pairs of diseases. The associative network connecting all four diseases was composed of 16 genes (PLAT, ADIPOQ, ADRB3, LEPR, HP, TGFB1, TNFA, INS, CRP, CSRP1, IGFBP1, MBL2, ACE, ESR1, SHBG, ADA). Such an analysis allowed us to reveal differential gene risk factors for these diseases, and to propose certain, most probable, theoretical mechanisms of pre-eclampsia development in pregnant women. The mechanisms may include the following pathways: [TGFB1 or TNFA]-[IL1B]-[pre-eclampsia]; [TNFA or INS]-[NOS3]-[pre-eclampsia]; [INS]-[HSPA4 or CLU]-[pre-eclampsia]; [ACE]-[MTHFR]-[pre-eclampsia].ConclusionsFor pre-eclampsia, diabetes mellitus, gestational diabetes and obesity, we showed that the size and connectivity of the associative molecular genetic networks, which describe interactions between comorbid diseases, statistically exceeded the size and connectivity of those built for randomly chosen pairs of diseases. Recently, we have shown a similar result for inversely comorbid diseases. This suggests that comorbid and inversely comorbid diseases have common features concerning structural organization of associative molecular genetic networks.

Dataset Information

Increased Neutrophil Activation and Plasma DNA Levels in Patients with Pre-Eclampsia.

Publications

Increased Neutrophil Activation and Plasma DNA Levels in Patients with Pre-Eclampsia.

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