Song Ji Eun, Park Seok Ju, Lee Keun Young, Lee Wang Jae
a Department of Obstetrics and Gynecology , Hallym University School of Medicine , Seoul , Republic of Korea.
b Ilsong Institute of Life Science , Hallym University , Anyang , Republic of Korea.
J Matern Fetal Neonatal Med. 2019 Jul;32(14):2287-2294. doi: 10.1080/14767058.2018.1432037. Epub 2018 Feb 15.
Hypoxia inducible factor 1α (HIF1α) has been reported to activate inflammatory cascade. Recently, exosomes have been known to have pivotal roles in intercellular communication. The aim of this study was to compare the concentration of amniotic fluid (AF) HIF1α, exosomal HIF1α, and inflammatory cytokines such as interleukin 1α (IL1α), interleukin 1β (IL1β), interleukin 6 (IL6), and tumor necrosis factor α (TNFα) between physical examination-indicated cerclage (PEIC) and control group. We also investigated the associations between biomarkers and amniocentesis-to-delivery interval and the correlations of inflammatory cytokines, HIF1α, and exosomal HIF1α.
Case-control study was performed. Cases are defined as 16 patients who underwent PEIC and controls are 19 women who underwent amniocentesis for confirming chromosomal abnormalities. The concentration of IL1α, IL1β, IL6, TNFα, HIF1α, and exosomal HIF1α were measured using enzyme-linked immunosorbent assay (ELISA). Exosomes were confirmed by tumor susceptibility Gene 101 (TSG 101) and transmission electron microscopy (TEM).
The mean HIF1α in PEIC group was higher than control group (PEIC, 15.03 ± 9.60-pg/mL versus control, 2.96 ± 1.99 pg/mL; p < .01). There were significant differences in inflammatory cytokines between two groups. A significant difference in exosomal HIF1α was shown between two groups (PEIC, 27.97 ± 28.61-µg/mL versus control, 12.42 ± 8.20 µg/mL; p < .01). HIF1α, IL1α, IL6, TNFα, and exosomal HIF1α showed significantly negative association with cerclage-to-delivery interval. However, IL1β was not associated with cerclage-to-delivery interval. HIF1α was positively correlated with exosomal HIF1α (rho = 0.93, p < .01). Both HIF1α and exosomal HIF1α were significantly associated with TNFα (rho = 0.94, p < .01; rho = 0.97, p < .01). Both HIF-1α and exosomal HIF1α had positive correlation with IL1α (rho = 0.96, p < .01; rho = 0.91, p < .01). However, IL1β showed no correlations with HIF1α and exosomal HIF1α. A positive correlation between HIF-1α and IL6 was observed (rho = 0.58, p = .01.) Exosomal HIF1α also had correlation with IL6 (rho = 0.52, p = .03).
This study demonstrated that amniotic fluid (AF) HIF1α and AF exosomal HIF1α were higher in physical examination-indicated cerclage (PEIC) group than control group. AF HIF1α and AF exosomal HIF1α were associated with shorter amniocentesis-to-delivery interval. More importantly, they had positive correlations with AF inflammatory cytokines such as IL1α, IL6, and TNFα. Our results may indicate that AF HIF1α and AF exosomes interact with AF inflammatory cytokines and contribute inflammatory cascade in complicated pregnancies.
据报道，缺氧诱导因子1α（HIF1α）可激活炎症级联反应。最近，已知外泌体在细胞间通讯中起关键作用。本研究的目的是比较体格检查指征性宫颈环扎术（PEIC）组和对照组羊水（AF）中HIF1α、外泌体HIF1α以及白细胞介素1α（IL1α）、白细胞介素1β（IL1β）、白细胞介素6（IL6）和肿瘤坏死因子α（TNFα）等炎性细胞因子的浓度。我们还研究了生物标志物与羊膜腔穿刺术至分娩间隔之间的关联，以及炎性细胞因子、HIF1α和外泌体HIF1α之间的相关性。
进行病例对照研究。病例定义为16例行PEIC的患者，对照为19例因确认染色体异常而行羊膜腔穿刺术的女性。采用酶联免疫吸附测定（ELISA）法检测IL1α、IL1β、IL－6、TNFα、HIF1α和外泌体HIF1α的浓度。通过肿瘤易感基因101（TSG 101）和透射电子显微镜（TEM）确认外泌体。
PEIC组的平均HIF1α高于对照组（PEIC组为15.03±9.60 pg/mL，对照组为2.96±1.99 pg/mL；p＜0.01）。两组之间炎性细胞因子存在显著差异。两组在外泌体HIF1α方面存在显著差异（PEIC组为27.97±28.61 μg/mL，对照组为12.42±8.20 μg/mL；p＜0.01）。HIF1α、IL1α、IL6、TNFα和外泌体HIF1α与宫颈环扎术至分娩间隔呈显著负相关。然而，IL1β与宫颈环扎术至分娩间隔无关。HIF1α与外泌体HIF1α呈正相关（rho＝0.93，p＜0.01）。HIF1α和外泌体HIF1α均与TNFα显著相关（rho＝0.94，p＜0.01；rho＝0.97，p＜0.01）。HIF－1α和外泌体HIF1α均与IL1α呈正相关（rho＝0.96，p＜0.01；rho＝0.91，p＜0.01）。然而，IL1β与HIF1α和外泌体HIF1α无相关性。观察到HIF－1α与IL6呈正相关（rho＝0.58，p＝0.01）。外泌体HIF1α也与IL6相关（rho＝0.52，p＝0.03）。
本研究表明，体格检查指征性宫颈环扎术（PEIC）组羊水（AF）中HIF1α和AF外泌体HIF1α高于对照组。AF HIF1α和AF外泌体HIF1α与较短的羊膜腔穿刺术至分娩间隔相关。更重要的是，它们与AF炎性细胞因子如IL1α、IL6和TNFα呈正相关。我们的结果可能表明，AF HIF1α和AF外泌体与AF炎性细胞因子相互作用，并在复杂妊娠中促成炎症级联反应。
