Akram Khondoker M, Frost Lucy I, Anumba Dilly Oc
Academic Unit of Reproductive and Developmental Medicine, Department of Oncology and Metabolism, The University of Sheffield, Sheffield, United Kingdom.
Front Mol Biosci. 2022 Aug 26;9:897228. doi: 10.3389/fmolb.2022.897228. eCollection 2022.
Despite decades of research, the pathogenesis of spontaneous preterm birth (PTB) remains largely unknown. Limited currently available data on PTB pathogenesis are based on rodent models, which do not accurately reflect the complexity of the human placenta across gestation. While much study has focused on placental infection and inflammation associated with PTB, two key potentially important cellular events in the placenta-apoptosis and autophagy-remained less explored. Understanding the role of these processes in the human placenta may unravel currently ill-understood processes in the pathomechanism of PTB. To address this necessity, we conducted qRT-PCR and ELISA assays on placental villous tissue from 20 spontaneous preterm and 20 term deliveries, to assess the inter-relationships between inflammation, apoptosis, and autophagy in villous tissue in order to clarify their roles in the pathogenesis of PTB. We found disrupted balance between pro-apoptotic BAX and anti-apoptotic BCL2 gene/protein expression in preterm placenta, which was associated with significant reduction of BCL2 and increase of BAX proteins along with upregulation of active CASP3 and CASP8 suggesting augmented apoptosis in PTB. In addition, we detected impaired autophagy in the same samples, evidenced by significant accumulation of autophagosome cargo protein p62/SQSTM1 in the preterm villous placentas, which was associated with simultaneous downregulation of an essential autophagy gene and upregulation of Ca-activated cysteine protease CAPN1. Placental aggregation of p62 was inversely correlated with newborn birth weight, suggesting a potential link between placental autophagy impairment and fetal development. These two aberrations were detected in a micromilieu where the genes of the Th2 cytokines and were downregulated, suggesting an alteration in the Th1/Th2 immune balance in the preterm placenta. Taken together, our observations suggest that impaired autophagy and augmented apoptosis in a Th1/Th2 imbalanced placental micro-environment may be associated with the pathogenesis of spontaneous PTB.
尽管经过了数十年的研究，但自发性早产（PTB）的发病机制在很大程度上仍然未知。目前关于PTB发病机制的可用数据有限，这些数据基于啮齿动物模型，而该模型无法准确反映人类胎盘在整个妊娠期的复杂性。虽然许多研究都集中在与PTB相关的胎盘感染和炎症上，但胎盘中两个关键的潜在重要细胞事件——细胞凋亡和自噬——仍较少被探索。了解这些过程在人类胎盘中的作用可能会揭示目前在PTB发病机制中尚未完全理解的过程。为了满足这一需求，我们对20例自发性早产和20例足月分娩的胎盘绒毛组织进行了qRT-PCR和ELISA检测，以评估绒毛组织中炎症、细胞凋亡和自噬之间的相互关系，从而阐明它们在PTB发病机制中的作用。我们发现早产胎盘中促凋亡蛋白BAX和抗凋亡蛋白BCL2的基因/蛋白表达平衡被破坏，这与BCL2的显著减少、BAX蛋白的增加以及活性CASP3和CASP8的上调有关，提示PTB中细胞凋亡增加。此外，我们在相同样本中检测到自噬受损，早产绒毛胎盘自噬体货物蛋白p62/SQSTM1的显著积累证明了这一点，这与一个关键自噬基因的同时下调和钙激活半胱氨酸蛋白酶CAPN1的上调有关。p62在胎盘中的聚集与新生儿出生体重呈负相关，提示胎盘自噬受损与胎儿发育之间可能存在联系。在Th2细胞因子基因下调的微环境中检测到了这两种异常，提示早产胎盘的Th1/Th2免疫平衡发生了改变。综上所述，我们的观察结果表明，在Th1/Th2失衡的胎盘微环境中自噬受损和细胞凋亡增加可能与自发性PTB的发病机制有关。
