Pollinzi Angela, Mirdamadi Kamelia, Karimian Pour Navaz, Asthana-Nijjar Rashi, Lee Dennis, Nevo Ori, Piquette-Miller Micheline
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
Drug Metab Dispos. 2025 Feb;53(2):100031. doi: 10.1016/j.dmd.2024.100031. Epub 2024 Dec 12.
Autoimmune diseases (ADs), such as systemic lupus erythematosus (SLE), require multiple medications to ensure maternal-fetal health during pregnancy. These medications are often substrates for placental transporters that could cross over to the fetal compartment. However, the effects of ADs on placental transporters remain poorly understood. This study aimed to investigate the impact of ADs on placental transporters and key inflammatory cytokines. Human preterm and term placentas from AD-affected women (n = 28) and gestational age-matched controls (n = 38) were collected. The placentas were examined for transporter expression via quantitative real-time PCR and immunodetection. Subgroup analysis and untargeted proteomic analysis of samples from patients with SLE were performed. P-glycoprotein (P-gp/ABCB1) and organic anion transporter 4 (OAT4/SLC22A11) mRNA expression were significantly decreased and expression of T helper 17- associated cytokines were increased in preterm and term AD placenta relative to controls. P-gp protein expression was also downregulated in preterm, but not in term AD placenta. Subgroup analysis of SLE also detected downregulation of P-gp and OAT4 at the mRNA level in preterm samples. Proteomic analysis of SLE and control samples indicated global changes in proteins related to processes like inflammation, oxidative stress, angiogenesis, and hemostasis. These findings elucidate that ADs such as SLE are associated with the downregulation of the ABC transporter P-gp in the placenta as well as global changes to the placenta proteome. Dysregulation of cytokines and associated pathways was also observed and postulated to cause changes in placental transporters. Future studies that validate these mechanisms could offer potential strategies to mitigate inflammation-mediated alterations in placental transporters, ultimately improving fetal and neonatal health. SIGNIFICANCE STATEMENT: Autoimmune diseases have significant effects on the placenta, influencing pregnancy outcomes and the effectiveness of prescribed medications. The study revealed that autoimmune diseases induce inflammatory cytokines in the placenta and were associated with a significant downregulation of P-glycoprotein. Additionally, in patients affected by lupus, proteomics uncovered the enrichment of pathways associated with placental damage and dysfunction. This work will help inform care plans for these patients by identifying clinically relevant proteins that are affected by the disease, improving maternal-fetal outcomes.
自身免疫性疾病（ADs），如系统性红斑狼疮（SLE），在孕期需要多种药物来确保母婴健康。这些药物通常是胎盘转运蛋白的底物，可能会进入胎儿体内。然而，ADs对胎盘转运蛋白的影响仍知之甚少。本研究旨在调查ADs对胎盘转运蛋白和关键炎性细胞因子的影响。收集了受AD影响的女性的人类早产和足月胎盘（n = 28）以及孕周匹配的对照组胎盘（n = 38）。通过定量实时PCR和免疫检测检查胎盘的转运蛋白表达。对SLE患者的样本进行了亚组分析和非靶向蛋白质组分析。与对照组相比，早产和足月AD胎盘的P-糖蛋白（P-gp/ABCB1）和有机阴离子转运蛋白4（OAT4/SLC22A11）mRNA表达显著降低，辅助性T细胞17相关细胞因子的表达增加。早产AD胎盘中P-gp蛋白表达也下调，但足月AD胎盘中未下调。SLE的亚组分析还检测到早产样本中P-gp和OAT4在mRNA水平的下调。SLE和对照样本的蛋白质组分析表明，与炎症、氧化应激、血管生成和止血等过程相关的蛋白质发生了全局性变化。这些发现表明，SLE等ADs与胎盘中ABC转运蛋白P-gp的下调以及胎盘蛋白质组的全局性变化有关。还观察到细胞因子及其相关途径的失调，并推测其会导致胎盘转运蛋白的变化。未来验证这些机制的研究可能会提供潜在策略，以减轻炎症介导的胎盘转运蛋白改变，最终改善胎儿和新生儿健康。意义声明：自身免疫性疾病对胎盘有重大影响，影响妊娠结局和处方药的疗效。该研究表明，自身免疫性疾病会在胎盘中诱导炎性细胞因子，并与P-糖蛋白的显著下调有关。此外，在狼疮患者中，蛋白质组学发现了与胎盘损伤和功能障碍相关的通路富集。这项工作将通过识别受疾病影响的临床相关蛋白质来为这些患者的护理计划提供参考，改善母婴结局。
