Liu Yang, Na Quan, Liu Jin, Liu Anguo, Oppong Akosua, Lee Ji Yeon, Chudnovets Anna, Lei Jun, Sharma Rishi, Kannan Sujatha, Kannan Rangaramanujam M, Burd Irina
Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Center for Nanomedicine, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Front Bioeng Biotechnol. 2022 Jan 28;10:819593. doi: 10.3389/fbioe.2022.819593. eCollection 2022.
Intrauterine inflammation (IUI) is the primary cause of spontaneous preterm birth and predisposes neonates to long-term sequelae, including adverse neurological outcomes. N-acetyl-L-cysteine (NAC) is the amino acid L-cysteine derivative and a precursor to the antioxidant glutathione (GSH). NAC is commonly used clinically as an antioxidant with anti-inflammatory properties. Poor bioavailability and high protein binding of NAC necessitates the use of high doses resulting in side effects including nausea, vomiting, and gastric disruptions. Therefore, dendrimer-based therapy can specifically target the drug to the cells involved in inflammation, reducing side effects with efficacy at much lower doses than the free drug. Towards development of the new therapies for the treatment of maternal inflammation, we successfully administered dendrimer-based N-Acetyl Cysteine (DNAC) in an animal model of IUI to reduce preterm birth and perinatal inflammatory response. This study explored the associated immune mechanisms of DNAC treatment on placental macrophages following IUI, especially on M1/M2 type macrophage polarization. Our results demonstrated that intraperitoneal maternal DNAC administration significantly reduced the pro-inflammatory cytokine mRNA of and , and decreased CD45 leukocyte infiltration in the placenta following IUI. Furthermore, we found that DNAC altered placental immune profile by stimulating macrophages to change to the M2 phenotype while decreasing the M1 phenotype, thus suppressing the inflammatory responses in the placenta. Our study provides evidence for DNAC therapy to alleviate IUI the maintenance of macrophage M1/M2 imbalance in the placenta.
宫内炎症（IUI）是自发性早产的主要原因，并使新生儿易患长期后遗症，包括不良神经学后果。N-乙酰-L-半胱氨酸（NAC）是氨基酸L-半胱氨酸的衍生物，也是抗氧化剂谷胱甘肽（GSH）的前体。NAC在临床上通常用作具有抗炎特性的抗氧化剂。NAC的生物利用度差和高蛋白结合性使得必须使用高剂量，这会导致包括恶心、呕吐和胃部不适在内的副作用。因此，基于树枝状大分子的疗法可以将药物特异性地靶向参与炎症的细胞，以比游离药物低得多的剂量有效降低副作用。为了开发治疗母体炎症的新疗法，我们在IUI动物模型中成功施用了基于树枝状大分子的N-乙酰半胱氨酸（DNAC），以减少早产和围产期炎症反应。本研究探讨了IUI后DNAC治疗对胎盘巨噬细胞的相关免疫机制，特别是对M1/M2型巨噬细胞极化的影响。我们的结果表明，母体腹腔内给予DNAC可显著降低IUI后胎盘促炎细胞因子mRNA的表达，并减少CD45白细胞浸润。此外，我们发现DNAC通过刺激巨噬细胞转变为M2表型，同时减少M1表型，从而改变胎盘免疫谱，进而抑制胎盘炎症反应。我们的研究为DNAC疗法减轻IUI提供了证据，即维持胎盘巨噬细胞M1/M2失衡。
