Abstract
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 Il1β and Nos2, 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 via the maintenance of macrophage M1/M2 imbalance in the placenta.
Highlights
Intrauterine inflammation (IUI) is the primary cause of spontaneous preterm birth and predisposes neonates to longterm sequelae, including adverse neurological outcomes, and accounting for approximately 35% of neonatal deaths in 2017 (Chawanpaiboon et al, 2019; Hug et al, 2019)
We investigated the effect of maternal dendrimer-based N-Acetyl Cysteine (DNAC) therapy towards ameliorating placental inflammation through macrophage recruitment and polarization via M1/M2, following IUI
We found that DNAC decreased CD45+ leukocytes infiltration in the placenta following IUI
Summary
Intrauterine inflammation (IUI) is the primary cause of spontaneous preterm birth and predisposes neonates to longterm sequelae, including adverse neurological outcomes, and accounting for approximately 35% of neonatal deaths in 2017 (Chawanpaiboon et al, 2019; Hug et al, 2019). The proinflammatory cytokines induced by IUI lead to fetal inflammatory response syndrome (FIRS), which results in these neonatal complications (Romero et al, 2005; Burd et al, 2012; Cappelletti et al, 2016). Pro-inflammatory stimulation causes changes in the maternal immune system and placental microenvironment, a process in which placental macrophages may play an important role. The macrophage is the primary cell in the acute inflammatory response. Maternal decidual and fetal placental macrophages ( known as Hoffbauer cells) are maintained in an anti-inflammatory state to achieve immune tolerance of the fetus (Bolton and Bilbo, 2014)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
