The Role of Complement Modulation in Preterm Birth and Fetal Neural Inflammation

This study investigates the role of complement and the effect of its modulation in preterm birth (PTB) and fetal neural inflammation utilizing a murine model of inflammation mediated PTB. The complement inhibitor, CR2-Crry, which targets sites of complement activation C3d deposition, was employed to prevent activation of the complement cascade. To determine the latency between endotoxin insult and complement activation, timed pregnant C57/BL6 dams received intrauterine bacterial endotoxin (LPS) on embryo day 15 (E15). Animals were sacrificed at 1, 3, 6, 9, 18, and 24 hours after LPS administration and tissue isolated. Tissues were stained for complement deposition via immunofluorescence and analyzed for expression of cytokines to determine inflammatory response kinetics. To evaluate the role of complement modulation in PTB, E15 pregnant dams were randomized to receive CR2-Crry or vehicle (PBS) one hour after LPS. Animals were monitored for perinatal outcomes including PTB and maternal mortality. Dams were euthanized intrapartum and tissues were collected for staining and expression of cytokines. Complement activation and macrophage recruitment occurred in the maternal cervix as early as 1 hour after LPS administration (Fig 1). In maternal tissues, cytokine expression was greatest at 9 hrs after LPS administration, and 48 hrs in fetal neural tissues. Compared to vehicle (PBS), animals in the CR2-Crry treatment group had a significant prolongation in latency delivery (31 vs 103 hrs; p< 0.001) (Fig 2a). IL-6 expression in fetal neural tissue from dams treated with CR2-Crry was significantly reduced compared to dams treated with vehicle (p=0.016) and was similar to gestational-age matched naïve animals (p=0.395; Fig 2b). In a murine model of intrauterine inflammation and PTB, site-targeted complement inhibition significantly prolonged the latency between LPS administration and delivery and significantly reduced fetal inflammation. There appears to be a latency period between maternal and fetal inflammatory responses where intervention is possible.View Large Image Figure ViewerDownload Hi-res image Download (PPT)