Synthetic PreImplantation Factor (sPIF) reduces inflammation and prevents preterm birth

Abstract

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality and spontaneous PTB is a major contributor. The preceding inflammation/infection contributes not only to spontaneous PTB but is associated with neonatal morbidities including impaired brain development. Therefore, control of exaggerated immune response during pregnancy is an attractive strategy. A potential candidate is synthetic PreImplantation Factor (sPIF) as sPIF prevents inflammatory induced fetal loss and has neuroprotective properties. Here, we tested maternal sPIF prophylaxis in pregnant mice subjected to a lipopolysaccharides (LPS) insult, which results in PTB. Additionally, we evaluated sPIF effects in placental and microglial cell lines. Maternal sPIF application reduced the LPS induced PTB rate significantly. Consequently, sPIF reduced microglial activation (Iba-1 positive cells) and preserved neuronal migration (Cux-2 positive cells) in fetal brains. In fetal brain lysates sPIF decreased IL-6 and INFγ concentrations. In-vitro, sPIF reduced Iba1 and TNFα expression in microglial cells and reduced the expression of pro-apoptotic (Bad and Bax) and inflammatory (IL-6 and NLRP4) genes in placental cell lines. Together, maternal sPIF prophylaxis prevents PTB in part by controlling exaggerated immune response. Given the sPIF'FDA Fast Track approval in non-pregnant subjects, we envision sPIF therapy in pregnancy.

Understanding Host-Pathogen Interactions in Acute Chorioamnionitis Through the Use of Animal Models

“…-+ + 5 + + ( Akgul et al, 2014;Chin et al, 2016;Gomez-Lopez et al, 2018;Spinelli et al, systemic inflammation are the closest approximations of preterm birth in response to maternal systemic inflammation, which occurs in cases of pyelonephritis and influenza. Caution should be used when generalizing findings from these models to the more common scenario of acute chorioamnionitis in which inflammation is greatest within the uterus, remains local, and occurs in the absence of clinical signs or symptoms in the pregnant mother (Gravett et al, 1986;Gibbs et al, 1992;Gomez-Lopez et al, 2018).…”

“…Whether variations in this immune modulation could underlie individual differences in susceptibility to microbial invasion or production of inflammation is a fascinating area of ongoing research ( Firmal et al., 2020 ). It opens the possibility to maternal prophylactic treatments as well ( Di Simone et al., 2017 ; Spinelli et al., 2020 ).…”

“…The mice models are fairly well suited to projects aimed at understanding mechanisms of bacterial spread and preterm birth as germ-free environments/caging is possible ( Seferovic et al., 2019 ). These models provide further insights into the development of materno-fetal immunity and therapeutics ( Garcia-Flores et al., 2018 ; Gomez-Lopez et al., 2018 ; Ganal-Vonarburg et al., 2020 ; Spinelli et al., 2020 ). The effects of prenatal treatments can be visualized in crucial organs like the placenta or the fetal brain and correlated to basic functional outcomes ( Di Simone et al., 2017 ; Spinelli et al., 2020 ).…”

“…These models provide further insights into the development of materno-fetal immunity and therapeutics ( Garcia-Flores et al., 2018 ; Gomez-Lopez et al., 2018 ; Ganal-Vonarburg et al., 2020 ; Spinelli et al., 2020 ). The effects of prenatal treatments can be visualized in crucial organs like the placenta or the fetal brain and correlated to basic functional outcomes ( Di Simone et al., 2017 ; Spinelli et al., 2020 ). Differences in immune system components and the consequences of being raised in facilities devoid of microbial diversity should be kept in mind, given the central role of host immune responses in acute chorioamnionitis pathophysiology ( Tao and Reese, 2017 ).…”

“…Thus far, targeting the vaginal microbiome has not been successful in preventing premature birth and new approaches, such as modulation of the maternal immune response are increasingly in focus ( Al-Nasiry et al., 2020 ). These strategies target immune modulation such as a decrease in pro-inflammatory cytokine production rather than antibiotic treatments ( Mueller et al., 2014 ; Di Simone et al., 2017 ; Spinelli et al., 2020 ; Xiong and Wintermark, 2020 ). Although promising, these therapies have not yet been put into use clinically.…”