Hypoxia and oxidative stress induce sterile placental inflammation in vitro

Fetal growth restriction (FGR) and stillbirth are associated with placental dysfunction and inflammation and hypoxia, oxidative and nitrative stress are implicated in placental damage. Damage-associated molecular patterns (DAMPs) are elevated in pregnancies at increased risk of FGR and stillbirth and are associated with increase in pro-inflammatory placental cytokines. We hypothesised that placental insults lead to release of DAMPs, promoting placental inflammation. Placental tissue from uncomplicated pregnancies was exposed in vitro to hypoxia, oxidative or nitrative stress. Tissue production and release of DAMPs and cytokines was determined. Oxidative stress and hypoxia caused differential release of DAMPs including uric acid, HMGB1, S100A8, cell-free fetal DNA, S100A12 and HSP70. After oxidative stress pro-inflammatory cytokines (IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, CCL2) were increased both within explants and in conditioned culture medium. Hypoxia increased tissue IL-1 alpha/beta, IL-6, IL-8 and TNF alpha levels, and release of IL-1 alpha, IL-6 and IL-8, whereas CCL2 and IL-10 were reduced. IL1 receptor antagonist (IL1Ra) treatment prevented hypoxia- and oxidative stress-induced IL-6 and IL-8 release. These findings provide evidence that relevant stressors induce a sterile inflammatory profile in placental tissue which can be partially blocked by IL1Ra suggesting this agent has translational potential to prevent placental inflammation evident in FGR and stillbirth.

Automated summary

Fetal growth restriction (FGR) and stillbirth are associated with placental dysfunction and inflammation, with oxidative and nitrative stress implicated in causing placental damage. Elevated levels of damage-associated molecular patterns (DAMPs) in high-risk pregnancies are linked to increased pro-inflammatory placental cytokines. In vitro exposure of placental tissue from uncomplicated pregnancies to hypoxia, oxidative, or nitrative stress resulted in differential release of DAMPs and pro-inflammatory cytokines. IL1 receptor antagonist (IL1Ra) treatment was shown to partially block hypoxia- and oxidative stress-induced placental inflammation, suggesting translational potential for preventing FGR and stillbirth-related placental inflammation.