Hypoxic treatment of human dual placental perfusion induces a preeclampsia-like inflammatory response

Abstract

Preeclampsia is a human pregnancy-specific disorder characterized by a placental pro-inflammatory response in combination with an imbalance of angiogenic factors and clinical symptoms, including hypertension and proteinuria. Insufficient uteroplacental oxygenation in preeclampsia due to impaired trophoblast invasion during placentation is believed to be responsible for many of the molecular events leading to the clinical manifestations of this disease. We investigated the use of hypoxic treatment of the dual placental perfusion system as a model for preeclampsia. A modified perfusion technique allowed us to achieve a mean soluble oxygen tension within the intervillous space (IVS) of 5-7% for normoxia and o3% for hypoxia (as a model for preeclampsia). We assayed for the levels of different inflammatory cytokines, oxidative stress markers, as well as other factors, such as endothelin (ET)-1 that are known to be implicated as part of the inflammatory response in preeclampsia. Our results show a significant increase under hypoxia in the levels of different inflammatory cytokines, including IL-6 (P ¼ 0.002), IL-8 (Po0.0001), TNF-a (P ¼ 0.032) and IFN-g (P ¼ 0.009) at 360 min in maternal venous samples (n ¼ 6). There was also a significant increase in ET-1 levels under hypoxia both on the maternal side at 30 min (P ¼ 0.003) and fetal side at 360 min (P ¼ 0.036) (n ¼ 6). Other markers of oxidative stress, including malondialdehyde and 8-iso-protaglandin F2a (P ¼ 0.009) also show increased levels. Overall, these findings indicate that exposure of ex vivo dually perfused placental tissue to hypoxia provides a useful model for mimicking the inflammatory response characteristic of preeclampsia. This would therefore provide a powerful tool for studying and further delineating the molecular mechanisms involved in the underlying pathophysiology of preeclampsia.

Cytokines, angiogenic, and antiangiogenic factors and bioactive lipids in preeclampsia

“…Thus, LXA4 by enhancing the activity of 11β-HSD2 is able to reduce the exposure of fetus to maternal cortisol and prevent IUGR, one of the complications of pre-eclampsia. These evidences (199)(200)(201)(202) HETEs and lipoxins. The P450 monooxygenases AA to mid-chain HETEs, ω-terminal HETEs and EETs.…”

“…In addition, Jain et al (200) reported a significant increase in the levels of IL-6, IL-8, TNF-α, IFN-γ, endothelin-1, malondialdehyde and 8-iso-protaglandin F2α occurred on hypoxic treatment of the dual placental perfusion system as a model for pre-eclampsia. These results are in support of the contention that pre-eclampsia is an inflammatory condition and oxidative stress occurs in these patients.…”

Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia

“…300 In perfused placentas under hypoxia, both the maternal and fetal side produced increased levels of ET-1. 304 In RUPP rats, preproET levels show a 45% increase in renal cortex and 22% increase in renal medulla. 305 Thus, measurements of circulating ET-1 may not always reflect ET-1 levels locally in tissues.…”

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

“…Studies have shown a 4- to 8-fold increase in ET-1 levels in umbilical cord cells (Kourembanas et al, 1993) and in renal tissues during later stages of PE (Taylor et al, 1990). In perfused placentas under hypoxia, both the maternal and fetal side produced increased levels of ET-1 (Jain et al, 2014). In RUPP rats, preproET levels show a 45% increase in renal cortex and 22% increase in the medulla (Alexander et al, 2001b).…”