Decreased placental tumor necrosis factor-alpha in response to neutralization of FAS ligand during pregnancy complicated with HELLP syndrome
John Polk Dumas1, Jacob Gibbens1, Shauna-Kay Spencer1, Teylor Bowles1, Patrick B. Kyle2, Kedra Wallace1
1Department of Obstetrics & Gynecology, University of Mississippi Medical Center, Jackson, MS
2Department of Pathology, University of Mississippi Medical Center, Jackson, MiS
The Fas ligand (FasL) system has an impact on inflammation and hypertension during pregnancy and is dysregulated in women with severe preeclampsia and HELLP syndrome. We have recently reported that endothelin antagonism impacted the Fas/FasL system, therefore in the current study we tested the hypothesis that FasL blockade in an animal model of HELLP syndrome decreases inflammation, improves endothelial damage and in turn improves hypertension. Mini-osmotic pumps infusing anti-angiogenic factors sFlt-1 and sEng were placed into normal pregnant (NP) rats on gestational day (GD) 12 to induce HELLP syndrome (n=15). On GD13, 7 of these HELLP rats were infused with 500ng/kg of MFL4 via the jugular vein to inhibit FasL. Untreated NP rats (n=5) served as controls. On GD19 mean arterial pressure (MAP) was measured and all rats were euthanized and maternal tissues were collected. Administration of FasL to HP rats significantly decreased MAP (p=0.03) compared to untreated HP rats. Circulating FasL was significantly increased in HELLP rats compared to NP rats (p=0.0006) but was attenuated with infusion of MFL4 (p=0.0005). Placental protein expression of TNF-alpha, measured via ELISA, was significantly reduced due to MFL4 infusion in HELLP rats (p=0.0009). These data suggest that neutralization of FasL decreases MAP and improves placental inflammation in an animal model of HELLP syndrome.