BACKGROUND: Preeclampsia is a deadly pregnancy complication characterised by placental dysfunction, maternal systemic inflammation and vasoconstriction. Tumor necrosis factor (TNF) is a pro-inflammatory cytokine elevated in the maternal circulation in preeclampsia. Here, we aimed to evaluate whether TNF inhibitors - biologic monoclonal antibodies targeting TNF and clinically used to treat chronic inflammatory conditions - could be repurposed to mitigate inflammation and vascular dysfunction in human placental and vascular models of preeclampsia.
METHODS: Placental tissue collected from pregnancies complicated by preterm preeclampsia and primary human umbilical vein endothelial cells (HUVECs) isolated from healthy term pregnancies were treated with biologic TNF inhibitors: 100-700nM infliximab and 5-50nM certolizumab pegol (± recombinant human TNF protein to model endothelial dysfunction) (n=5). Production of pro-inflammatory cytokines, chemokines, endothelial activation and angiogenic factors were assessed (qPCR, multiplex protein assays, western blotting). Using wire myography, healthy pregnant human omental arteries were pre-constricted with preeclamptic serum, and vasodilation to infliximab and certolizumab pegol measured.
RESULTS: The TNF inhibitors did not alter placental expression of pro-inflammatory factors IL-6, IL-8, TNF, PTGS2, angiogenic PlGF or secretion of anti-angiogenic sFLT1. In response to TNF induced endothelial dysfunction, both infliximab and certolizumab pegol significantly reduced endothelial activation markers: VCAM, ICAM and cytokines/chemokines IL-6, IL-8, and CCL2. Neither TNF inhibitor altered HUVEC production of markers in the absence of TNF stimulation, nor did they alter sFLT1 secretion. Both TNF inhibitors induced HUVEC production of endothelial nitric oxide synthase, but only infliximab induced direct vasodilation of omental arteries.
CONCLUSION: With known safety profiles for use in pregnancy, TNF inhibitors offer a novel strategy to mitigate vascular dysfunction and systemic vasoconstriction associated with preeclampsia. These data suggest that infliximab provides the most promising option of the two, and warrants further investigation to progress to clinical trials.