BACKGROUND: Tumor necrosis factor (TNF) is a pro-inflammatory cytokine elevated in the maternal circulation in preeclampsia, contributing to systemic inflammation and vasoconstriction. Here, we aimed to evaluate whether biologic TNF inhibitors, clinically used to treat chronic inflammatory conditions, could be repurposed to mitigate inflammation and vascular dysfunction in preclinical models of preeclampsia.
METHODS: Isolated primary human umbilical vein endothelial cells (HUVECs) from term healthy pregnancies were treated with biologic TNF inhibitors: 100-700nM infliximab and 5-50nM certolizumab pegol (± recombinant human TNF protein to model endothelial dysfunction). Production of pro-inflammatory cytokines, chemokines, endothelial activation and angiogenic factors were assessed via molecular analysis. Using wire myography, healthy pregnant human omental arteries were pre-constricted with preeclamptic serum, and vasodilation to infliximab and certolizumab pegol was measured.
RESULTS: In response to TNF induced endothelial dysfunction, both infliximab and certolizumab pegol significantly reduced endothelial activation markers: vascular cell adhesion molecule (VCAM), intracellular adhesion molecule (ICAM), and cytokines/chemokines Interleukin (IL)-6, IL-8, and C-C motif chemokine ligand 2 (CCL2). Neither TNF inhibitor however altered production of markers in the absence of TNF stimulation, nor did they alter anti-angiogenic factor sFLT1. Both TNF inhibitors induced HUVEC production of endothelial nitric oxide synthase, but only infliximab induced direct vasodilation of omental arteries.
CONCLUSION: TNF inhibition via biologic therapies possessing strong safety profiles for use in pregnancy offer a novel strategy to block vascular dysfunction 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.