A Novel Anti‐Inflammatory Agent for the Management of Preeclampsia

Preeclampsia (PE) is a hypertensive disorder of pregnancy which impacts approximately 5–8% of all pregnancies worldwide and is the leading cause of maternal and fetal morbidity and mortality. PE is characterized by new onset of hypertension, typically after 20 weeks gestation, in addition to at least one other symptom such as proteinuria, liver dysfunction or low platelet count. Though the etiology of PE has yet to be elucidated, placental ischemia is believed to be central to the development of this disease. In response, the hypo‐perfused placenta releases a number of factors into the maternal circulation, including inflammatory cytokines like TNFα. Targeting this inflammatory response has been shown to lower blood pressure and improve endothelial function in preclinical PE models. We have recently developed a synthetic polypeptide drug carrier, elastic‐like polypeptide (ELP), for delivery of drugs during pregnancy. ELP prolongs the half‐life of small peptide‐based therapeutics in the circulation and prevents fetal exposure of the agents by preventing placental transfer to the fetal circulation. In order to target placental inflammation, we have produced an ELP‐ fusion protein (ELP‐P50) targeting a master regulator of inflammation, nuclear factor‐ κB (NF‐κB). Because NF‐κB has been shown to be elevated in preeclamptic women and the immune system has been shown to be activated in this disease, we tested the hypothesis that administration of ELP‐P50 would attenuate the maternal hypertension and inflammation in the reduced uterine perfusion pressure (RUPP) model of pregnancy‐induced hypertension. Compared to the sham operated rat, RUPP rats have significantly higher MAP (99 ± 4 mmHg vs 122 ± 3 mmHg; p< 0.001). Administration of ELP‐P50 from GD14–19 in RUPP rats significantly reduces MAP, at both low 50 mg/kg (122 ± 3 mmHg vs 111 ± 2 mmHg; p< 0.05) or high 75 mg/kg (122 ± 3 mmHg vs 111 ± 2 mmHg; p< 0.05) dose. As TNFα is a known target upregulated by NF‐κB, we measured the effects of ELP‐P50 on placental production of TNFα. As measured by ELISA, there was a trend for increased TNFα in RUPP animals compared to shams (4.4 ± 0.7 μg/mL/mg vs 3.2 ± 0.3 μg/mL/mg total protein; p= 0.15). When the RUPP animals were treated with the ELP‐P50, there was a significant reduction in TNFα. There was a 50% reduction in placental TNFα in both animals receiving 50 mg/kg (2.2 ± 0.3 μg/mL/mg vs 4.4 ± 0.7 μg/mL/mg total protein; p<0.05), and the animals receiving 75 mg/kg of ELP‐P50 (2.2 ± 0.1 μg/mL/mg vs 4.4 ± 0.7 μg/mL/mg total protein; p< 0.05). It is known that TNFα can also act as a cytokine to promote immune cell infiltration. For this reason, we measured T‐cell populations in the animal placentas by flow cytometry. There were no significant differences, however, in either helper T‐cells or cytotoxic T‐cells suggesting the NF‐κB activation has no impact on these resident immune cells. ELP‐P50 is able to significantly reduce blood pressure and lower levels of placental TNFα in the rodent RUPP model of placental ischemia. The fact that blood pressure is not completely returned to normal, however, unsurprisingly suggests that there are other pathways involved in the development of hypertension in the RUPP model. Future studies will further characterize the mechanism of action of this agent and confirmatory studies will be performed in other experimental models of PE to advance the translation of this agent as a possible therapeutic agent for PE. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .