Abstract P1110: Tumor Necrosis Factor Alpha Blockade Improves Natural Killer Cell Activation, Hypertension, and Mitochondrial Oxidative Stress in a Preclinical Rat Model of Preeclampsia

Abstract

Preeclamptic (PE) women have placental ischemia, hypertension (HTN), mitochondrial (mt) dysfunction, increased mt-reactive oxygen species (ROS), cytolytic natural killer (NK) cells, and pro-inflammatory cytokines, such as tumor necrosis factor (TNFα). The reduced uterine perfusion pressure (RUPP) preclinical rat model of PE, is a well-established model to study mechanisms of hypertension in response to placental ischemia during pregnancy. Previous studies from our lab have shown that TNFα is elevated in RUPP rats and that blockade of TNFα, via etanercept (ETAN) decreases TNFα and HTN. However, the effect of TNFα blockade on NK cell activation, mt protein/function, and mtROS is unknown. We hypothesized that ETAN would decrease blood pressure, NK cell activation, mtROS, and improve mt function in RUPP rats. Rats were divided into 4 groups: normal pregnant (NP) (n=41), RUPP (n=34), RUPP+low dose (LD) ETAN (0.4 mg/kg) (n=11), RUPP+high dose (HD) ETAN (0.8 mg/kg) (n=19). LD was used previously, while HD is clinically used to treat chronic inflammatory diseases. Gestational day 14, RUPP surgery was performed and ETAN administered subcutaneous on day 18. Day 19, conscious blood pressure (MAP), blood and tissues were collected, and mt were isolated. Flow cytometry was used for quantification of NK cells. MAP was elevated in RUPP vs. NP (119 ± 1 vs. 102± 1 mmHg, p<0.05) which was reduced to 110 ± 2 in RUPP + LD ETAN (p<0.05 vs. RUPP) and 116 ± 1 in RUPP + HD ETAN. Activated NK cells were increased in circulation (5.9 ± 1.8 vs. 4.0 ± 1.4 %), placenta (4.8 ± 1.3 vs. 1.9 ± 0.7 %), and kidneys (3.1 ± 0.5 vs. 0.8 ± 0.5%) of RUPP vs. NP (p<0.05). Both LD (2.1 ± 0.7%, 1.7 ± 0.7%, 0.8 ± 0.5%) and HD (0.2 ± 0.1%, 0.4 ± 0.1%, 0.8 ± 0.2%) ETAN decreased activated NK cells in circulation, placenta, and kidney respectively (p<0.05 vs RUPP). Placental (0.79± 0.02 vs 1±0.05 fold) and renal (0.67± 0.05 vs 1±0.06 fold) mtROS was reduced with LD ETAN vs RUPP (p<0.05). ETAN treatment lowers blood pressure and reduces circulating, placental, and renal activated NK cells and mtROS in placental ischemic rats. Therefore ETAN could be a potential therapeutic for improving HTN, inflammation, and mitochondrial function during complicated pregnancies. Supported: AHA18CDA34110264, HL130456, R01HD067541, & P20GM121334

Anti-Inflammatory Therapies for Treatment of Inflammation-Related Preterm Brain Injury

“…For example, in pregnant mice, inhibiting TNF-α activity was reported to have no effect in preventing preterm labor or prolonging pregnancy [ 251 ]. By contrast, inhibiting TNF-α using antibodies against TNF-α or etanercept reduced fetal deaths and the rate of preterm delivery in an endotoxin-induced mouse model of preterm delivery [ 252 ] and significantly lowered blood pressure in response to placental ischemia in rodents [ 253 ]. Etanercept administration was also associated with reduced neuronal apoptosis and synaptic loss, and improved long-term cognitive outcomes, following propofol-induced neurotoxicity in neonatal rats [ 254 ], largely abolished cerebral TNF-α production and brain injury following inflammatory and excitotoxic brain injuries in mice [ 123 ], and improved white matter myelination in septic neonatal rats [ 255 ].…”