17-Hydroxyprogesterone Caproate Significantly Improves Clinical Characteristics of Preeclampsia in the Reduced Uterine Perfusion Pressure Rat Model

IL-2 is a cytokine released from CD4+T cells with dual actions and can either potentiate the inflammatory response or quell a chronic inflammatory response depending on its circulating concentration. IL-2 is elevated in many chronic inflammatory conditions and is increased during preeclampsia (PE). PE is characterized by new-onset hypertension during pregnancy and organ dysfunction and increasing evidence indicates that proinflammatory cytokines cause hypertension and mitochondrial (mt) dysfunction during pregnancy. The reduced uterine perfusion pressure (RUPP) model of placental ischemia is a rat model of PE that we commonly use in our laboratory and we have previously shown that low doses of recombinant IL-2 can decrease blood pressure in RUPP rats. The objective of this study was to determine the effects of a low dose of recombinant IL-2 on multi-organ mt dysfunction in the RUPP rat model of PE. We tested our hypothesis by infusing recombinant IL-2 (0.05 ng/mL) into RUPP rats on GD14 and examined mean arterial pressure (MAP), renal, placental and endothelial cell mt function compared to control RUPP. MAP was elevated in RUPP rats (n = 6) compared to controls (n = 5) (122 ± 5 vs. 102 ± 3 mmHg, p < 0.05), but was reduced by administration of LD recombinant IL-2 (107 ± 1 vs. 122 ± 5 mmHg, n = 9, p < 0.05). Renal, placental and endothelial mt ROS were significantly increased in RUPP rats compared to RUPP+ IL-2 and controls. Placental and renal respiration rates were reduced in RUPP rats compared to control rats but were normalized with IL-2 administration to RUPPs. These data indicate that low-dose IL-2 normalized multi-organ mt function and hypertension in response to placental ischemia.

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Abstract P174: 17-hydroxyprogesterone Caproate Improves Blood Pressures and Placental Cytolytic Nk Cells in Response to Placental Ischemia During Pregnancy

Hypertension ◽

10.1161/hyp.68.suppl_1.p174 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Lorena M Amaral ◽

Jamil Elfarra ◽

Denise C Cornelius ◽

Mark W Cunningham ◽

Tarek Ibrahim ◽

...

Keyword(s):

Nk Cells ◽

Premature Births ◽

Fetal Demise ◽

Hydroxyprogesterone Caproate ◽

Blood Pressures ◽

17 Hydroxyprogesterone ◽

Uterine Perfusion ◽

Placental Ischemia ◽

Do So ◽

New Onset

Preeclampsia (PE), new onset hypertension, is characterized by decreased fetal weight, elevated cytolytic natural killer (NK) cells and placental ischemia during pregnancy. Cytolytic NK are thought to play a role in fetal demise as they have also been shown to be increased in patients suffering from miscarriage.Currently, there is no effective treatment for PE except for early delivery, making PE the leading cause for premature births worldwide. Multiple injections of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of preterm labor, but not for management of PE. We have shown that injections of 17-OHPC to the RUPP rat model of PE improves some but not all facets of PE observed in this model. Therefore this study was designed to test the hypothesis that injections of 17-OHPC on both day 15 (GD15) and GD (18) improve outcomes of hypertension in response to placental ischemia. To do so, 17-OHPC (3.32mg/kg) was administered intraperitoneally on GD 15 and 18 to reduced uterine perfusion pressure (RUPP) rats, carotid catheters were inserted on GD 18 and blood pressure (MAP) andplacental cytolytic NK cells were measured on GD 19. MAP in normal pregnant (NP) rats (n=8) was 104±4,119± 5 in RUPP rats (n=5) and 102±5 mmHgin RUPP+17-OHPC GD15 &18 (n=4), p <0.05.Total number of placental NK cells was 8.5± 3 in NP, 20±2 in RUPP rats, which decreased to 4.7± 3 % in RUPP+17-OHPC GD15 &18, p<0.05. Activated placental NK cells was 3.4± 1.6 in NP, 10.5±2.3 in RUPP, which improved to 2.7± 2.7 % in RUPP+17-OHPCGD15 & 18, p <0.05.In conclusion, administration of 17-OHPC on days 15 and 18 decreased hypertension and NK cells that are associated with PE in the RUPP ratand should be considered for addition to the management of PE.

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Role of Mitochondrial Dysfunction and Reactive Oxygen Species in Mediating Hypertension in the Reduced Uterine Perfusion Pressure Rat Model of Preeclampsia

Hypertension ◽

10.1161/hypertensionaha.118.11290 ◽

2018 ◽

Vol 72 (3) ◽

pp. 703-711 ◽

Cited By ~ 39

Author(s):

Venkata Ramana Vaka ◽

Kristen M. McMaster ◽

Mark W. Cunningham ◽

Tarek Ibrahim ◽

Rebekah Hazlewood ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Mitochondrial Dysfunction ◽

Rat Model ◽

Perfusion Pressure ◽

Reactive Oxygen ◽

Oxygen Species ◽

Uterine Perfusion

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Progesterone induced blocking factor improves blood pressure, inflammation and pup weight in response to reduced uterine perfusion pressure (RUPP)

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00152.2020 ◽

2021 ◽

Author(s):

Jesse N Cottrell ◽

Alexis Witcher ◽

Kyleigh M Comley ◽

Mark W Cunningham ◽

Tarek Ibrahim ◽

...

Keyword(s):

Blood Pressure ◽

Nk Cells ◽

Rat Model ◽

Perfusion Pressure ◽

Normal Pregnancy ◽

Th2 Cells ◽

Arterial Blood ◽

Blocking Factor ◽

Uterine Perfusion ◽

New Onset

Preeclampsia (PE) is characterized by new onset hypertension in association with elevated natural killer (NK) cells and inflammatory cytokines which are likely culprits for decreased fetal weight during PE pregnancies. As progesterone increases during normal pregnancy, it stimulates Progesterone Induced Blocking Factor (PIBF). PIBF has been shown to decrease inflammation and cytolytic NK cells, both of whichare increased during PE. We hypothesized that PIBF reduces inflammation as a mechanism to improve hypertension in the preclinical RUPP rat model of PE. PIBF (2.0 µg/mL) was administered intraperitoneally on gestational day 15 to either RUPP or normal pregnant (NP) rats. On day 18 carotid catheters were inserted. Mean arterial blood pressure (MAP) and samples were collected on day 19. MAP in NP rats (n=11) was 100±2 mmHg and 105±3 in NP+PIBF (n=8), 122±1 in RUPP rats (n=10), which improved to 110±2 mmHg in RUPP+PIBF rats (n=11), p<0.05. Pup weight was 2.4±0.1 grams (g) in NP, 2.5±0.1 g in NP+PIBF, 1.9±0.1 g in RUPP and improved to 2.1±0.1gin RUPP+PIBF rats. Circulating and placental cytolytic NK cells, IL-17 and IL-6 were significantly reduced while IL-4 and TH2 cells were significantly increased in RUPP rats after PIBF administration. Importantly, vasoactive pathways preproendothelin-1, nitric oxide and sFlt-1 were normalized in RUPP+PIBF rats compared to RUPP rats, p<0.05. Our findings suggest that PIBF normalized IL-4/TH2 cells which was associated with improved inflammation, fetal growth restriction and blood pressure in the RUPP rat model of PE.

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The Influence of Prior Obstetrical History on Current 17-Hydroxyprogesterone Caproate Use

Journal of Pregnancy ◽

10.1155/2011/286483 ◽

2011 ◽

Vol 2011 ◽

pp. 1-4

Author(s):

Carla E. Ransom ◽

Jeanette R. Chin ◽

Hilary A. Roeder ◽

Tammy R. Sinclair ◽

R. Phillips Heine ◽

...

Keyword(s):

Medical Record ◽

Preterm Delivery ◽

Gestational Age ◽

Retrospective Cohort ◽

Clinical Characteristics ◽

Medical Record Review ◽

Term Delivery ◽

Hydroxyprogesterone Caproate ◽

17 Hydroxyprogesterone ◽

Record Review

Objective. To determine if gestational age of prior preterm delivery influences a woman's receipt of 17-hydroxyprogesterone caproate (17-OHP-C).Methods. Retrospective cohort of women eligible for 17-OHP-C at Duke Obstetrics Clinic were identified by medical record review. Sociodemographic and clinical characteristics were abstracted.Results. Of 104 eligible subjects, 82 (78.8%) were offered 17-OHP-C. Of these, thirty-four (41.5%) declined. The median gestational age of the most recent preterm delivery was significantly lower among subjects who accepted 17-OHP-C as compared to those who declined (28.7 vs. 34.0 weeks,P=.02) and in subjects offered 17-OHP-C compared to those not offered 17-OHP-C (30.2 vs. 36.0 weeks,P=.03). Subjects not offered 17-OHP-C were more likely to have had an interval term delivery (31.8% vs. 9.7%,P=.009)Conclusion. Women with earlier preterm deliveries were more likely to be offered and accept 17-OHP-C. Prior obstetric history may influence both providers' and patients' willingness to discuss and/or accept 17-OHP-C.

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