RESUMEN
Preeclampsia (PE) is a multisystem disorder characterized by new onset hypertension in mid-late gestation and can include multi-organ dysfunction with or without proteinuria. It affects 5%-7% of all pregnancies in the U.S., making PE a major contributor to maternal and fetal morbidity and mortality. Currently, there is no cure for this pregnancy complication except for early delivery of the placenta and fetus. Moreover, the therapeutic options to treat PE are very limited. One potential trigger for the development of PE is progesterone deficiency-induced imbalance between T Helper 1(Th1)/Th2 cells, an increase in cytolytic natural killer (NK) cells and inflammatory cytokines that in turn leads to endothelial dysfunction, intrauterine growth restriction (IUGR) and hypertension. Importantly, progesterone signals the synthesis of progesterone-induced blocking factor (PIBF) which has anti-inflammatory effects and could promote the regulation of inflammation balance during pregnancy. However, the role of progesterone and PIBF in the pathophysiology of PE is still not fully understood. Thus, this current study was designed to test the hypothesis that inhibition of PIBF causes signs of PE in pregnant Sprague Dawley rats. In order to address our hypothesis, rabbit anti-PIBF IgG (0.25, low dose-LD or 0.50 mg/mL, high dose-HD) was administered intraperitoneally on gestation day (GD) 15 to normal pregnant Sprague Dawley (NP) rats. On GD 18, carotid catheters were inserted and on GD 19 mean blood pressure (MAP) and samples were collected for further analysis. MAP in normal pregnant rats (NP) rats (n = 7) was 99 ± 3 mmHg, which increased to 116 ± 2 mmHg in NP+ anti-PIBF LD (n = 10) and 113 ± 4 mmHg in NP+ anti-PIBF HD (n = 4), p <0 .05. Plasma TNF-alpha levels were 35 ± 8 pg/mL in NP rats and increased to 84 ± 21 pg/mL in NP+ Anti-PIBF HD (n = 4), p <0 .05. Plasma IL-4 and IL-10 levels were 22 ± 5 and 25+6 pg/mL in NP (n = 5), which decreased to 6 ± 1 and 8 ± 1 pg/mL in NP+ Anti-PIBF LD (n = 6, p < 0.05) and 16 ± 4 and 15 ± 5 pg/mL in NP+ Anti-PIBF HD (n = 4). Circulating total NK cells were 67 ± 11 % gate in NP rats (n = 3), which decreased to 28 ± 7% gate in NP+ Anti-PIBF LD and 45 ± 6% gate in NP+ Anti-PIBF HD. Cytolytic NK cells were increased in NP+ Anti-PIBF HD, p <0 .05. Moreover, circulating NO levels were significantly decreased while renal cortex PPET-1 levels increased NP+ Anti-PIBF HD. Our study demonstrates that PIBF blockade causes hypertension, inflammation and signs of endothelial dysfunction, all of which are associated with PE, thus indicating the importance of progesterone signalling pathways during a healthy pregnancy.
Asunto(s)
Antígenos de Neoplasias , Hipertensión , Preeclampsia , Humanos , Femenino , Embarazo , Ratas , Animales , Conejos , Progesterona/metabolismo , Ratas Sprague-Dawley , Placenta/metabolismo , Preeclampsia/metabolismo , Inflamación/metabolismoRESUMEN
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 which are increased during PE. We hypothesized that PIBF reduces inflammation as a mechanism to improve hypertension in the preclinical reduced uterine perfusion pressure (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 mmHg in NP + PIBF rats (n = 8) and 122 ± 1 mmHg 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 g in NP, 2.5 ± 0.1 g in NP + PIBF, 1.9 ± 0.1 g in RUPP, and improved to 2.1 ± 0.1 g in RUPP + PIBF rats. Circulating and placental cytolytic NK cells, IL-17, and IL-6 were significantly reduced while IL-4 and T helper (TH) 2 cells were significantly increased in RUPP rats after PIBF administration. Importantly, vasoactive pathways preproendothelin-1, nitric oxide, and soluble fms-Like tyrosine Kinase-1 (sFlt-1) were normalized in RUPP + PIBF rats compared with 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.
Asunto(s)
Antígenos de Neoplasias/farmacología , Presión Sanguínea/fisiología , Inflamación/tratamiento farmacológico , Progesterona/farmacología , Útero/efectos de los fármacos , Animales , Citocinas/metabolismo , Femenino , Retardo del Crecimiento Fetal/fisiopatología , Feto/efectos de los fármacos , Feto/metabolismo , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Inflamación/inducido químicamente , Inflamación/metabolismo , Isquemia/fisiopatología , Células Asesinas Naturales/metabolismo , Placenta/metabolismo , Embarazo , Ratas , Arteria Uterina/efectos de los fármacos , Arteria Uterina/fisiopatología , Útero/fisiopatologíaRESUMEN
Preeclampsia (PE) is characterized by new onset hypertension in association with elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and preproendothelin-1 (PPET-1) levels. Currently there is no effective treatment for PE except for early delivery of the fetal placental unit, making PE a leading cause for premature births worldwide. Administration of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of recurrent preterm birth. This study was designed to test the hypothesis that 17-OHPC improves hypertension and ET-1 in response to elevated sFlt-1 in pregnant rats. sFlt-1 was infused into normal pregnant (NP) Sprague-Dawley rats (3.7 µg·kg-1·day-1 for 6 days, gestation days 13-19) in the presence or absence of 17-OHPC (3.32 mg/kg) administered via intraperitoneal injection on gestational days 15 and 18. Mean arterial blood pressure (MAP), pup and placenta weights, renal cortex PPET-1 mRNA levels and nitrate-nitrite levels were measured on GD 19. Infusion of sFlt-1 into NP rats elevated mean arterial pressure (MAP) compared with control NP rats: 115 ± 1 (n = 13) vs. 99 ± 2 mmHg (n = 12, p < 0.05). 17-OHPC attenuated this hypertension reducing MAP to 102 ± 3 mmHg in sFlt-1 treated pregnant rats (n = 8). Neither pup nor placental weight was affected by sFlt-1 or 17-OHPC. Importantly, renal cortex PPET-1 mRNA levels were elevated 3 fold in NP + sFlt-1 rats compare to NP rats, which decreased with 17-OHPC administration. Plasma nitrate-nitrite levels were 44 ± 9 µM in NP rats (n = 9), 20 ± 3 µM in NP + sFlt-1 (n = 7), which increased to 42 ± 11 µM NP + sFlt-1 + 17OHPC (n = 6). Administration of 17-OHPC improves clinical characteristics of preeclampsia in response to elevated sFlt-1 during pregnancy.
Asunto(s)
Caproato de 17 alfa-Hidroxiprogesterona/farmacología , Presión Sanguínea/efectos de los fármacos , Endotelina-1/efectos de los fármacos , Caproato de 17 alfa-Hidroxiprogesterona/administración & dosificación , Animales , Femenino , Humanos , Hipertensión/fisiopatología , Riñón/efectos de los fármacos , Embarazo , Ratas , Ratas Sprague-Dawley , Factor A de Crecimiento Endotelial VascularRESUMEN
Thyroid disorders are a frequently encountered issue during pregnancy and a cause of maternal and fetal morbidity. In regions like Appalachia that are particularly susceptible to health disparities, descriptive studies are needed to assist in identifying pathologic derangements. We sought to characterize fetal thyroid hormone levels at delivery and investigate whether or not maternal demographic characteristics affect the prevalence of neonatal thyroid disease. A cross-sectional analysis was conducted on 130 pregnant women recruited from the Tri-State region, incorporating areas of Kentucky, Ohio, and West Virginia. Total triiodothyronine (T3) (p = 0.4799), free T3 (p = 0.6323), T3 uptake (p = 0.0926), total thyroxine (T4) (p = 0.8316), free T4 (p = 0.0566), and Thyroid stimulating hormone (TSH) (p = 0.8745) levels were comparable between urban and rural newborns. We found no effect of hypertension status or nicotine levels on fetal umbilical cord thyroid hormone levels. Maternal diabetic status was associated with lower T4 (p = 0.0099) and free T4 (p = 0.0025) levels. Cotinine affected levels of T4 (p = 0.0339). In regard to maternal Body Mass Index (BMI), there was an increase in total T3 as BMI increased (p = 0.0367) and no significant difference in free T3, T3 uptake, T4, free T4, or TSH. There was a negative correlation between TSH and 1 min Apgar scores (p = 0.0058). Lead and cadmium have been implicated to alter TSH levels, but no correlation was found in our study (r2 = 0.0277). There were no differences in cord blood between urban (37.3 ± 10.3 fmol/ug DNA) and rural (70.5 ± 26.8 fmol/ug DNA) benzo(a)pyrene DNA adducts (p = 0.174). Thyroid disorders present a unique opportunity for the prevention of perinatal morbidity and mortality, since maternal treatment, as well as maternal demographic characteristics, can have direct fetal effects.
RESUMEN
Preeclampsia (PE) is new onset hypertension during pregnancy associated with increased uterine artery resistance (UARI) and an imbalance among CD4 + T lymphocytes and natural killer (NK) cells. We have shown an important role for 17-hydroxyprogesterone caproate (17-OHPC) to improve hypertension and fetal demise in the RUPP rat model of PE. However we have not examined a role for 17-OHPC to improve NK cells and CD4+TH2 cells as possible mechanisms for improved fetal weight and hypertension. Therefore, we hypothesized that 17-OHPC lowers NK cells while improving the T cell ratio in the RUPP rat. RUPP was surgically induced on gestational day 14 in pregnant rats. 17-OHPC (3.32 mg/kg) was administered intraperitoneal on day 15, UARI was measured on day 18. Blood pressure (MAP), blood and tissues were collected on GD 19. MAP in NP rats (n = 9) was 100 ± 2, 104 ± 6 in Sham rats (n = 8), 128 ± 2 in RUPP (n = 11) and 115 ± 3 mmHg in RUPP + 17-OHPC (n = 10), p < 0.05. Pup weight and UARI were improved after 17-OHPC. Total and cytolytic placental NK cells were 38 ± 5, and 12 ± 2% gate in RUPP rats which decreased to 1.6 ± 0.5 and 0.4 ± 0.2% gate in RUPP + 17OHPC rats. CD4+ T cells were 40 ± 3 in RUPP rats, which significantly decreased to 7 ± 1 RUPP + 17-OHPC rats. Circulating and placental TH2 cells were 6.0 ± 1, 0.3 ± 0.1% gate in RUPP rats and 12 ± 1%, 2 ± 0.5% gate in RUPP + 17-OHPC rats, p < 0.05 This study identifies new mechanisms whereby 17-OHPC improves outcomes in response to placental ischemia.
Asunto(s)
Caproato de 17 alfa-Hidroxiprogesterona/farmacología , Hipertensión/tratamiento farmacológico , Isquemia/complicaciones , Células Asesinas Naturales/metabolismo , Progestinas/farmacología , Células Th2/metabolismo , Animales , Animales Recién Nacidos , Peso al Nacer/efectos de los fármacos , Recuento de Células , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Hipertensión/etiología , Placenta/irrigación sanguínea , Placenta/citología , Embarazo , Ratas Sprague-Dawley , Arteria Uterina , Resistencia Vascular/efectos de los fármacosRESUMEN
Preeclampsia (PE) is characterized by chronic inflammation and elevated agonistic autoantibodies to the angiotensin type 1 receptor (AT1-AA), endothelin-1, and uterine artery resistance index (UARI) during pregnancy. Previous studies report an imbalance among immune cells, with T-helper type 2 (Th2) cells being decreased during PE. We hypothesized that interleukin-4 (IL-4) would increase Th2 cells and improve the pathophysiology in response to placental ischemia during pregnancy. IL-4 (600 ng/day) was administered via osmotic minipump on gestational day 14 to normal pregnant (NP) and reduced uterine perfusion pressure (RUPP) rats. Carotid catheters were inserted, and Doppler ultrasound was performed on gestational day 18. Blood pressure (mean arterial pressure), TNF-α, IL-6, AT1-AA, natural killer cells, Th2 cells, and B cells were measured on gestational day 19. Mean arterial pressure was 97 ± 2 mmHg in NP ( n = 9), 101 ± 3 mmHg in IL-4-treated NP ( n = 14), and 137 ± 4 mmHg in RUPP ( n = 8) rats and improved to 108 ± 3 mmHg in IL-4-treated RUPP rats ( n = 17) ( P < 0.05). UARI was 0.5 ± 0.03 in NP and 0.8 in RUPP rats and normalized to 0.5 in IL-4-treated RUPP rats ( P < 0.05). Plasma nitrate-nitrite levels increased in IL-4-treated RUPP rats, while placental preproendothelin-1 expression, plasma TNF-α and IL-6, and AT1-AA decreased in IL-4-treated RUPP rats compared with untreated RUPP rats ( P < 0.05). Circulating B cells and placental cytolytic natural killer cells decreased after IL-4 administration, while Th2 cells increased in IL-4-treated RUPP compared with untreated RUPP rats. This study illustrates that IL-4 decreased inflammation and improved Th2 numbers in RUPP rats and, ultimately, improved hypertension in response to placental ischemia during pregnancy.
Asunto(s)
Hipertensión/tratamiento farmacológico , Interleucina-4/farmacología , Isquemia/inducido químicamente , Placenta/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Modelos Animales de Enfermedad , Femenino , Hipertensión/fisiopatología , Isquemia/fisiopatología , Placenta/irrigación sanguínea , Embarazo , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/metabolismo , Arteria Uterina/efectos de los fármacos , Arteria Uterina/fisiopatología , Útero/irrigación sanguínea , Útero/efectos de los fármacosRESUMEN
Excess or inadequate levels of inorganic ions may induce significant acute and long-term irreversible dysfunction in humans. The fetus and placenta are particularly vulnerable to toxins due to the immaturity of the blood-brain barrier and diminished biotransformation enzymatic activity. A comparative cross-sectional study was conducted on 172 pregnant women, 79 rural, and 93 urban. Umbilical cord blood was collected at the time of delivery and analyzed for 20 inorganic elements. Significant differences were found between urban and rural samples for two elements where copper (Cu) and molybdenum (Mo) were higher in urban samples. No marked differences between groups occurred for: arsenic, barium, cadmium, calcium, cobalt, lead, lithium, magnesium, manganese, mercury, selenium, strontium, or zinc. All samples were devoid of platinum, silver, thallium or uranium. Data demonstrated significant differences in urban and rural prenatal exposure to Cu and Mo. Further study is needed to determine if there is a causal link between neonatal outcomes and prenatal exposure to these elements.