Amaral Lorena M, Kiprono Luissa, Cornelius Denise C, Shoemaker Carrie, Wallace Kedra, Moseley Janae, Wallukat Gerd, Martin James N, Dechend Ralf, LaMarca Babbette
Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS.
Division of Maternal-Fetal Medicine, University of Mississippi Medical Center, Jackson, MS.
Am J Obstet Gynecol. 2014 Aug;211(2):158.e1-6. doi: 10.1016/j.ajog.2014.02.018. Epub 2014 Feb 15.
Preeclampsia is a multisystem disorder recognized as hypertension with proteinuria developing >20 weeks' gestation. Preeclampsia is associated with chronic immune activation characterized by increased T and B lymphocytes, cytokines, and antibodies activating the angiotensin II type I receptor (AT1-AA). Hypertension in response to elevated interleukin (IL)-6 during pregnancy occurs with increased renin activity and AT1-AA, and reduced kidney function.
We aim to determine whether 17-alpha-hydroxyprogesterone caproate (17-OHPC), progesterone, improved inflammatory pathways during elevated IL-6 in pregnant rats. IL-6 (5 ng/d) was infused via miniosmotic pumps into normal pregnant (NP) rats beginning on day 14 of gestation and 17-OHPC (3.32 mg/kg) was diluted in normal saline and injected on day 18. Blood pressure (mean arterial pressure [MAP]) determination and serum collection were performed on day 19 of gestation.
MAP in NP was 100 ± 3 mm Hg, which increased with IL-6 to 112 ± 4 mm Hg (P < .05). Pregnant rats given 17-OHPC alone had a MAP of 99 ± 3 mm Hg and MAP increased to 103 ± 2 mm Hg in IL-6+17-OHPC. AT1-AA was 1.2 ± 0.5 bpm in NP rats, increased to 17 ± 9 bpm with IL-6 infusion but administration of 17-OHPC significantly blunted AT1-AA to 4 ± 0.8 bpm in NP+IL-6+17-OHPC. Total circulating nitrate/nitrite was significantly decreased and placental Ser(1177)-phosporylated-eNOS/eNOS was lowered with IL-6 infusion. Supplementation of 17-OHPC significantly improved placental Ser(1177)-phosporylated-eNOS/eNOS however, circulating nitrate/nitrite was unchanged with 17-OHPC supplementation.
This study illustrates that 17-OHPC attenuated hypertension, decreased AT1-AA activity, and improved placental nitric oxide in response to elevated IL-6 during pregnancy and could lend hope to a new potential therapeutic for preeclampsia.
子痫前期是一种多系统疾病，被认为是妊娠20周后出现高血压伴蛋白尿。子痫前期与慢性免疫激活有关，其特征为T和B淋巴细胞、细胞因子以及激活血管紧张素II 1型受体的抗体（AT1-AA）增加。孕期白细胞介素（IL）-6升高时出现的高血压与肾素活性和AT1-AA增加以及肾功能降低有关。
我们旨在确定己酸17-α-羟孕酮（17-OHPC），即孕酮，是否能改善妊娠大鼠IL-6升高时的炎症途径。从妊娠第14天开始，通过微量渗透泵将IL-6（5 ng/d）注入正常妊娠（NP）大鼠体内，并将17-OHPC（3.32 mg/kg）用生理盐水稀释后于第18天注射。在妊娠第19天测定血压（平均动脉压[MAP]）并采集血清。
NP组的MAP为100±3 mmHg，随着IL-6升高至112±4 mmHg（P<.05）。单独给予17-OHPC的妊娠大鼠MAP为99±3 mmHg，在IL-6 + 17-OHPC组中MAP升高至103±2 mmHg。NP大鼠的AT1-AA为1.2±0.5 bpm，注入IL-6后升高至17±9 bpm，但给予17-OHPC可使NP + IL-6 + 17-OHPC组的AT1-AA显著降至4±0.8 bpm。循环中总硝酸盐/亚硝酸盐显著降低，注入IL-6后胎盘Ser(1177)-磷酸化-eNOS/eNOS降低。补充17-OHPC可显著改善胎盘Ser(1177)-磷酸化-eNOS/eNOS，然而，补充17-OHPC后循环中硝酸盐/亚硝酸盐无变化。
本研究表明，17-OHPC可减轻孕期IL-6升高引起的高血压，降低AT1-AA活性，并改善胎盘一氧化氮水平，有望为子痫前期提供一种新的潜在治疗方法。
