Placental inflammation in high risk pregnancies: a novel therapeutic target to prevent stillbirth?

高危妊娠中的胎盘炎症：预防死产的新治疗靶点？

• 批准号: MR/N010892/1
• 负责人: Rebecca Jones
• 金额: $ 56.05万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN010892%2F1
• 关键词: Placental; inflammation; risk; pregnancies; novel

Stillbirth describes the death of a baby before birth after 24 weeks of pregnancy. This occurs in approximately 1 in 220 pregnancies in the UK; in 2012 there were 3,696 stillborn babies in the UK. The rate of stillbirth has decreased much more slowly than deaths of babies after birth. The UK has a higher stillbirth rate than neighbouring countries in Europe. Experts have called upon countries such as ours to halve the number of stillbirths by 2020.In the UK, the most common condition associated with stillbirth is fetal growth restriction (FGR); this describes a baby that does not reach their expected size. Over 40% of stillbirths are associated with FGR, and FGR babies are 17 times more likely to be stillborn. To prevent stillbirths, babies with FGR may be delivered prematurely, placing them at an increased risk of disability due to brain damage sustained before and after birth. They also have a higher likelihood of becoming obese, diabetic and having higher blood pressure in later life than babies of a healthy birthweight. This project therefore focuses on clinical conditions that need to be addressed.The placenta (afterbirth) is essential for a healthy pregnancy. Over 65% of stillbirths are associated with abnormalities of the placenta. Abnormalities in the placenta include reduction in blood flow from the mother and damage from inflammation or infection. Although inflammation during pregnancy is a major cause of pregnancy complications and lifelong problems for surviving babies, we do not understood how inflammation leads to these poor outcomes. As a result, we cannot identify inflammation during pregnancy and do not have any treatments to prevent poor outcomes. We have shown in humans and animals that the placenta is damaged by inflammation making it unable to function normally. We found higher levels of inflammatory factors in the placenta and mothers' blood in pregnancies at high risk of stillbirth. Importantly, in an animal model of inflammation during pregnancy, treatment with a new anti-inflammatory drug prevented placental damage and the adverse effects on growth and survival of the offspring. This provides hope that anti-inflammatory treatment targeting the placenta could prevent FGR and stillbirth in human pregnancies.It is currently too early to give these anti-inflammatory treatments to pregnant women; however, the current study will provide further evidence of the role of inflammation in placental damage and FGR/stillbirth. We will perform detailed studies of human high risk pregnancies and test whether addition of a blood test for placental inflammation can improve current methods to detect babies at greatest risk of stillbirth. To do thus, we will use human placental and maternal blood samples from healthy pregnancies and those with FGR and stillbirth to understand the link between inflammation and adverse pregnancy outcomes. We have already collected over 1,000 blood samples from mothers with high risk pregnancies, with detailed clinical information on mothers and babies. We will study how inflammatory factors cause placental damage and test anti-inflammatory treatments in human and animal pregnancies. These experiments will provide further evidence that treating inflammation can protect the placenta from damage and reduce the incidence of FGR and stillbirth. These studies are essential first steps in our goal to develop new treatments to prevent babies from dying or being born with serious disabilities and will facilitate human clinical trials.

死产是指婴儿在怀孕24周后出生前死亡。在英国，每220次怀孕中就有1次发生这种情况; 2012年，英国有3,696名死胎。死产率的下降速度比出生后婴儿死亡率的下降速度慢得多。英国的死胎率高于欧洲邻国。专家们呼吁像我们这样的国家到2020年将死产数量减半。在英国，与死产相关的最常见的情况是胎儿生长受限（FGR）;这描述了一个婴儿没有达到预期的大小。超过40%的死产与FGR有关，FGR婴儿死产的可能性是FGR婴儿的17倍。为了防止死产，患有FGR的婴儿可能会早产，由于出生前后持续的脑损伤，使他们面临更大的残疾风险。他们也有更高的可能性成为肥胖，糖尿病和高血压在以后的生活比婴儿的健康出生体重。因此，该项目的重点是需要解决的临床条件。胎盘（胞衣）是健康怀孕所必需的。超过65%的死产与胎盘异常有关。胎盘中的流产包括来自母亲的血流减少以及炎症或感染造成的损害。虽然妊娠期间的炎症是妊娠并发症和存活婴儿终身问题的主要原因，但我们不了解炎症如何导致这些不良结果。因此，我们无法识别怀孕期间的炎症，也没有任何治疗方法来预防不良结局。我们已经在人类和动物身上证明，胎盘因炎症而受损，使其无法正常发挥功能。我们发现，在死胎风险较高的孕妇中，胎盘和母亲血液中的炎症因子水平较高。重要的是，在妊娠期间炎症的动物模型中，使用新型抗炎药物治疗可以预防胎盘损伤以及对后代生长和生存的不利影响。这为针对胎盘的抗炎治疗可以预防人类妊娠中的FGR和死胎提供了希望。目前对孕妇进行这些抗炎治疗还为时过早;然而，目前的研究将为炎症在胎盘损伤和FGR/死胎中的作用提供进一步的证据。我们将对人类高风险妊娠进行详细研究，并测试是否增加胎盘炎症的血液检测可以改善目前检测死胎风险最大的婴儿的方法。为此，我们将使用来自健康妊娠以及FGR和死胎的人类胎盘和母体血液样本，以了解炎症与不良妊娠结局之间的联系。我们已经收集了1,000多个高危孕妇的血液样本，并提供了母亲和婴儿的详细临床信息。我们将研究炎症因子如何导致胎盘损伤，并在人类和动物妊娠中测试抗炎治疗。这些实验将提供进一步的证据，证明治疗炎症可以保护胎盘免受损伤，并减少FGR和死胎的发生率。这些研究是我们开发新疗法以防止婴儿死亡或出生时患有严重残疾的目标的重要第一步，并将促进人体临床试验。

项目成果

Immunomodulatory Therapy Reduces the Severity of Placental Lesions in Chronic Histiocytic Intervillositis.

免疫调节疗法可减轻慢性组织细胞绒毛间炎胎盘病变的严重程度。

• DOI: 10.3389/fmed.2021.753220
• 发表时间: 2021
• 期刊: Frontiers in medicine
• 影响因子: 3.9
• 作者: Brady CA;Williams C;Batra G;Church E;Tower CL;Crocker IP;Heazell AEP
• 通讯作者: Heazell AEP

Cell free hemoglobin in the fetoplacental circulation: a novel cause of fetal growth restriction?

• DOI: 10.1096/fj.201800264r
• 发表时间: 2018-10-01
• 期刊: FASEB JOURNAL
• 影响因子: 4.8
• 作者: Brook, Adam;Hoaksey, Annie;Brownbill, Paul
• 通讯作者: Brownbill, Paul

Uric Acid Crystals Induce Placental Inflammation and Alter Trophoblast Function via an IL-1-Dependent Pathway: Implications for Fetal Growth Restriction.

• DOI: 10.4049/jimmunol.1601179
• 发表时间: 2017-01-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Brien ME;Duval C;Palacios J;Boufaied I;Hudon-Thibeault AA;Nadeau-Vallée M;Vaillancourt C;Sibley CP;Abrahams VM;Jones RL;Girard S
• 通讯作者: Girard S

Hypoxia and oxidative stress induce sterile placental inflammation in vitro.

• DOI: 10.1038/s41598-021-86268-1
• 发表时间: 2021-03-31
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Baker BC;Heazell AEP;Sibley C;Wright R;Bischof H;Beards F;Guevara T;Girard S;Jones RL
• 通讯作者: Jones RL

Chronic histiocytic intervillositis: A breakdown in immune tolerance comparable to allograft rejection?

• DOI: 10.1111/aji.13373
• 发表时间: 2021-03
• 期刊: American journal of reproductive immunology (New York, N.Y. : 1989)
• 作者: Brady CA;Williams C;Sharps MC;Shelleh A;Batra G;Heazell AEP;Crocker IP
• 通讯作者: Crocker IP