A1M Ameliorates Preeclampsia-Like Symptoms in Placenta and Kidney Induced by Cell-Free Fetal Hemoglobin in Rabbit

Preeclampsia is one of the most serious pregnancy-related diseases and clinically manifests as hypertension and proteinuria after 20 gestational weeks. The worldwide prevalence is 3-8% of pregnancies, making it the most common cause of maternal and fetal morbidity and mortality. Preeclampsia lacks an effective therapy, and the only “cure” is delivery. We have previously shown that increased synthesis and accumulation of cell-free fetal hemoglobin (HbF) in the placenta is important in the pathophysiology of preeclampsia. Extracellular hemoglobin (Hb) and its metabolites induce oxidative stress, which may lead to acute renal failure and vascular dysfunction seen in preeclampsia. The human endogenous protein, α1-microglobulin (A1M), removes cell-free heme-groups and induces natural tissue repair mechanisms. Exogenously administered A1M has been shown to alleviate the effects of Hb-induced oxidative stress in rat kidneys. Here we attempted to establish an animal model mimicking the human symptoms at stage two of preeclampsia by administering species-specific cell-free HbF starting mid-gestation until term, and evaluated the therapeutic effect of A1M on the induced symptoms. Female pregnant rabbits received HbF infusions i.v. with or without A1M every second day from gestational day 20. The HbF-infused animals developed proteinuria and a significantly increased glomerular sieving coefficient in kidney that was ameliorated by co-administration of A1M. Transmission electron microscopy analysis of kidney and placenta showed both intracellular and extracellular tissue damages after HbF-treatment, while A1M co-administration resulted in a significant reduction of the structural and cellular changes. Neither of the HbF-treated animals displayed any changes in blood pressure during pregnancy. In conclusion, infusion of cell-free HbF in the pregnant rabbits induced tissue damage and organ failure similar to those seen in preeclampsia, and was restored by co-administration of A1M. This study provides preclinical evidence supporting further examination of A1M as a potential new therapy for preeclampsia.子痫前期（Preeclampsia）是最严重的妊娠相关疾病之一，临床表现为妊娠20周后出现高血压与蛋白尿。全球范围内其发病率占妊娠人群的3%~8%，是引发孕产妇与围产儿发病及死亡的最常见原因。目前子痫前期尚无特效治疗手段，唯一的临床治愈方式为终止妊娠。我们此前的研究证实，胎盘中游离胎儿血红蛋白（HbF）的合成与积累增加，在子痫前期的病理生理进程中发挥关键作用。细胞外血红蛋白（Hb）及其代谢产物可诱导氧化应激，进而引发子痫前期中观察到的急性肾衰竭与血管功能异常。人体内源性蛋白α1-微球蛋白（A1M）可清除游离血红素基团，并激活天然组织修复通路。已有研究表明，外源性给予A1M可减轻大鼠肾脏中Hb诱导的氧化应激损伤。本研究旨在通过于妊娠中期至足月期间给予种属特异性游离HbF，构建模拟人类子痫前期二期症状的动物模型，并评估A1M对该模型诱导出的症状的治疗效果。妊娠雌性家兔自妊娠第20天起，每隔一日接受静脉输注HbF，同时联合或不联合A1M干预。接受HbF输注的家兔出现了蛋白尿，且肾脏肾小球滤过系数显著升高，该异常可通过联合A1M治疗得到改善。对肾脏与胎盘组织的透射电子显微镜（transmission electron microscopy）分析显示，HbF处理组出现了细胞内与细胞外的组织损伤；而A1M联合给药组的结构与细胞病变显著减少。所有HbF处理组家兔在妊娠期间均未出现血压异常变化。综上，在妊娠家兔中输注游离HbF可诱导出与子痫前期相似的组织损伤与器官功能异常，且该异常可通过联合A1M治疗得到逆转。本研究提供了临床前证据，支持进一步探索A1M作为子痫前期潜在新型治疗手段的可行性。