Abstract：
Preeclampsia (PE) is often associated with multiple organ damage that remains noticeable postnatally. Here, we tested the hypotheses that antenatal therapy with nonsteroidal antiinflammatory drugs (NSAIDs) refashions liver damage induced by PE in weaning rats and that the high mobility group box 1 (HMGB1) signaling modulates this interaction. PE was induced by pharmacologic nitric oxide deprivation during the last week of gestation (Nω-nitro-L-arginine methyl ester, L-NAME, 50 mg/kg/day, oral gavage). Compared with control rats, weaning PE rats revealed substantial rises in serum transaminases together with histopathological signs of hepatic cytoplasmic changes, portal inflammation, and central vein dilation. While gestational NSAIDs reversed the elevated transaminases, they had no effects (celecoxib, naproxen) or even worsened (diclofenac) the structural damage. Molecularly, celecoxib was the most effective NSAID in (i) reversing PE-evoked upregulation of hepatic HMGB1 gene expression and concomitant increments and decrements in mitogen-activated protein kinases MAPKERK and MAPKp38 expression, respectively, and (ii) elevating and suppressing serum interleukin-10 and tumor necrosis factor-α, respectively. Alternatively, rises in serum interleukin-1β and shifts in macrophage polarization towards an inflammatory phenotype caused by PE were comparably diminished by all NSAIDs. The data disclose an advantageous therapeutic potential for gestational celecoxib over diclofenac or naproxen in controlling hepatic dysfunction and HMGB1-interrelated inflammatory and oxidative sequels of PE.
摘要：
先兆子痫（PE）通常与多器官损伤有关，在出生后仍然很明显。这里,我们检验了以下假设:非甾体类抗炎药(NSAIDs)的产前治疗可改善断奶大鼠PE诱导的肝损伤,高迁移率族蛋白B1(HMGB1)信号调节这种相互作用.在妊娠的最后一周，通过药理一氧化氮剥夺诱导PE（Nω-硝基-L-精氨酸甲酯，L-NAME,50毫克/千克/天，口服管饲法)。与对照组大鼠相比,断奶PE大鼠显示血清转氨酶的大幅升高以及肝细胞质变化的组织病理学征象，门静脉炎症,和中央静脉扩张。虽然妊娠期NSAIDs逆转了转氨酶升高，他们没有影响(塞来昔布，萘普生）或甚至恶化（双氯芬酸）的结构损伤。分子上，塞来昔布是最有效的NSAID（i）逆转PE引起的肝HMGB1基因表达上调以及丝裂原活化蛋白激酶MAPKERK和MAPKp38表达的增加和减少，分别,和（ii）升高和抑制血清白细胞介素-10和肿瘤坏死因子-α，分别。或者，所有NSAIDs均可显著减少PE引起的血清白细胞介素-1β的升高和巨噬细胞向炎症表型的分化.数据揭示了妊娠塞来昔布在控制肝功能障碍和HMGB1相关的PE的炎症和氧化后遗症方面优于双氯芬酸或萘普生的有利治疗潜力。
