Liu Haojing, Huang Wei, Chen Liping, Xu Qiang, Ye Duyun, Zhang Dongxin
Department of Science and Education, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Clinical Laboratory, Wuhan First Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Pharmacol. 2020 Jul 28;11:1131. doi: 10.3389/fphar.2020.01131. eCollection 2020.
The pathogenesis of preeclampsia (PE) involves several pathophysiological processes that may be affected by glucocorticoid (GC). We confirmed previously that GC exposure could result in PE, while PE is linked to a deficiency of lipoxin A (LXA), an endogenous dual anti-inflammatory and proresolving mediator. The present study was to investigate whether GC exposure induces PE dampening LXA. In the study, cortisol levels of PE women were higher than those of normal pregnancies, LXA levels were downregulated in both PE patients and GC-mediated PE rats, and leukotriene B (LTB) levels were upregulated in both PE patients and GC- mediated PE rats. Moreover, cortisol levels were negatively correlated to LXA levels, while positively correlated to LTB levels in PE patients. Mechanically, GC downregulated LXA disturbing its biosynthetic enzymes, including ALOX15, ALOX5B and ALOX5, especially activating ALOX5, the key enzyme for class switching between LXA and LTB. Importantly, replenishing LXA could ameliorate PE-related symptoms and placental oxidative stress in PE rat model induced by GC. Moreover, LXA could inhibit GC-mediated ALOX5 activation and LTB increase, and also suppress 11β-HSD2 expression and corticosterone upregulation. The protective actions of LXA might be explained by its roles in antagonizing the adverse effects of GC on trophoblast development. Together, our findings indicate that GC exposure could contribute to PE through dampening LXA, and GC/LXA axis may represent a common pathway through which PE occurs.
子痫前期（PE）的发病机制涉及多个可能受糖皮质激素（GC）影响的病理生理过程。我们之前证实，暴露于GC可导致PE，而PE与脂氧素A（LXA）缺乏有关，LXA是一种内源性的双重抗炎和促消退介质。本研究旨在探讨GC暴露是否通过抑制LXA诱导PE。在该研究中，PE女性的皮质醇水平高于正常妊娠女性，PE患者和GC介导的PE大鼠的LXA水平均下调，而PE患者和GC介导的PE大鼠的白三烯B（LTB）水平均上调。此外，在PE患者中，皮质醇水平与LXA水平呈负相关，而与LTB水平呈正相关。机制上，GC下调LXA，干扰其生物合成酶，包括ALOX15、ALOX5B和ALOX5，尤其是激活ALOX5，这是LXA和LTB之间类别转换的关键酶。重要的是，补充LXA可改善GC诱导的PE大鼠模型中与PE相关的症状和胎盘氧化应激。此外，LXA可抑制GC介导的ALOX5激活和LTB增加，还可抑制11β-HSD2表达和皮质酮上调。LXA的保护作用可能是通过其拮抗GC对滋养层细胞发育的不利影响来解释的。总之，我们的研究结果表明，GC暴露可能通过抑制LXA导致PE，并且GC/LXA轴可能是PE发生的共同途径。
