Glucocorticoid Exposure Induces Preeclampsia via DampeningLipoxin A(4), an Endogenous Anti-Inflammatory and Proresolving Mediator

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(4) (LXA(4)), an endogenous dual anti-inflammatory and proresolving mediator. The present study was to investigate whether GC exposure induces PE via dampening LXA(4). In the study, cortisol levels of PE women were higher than those of normal pregnancies, LXA(4) levels were downregulated in both PE patients and GC-mediated PE rats, and leukotriene B(4) (LTB(4)) levels were upregulated in both PE patients and GC- mediated PE rats. Moreover, cortisol levels were negatively correlated to LXA(4) levels, while positively correlated to LTB(4) levels in PE patients. Mechanically, GC downregulated LXA(4) via disturbing its biosynthetic enzymes, including ALOX15, ALOX5B and ALOX5, especially activating ALOX5, the key enzyme for class switching between LXA(4) and LTB(4). Importantly, replenishing LXA(4) could ameliorate PE-related symptoms and placental oxidative stress in PE rat model induced by GC. Moreover, LXA(4) could inhibit GC-mediated ALOX5 activation and LTB(4) increase, and also suppress 11β-HSD2 expression and corticosterone upregulation. The protective actions of LXA(4) 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(4), and GC/LXA(4) axis may represent a common pathway through which PE occurs.