title: Spontaneous miscarriages are explained by the stress/glucocorticoid/lipoxin A4 axis.
abstract: Despite various suspected causes, ranging from endocrine and genetic to infectious and immunological aspects, the molecular mechanisms of miscarriage still remain enigmatic. This work provides evidence that downregulation of 11β-hydroxysteroid dehydrogenase (HSD) type 2, the key enzyme inactivating glucocorticoid activities, insults the pregnant inflammatory milieu by inhibiting the biosynthesis of lipoxin A4 (LXA4), a metabolite of arachidonic acid, leading to an early loss of the pregnancy. Both LXA4 and its biosynthetic enzymes were found to be decreased in women with spontaneous miscarriages and in the murine miscarriage model. Replenishing LXA4 reversed LPS-induced miscarriages in mouse models, whereas blocking LXA4 signaling resulted in miscarriages in the pregnant mice. The protective effect of LXA4 might be explained by LXA4's role in regulating uterine and placental inflammatory factors and mast cells. The underlying molecular mechanism involved miscarriage-inducing infections or stresses that downregulate the expression of 11β-HSD2, but not 11β-HSD1, resulting in increases in glucocorticoid activity and decreases in LXA4. Together, these findings suggest that the stress/glucocorticoid/LXA4 axis might be a common pathway through which miscarriages occur.
authors.affiliation: Department of Gynecology and Obstetrics, First Affiliated Hospital, Wenzhou Medical College, Wenzhou 325003, People's Republic of China.
authors.forename: Zhangye
authors.initials: Z
authors.lastname: Xu
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Tang
authors.initials: T
authors.lastname: Ke
authors.forename: Pingwei
authors.initials: P
authors.lastname: Xu
authors.forename: Wenqian
authors.initials: W
authors.lastname: Cai
authors.forename: Foad
authors.initials: F
authors.lastname: Katirai
authors.forename: Duyun
authors.initials: D
authors.lastname: Ye
authors.forename: Yingping
authors.initials: Y
authors.lastname: Huang
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000022:Abortion, Spontaneous / Q000503:physiopathology*; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D044045:Lipoxins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D005938:Glucocorticoids; D044045:Lipoxins; C040527:lipoxin A4; D042842:11-beta-Hydroxysteroid Dehydrogenases