Abstract
Chorioamnionitis (CAM) is primarily a polymicrobial bacterial infection involving chorionic and amniotic membranes that is associated with increased risk of preterm delivery. Epoxyeicosatrienoic acids (EETs) are eicosanoids generated from arachidonic acid by cytochrome P450 enzymes and further metabolized mainly by soluble epoxide hydrolase (sEH) to produce dihydroxyeicosatrienoic acids (DHETs). As a consequence of this metabolism of EETs, sEH reportedly exacerbates several disease states; however, its role in CAM remains unclear. The objectives of this study were to (1) determine the localization of sEH and compare the changes it undergoes in the gestational tissues (placentas and fetal membranes) of women with normal-term pregnancies and those with pregnancies complicated by acute CAM; (2) study the effects of lipopolysaccharide (LPS) on the expression of sEH in the human gestational tissues; and (3) investigate the effect of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), a specific sEH inhibitor, on LPS-induced changes in 14,15-DHET and cytokines such as interleukin- (IL-) 1β and IL-6 in human gestational tissues in vitro and in pregnant mice. We found that women with pregnancies complicated by acute CAM had higher levels of sEH mRNA and protein in fetal membranes and villous tissues compared to those in women with normal-term pregnancies without CAM. Furthermore, fetal membrane and villous explants treated with LPS had higher tissue levels of sEH mRNA and protein and 14,15-DHET than those present in the vehicle controls, while the administration of AUDA in the media attenuated the LPS-induced production of 14,15-DHET in tissue homogenates and IL-1β and IL-6 in the media of explant cultures. Administration of AUDA also reduced the LPS-induced changes of 14,15-DHET, IL-1β, and IL-6 in the placentas of pregnant mice. Together, these results suggest that sEH participates in the inflammatory changes in human gestational tissues in pregnancies complicated by acute CAM.
Highlights
Chorioamnionitis (CAM) is primarily a polymicrobial bacterial infection involving chorionic and amniotic membranes and amniotic fluid and is implicated in 0.5% to 10% of all pregnancies [1]
These include increased levels of arachidonic acid (AA) in the placentas of women with CAM and preterm delivery compared to women with preterm delivery but without CAM [6]; upregulation of COX-2 and prostaglandin (PG) G/H synthase, along with certain inflammatory genes, in the amnion and choriodecidua of women with CAM [7]; increased production of PGE2, PGF2α, and leukotriene B4 (LTB4) from the placentas and fetal membranes in women with CAM than in those without CAM [8, 9]; and greater concentrations of PGs and LTB4 in the amniotic fluid of women with intra-amniotic infections than in women without intra-amniotic infections [10,11,12]
The objectives of this study were to (1) determine and compare the localization and changes of soluble epoxide hydrolase (sEH) in human gestational tissues between women with normal-term pregnancies and those with pregnancies complicated by acute CAM; (2) study the effects of lipopolysaccharide (LPS)—an endotoxin found in gram-negative bacteria that is reportedly elevated in the amniotic fluid and choriodecidua during acute CAM—on the expression of sEH in human gestational tissues in vitro; and (3) investigate the effect of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA)—a specific sEH inhibitor—on LPS-induced changes in 14,15-dihydroxyeicosatrienoic acids (DHETs) and cytokines such as interleukin-1β and IL-6 in human gestational tissues in vitro and in pregnant mice
Summary
Chorioamnionitis (CAM) is primarily a polymicrobial bacterial infection involving chorionic and amniotic membranes and amniotic fluid and is implicated in 0.5% to 10% of all pregnancies [1]. Previous studies—mostly focusing on the COX and LOX pathways—have identified the essential roles of AA metabolism and eicosanoids in the pathophysiology of Mediators of Inflammation. These include increased levels of AA in the placentas of women with CAM and preterm delivery compared to women with preterm delivery but without CAM [6]; upregulation of COX-2 and prostaglandin (PG) G/H synthase, along with certain inflammatory genes, in the amnion and choriodecidua of women with CAM [7]; increased production of PGE2, PGF2α, and leukotriene B4 (LTB4) from the placentas and fetal membranes in women with CAM than in those without CAM [8, 9]; and greater concentrations of PGs and LTB4 in the amniotic fluid of women with intra-amniotic infections than in women without intra-amniotic infections [10,11,12]. The role of AA metabolism via the CYP450 pathway in human gestational tissues of pregnancies complicated by acute CAM remains unclear
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