Abstract
Infection-induced preterm birth is the largest cause of infant death and of neurological disabilities in survivors. Silibinin, from milk thistle, exerts potent anti-inflammatory activities in non-gestational tissues. The aims of this study were to determine the effect of silibinin on pro-inflammatory mediators in (i) human fetal membranes and myometrium treated with bacterial endotoxin lipopolysaccharide (LPS) or the pro-inflammatory cytokine IL-1β, and (ii) in preterm fetal membranes with active infection. The effect of silibinin on infection induced inflammation and brain injury in pregnant mice was also assessed. Fetal membranes and myometrium (tissue explants and primary cells) were treated with 200 μM silibinin in the presence or absence of 10 μg/ml LPS or 1 ng/ml IL-1β. C57BL/6 mice were injected with 70 mg/kg silibinin with or without 50 μg LPS on embryonic day 16. Fetal brains were collected after 6 h. In human fetal membranes, silibinin significantly decreased LPS-stimulated expression of IL-6 and IL-8, COX-2, and prostaglandins PGE2 and PGF2α. In primary amnion and myometrial cells, silibinin also decreased IL-1β-induced MMP-9 expression. Preterm fetal membranes with active infection treated with silibinin showed a decrease in IL-6, IL-8 and MMP-9 expression. Fetal brains from mice treated with silibinin showed a significant decrease in LPS-induced IL-8 and ninjurin, a marker of brain injury. Our study demonstrates that silibinin can reduce infection and inflammation-induced pro-labour mediators in human fetal membranes and myometrium. Excitingly, the in vivo results indicate a protective effect of silibinin on infection-induced brain injury in a mouse model of preterm birth.
Highlights
Preterm birth is the single leading cause of neonatal death worldwide, after exclusion of congenital defects, and can lead to numerous long-term health consequences for those surviving babies [1]
The first aim of this study was to determine the effect of silibinin on infection (LPS) and inflammation (IL-1b) induced pro-labour mediators in human fetal membranes and myometrium
IL-6 and IL-8 gene expression was quantified by qRT-PCR and the concentration of IL-6 and IL-8 in conditioned media assessed by ELISA
Summary
Preterm birth is the single leading cause of neonatal death worldwide, after exclusion of congenital defects, and can lead to numerous long-term health consequences for those surviving babies [1]. Chorioamnionitis complicates a third of patients with preterm labour [3] and is the most common complication associated with PPROM [4]. Chorioamnionitis predisposes the preterm infant to numerous organ disease, affecting cardiopulmonary, cerebral, and renal systems [5]; developmental delay and lifelong neurological impairments, such as mental retardation, cerebral palsy and learning and behavioural deficits, are caused by perinatal brain damage [6,7,8]. Besides the emotional burden on families, direct and indirect costs of preterm birth accounts for billions of health care dollars each year
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