Novel Insights into the Regulatory Role of Nuclear Factor (Erythroid-Derived 2)-Like 2 in Oxidative Stress and Inflammation of Human Fetal Membranes.

Ramkumar Menon,Morgan R Peltier

doi:10.3390/ijms21176139

Abstract

Fetal membrane dysfunction in response to oxidative stress (OS) is associated with adverse pregnancy outcomes. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is one of the regulators of innate OS response. This study evaluated changes in Nrf2 expression and its downstream targets heme oxygenase (HO-1) and peroxisome proliferator-activated receptor gamma (PPARγ) in fetal membranes during OS and infection in vitro. Furthermore, we tested the roles of sulforaphane (SFN; an extract from cruciferous vegetables) and trigonelline (TRN; an aromatic compound in coffee) in regulating Nrf2 and its targets. Fetal membranes (n = 6) collected at term were placed in an organ explant system were treated with water-soluble cigarette smoke extract (CSE), an OS inducer (1:10), and lipopolysaccharide (LPS; 100 ng/mL). Nrf2 expression, expression, its enhancement by sulforaphane (SFN, 10 µM/mL) and down regulation by TRN (10uM/mL) was determined by western blots. Expression of Nrf2 response elements PPARγ (western) heme oxygenase (HO-1), and IL-6 were quantified by ELISA. CSE and LPS treatment of fetal membranes increased nrf2, but reduced HO-1 and PPARγ and increased IL-6. Co-treatment of SFN, but not with TRN, with CSE and LPS increased Nrf2 substantially, as well as increased HO-1 and PPARγ and reduced IL-6 expression. Risk factor-induced Nrf2 increase is insufficient to generate an antioxidant response in fetal membranes. Sulforaphane may enhance innate antioxidant and anti-inflammatory capacity by increasing NRF-2 expression.

Highlights

The World Health Organization recently estimated the global preterm birth rate for singleton gestation at 10.5% [1]
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We evaluated the effects of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activator, Sulforaphane (SFN) and inhibitor, Trigonelline (TRN), on Nrf2-driven antioxidant pathways in human fetal membrane explants exposed to oxidative stress by infection or cigarette smoke components

Summary

Introduction

The World Health Organization recently estimated the global preterm birth rate for singleton gestation at 10.5% [1]. 60% PTB are spontaneous, and 30–40% of these are preceded by preterm prelabor rupture of the fetal membranes (pPROM) [2,3,4]. 50% of PTB and 70% of pPROM are associated with microbial invasion of the amniotic cavity (MIAC) and intraamniotic inflammation (IAI) [5,6,7]. Inflammatory changes that precede PTB, such as leukocyte activation, increased inflammatory cytokines and chemokines, and collagenolysis of the extracellular matrix by metalloproteinases (MMPs), resulting in loss of membrane structural integrity, myometrial activation, and cervical ripening, are well documented by experimental and clinical studies [8,9,10,11]. We have reported the heterogeneity in the inflammatory response (cytokines/chemokines, toll-like-receptors, and their interactions) associated with IAI and PTB risk factors [12,13,14]

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