Cigarette Smoke Condensate Exposure Induces Receptor for Advanced Glycation End-Products (RAGE)-Dependent Sterile Inflammation in Amniotic Epithelial Cells

Int J Mol Sci. 2021 Aug 3;22(15):8345. doi: 10.3390/ijms22158345.

Abstract

Maternal smoking is a risk factor of preterm prelabor rupture of the fetal membranes (pPROM), which is responsible for 30% of preterm births worldwide. Cigarettes induce oxidative stress and inflammation, mechanisms both implicated in fetal membranes (FM) weakening. We hypothesized that the receptor for advanced glycation end-products (RAGE) and its ligands can result in cigarette-dependent inflammation. FM explants and amniotic epithelial cells (AECs) were treated with cigarette smoke condensate (CSC), combined or not with RAGE antagonist peptide (RAP), an inhibitor of RAGE. Cell suffering was evaluated by measuring lactate dehydrogenase (LDH) medium-release. Extracellular HMGB1 (a RAGE ligand) release by amnion and choriodecidua explants were checked by western blot. NF-κB pathway induction was determined by a luciferase gene reporter assay, and inflammation was evaluated by cytokine RT-qPCR and protein quantification. Gelatinase activity was assessed using a specific assay. CSC induced cell suffering and HMGB1 secretion only in the amnion, which is directly associated with a RAGE-dependent response. CSC also affected AECs by inducing inflammation (cytokine release and NFκB activation) and gelatinase activity through RAGE engagement, which was linked to an increase in extracellular matrix degradation. This RAGE dependent CSC-induced inflammation associated with an increase of gelatinase activity could explain a pathological FM weakening directly linked to pPROM.

Keywords: RAGE; fetal membranes; maternal smoking; pPROM.

MeSH terms

  • Adult
  • Amnion / drug effects
  • Amnion / immunology
  • Amnion / metabolism
  • Amnion / pathology*
  • Cells, Cultured
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology*
  • Female
  • Gene Expression Regulation / drug effects*
  • Humans
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced
  • Prenatal Exposure Delayed Effects / immunology
  • Prenatal Exposure Delayed Effects / metabolism
  • Prenatal Exposure Delayed Effects / pathology*
  • Receptor for Advanced Glycation End Products
  • Smoke / adverse effects*

Substances

  • Receptor for Advanced Glycation End Products
  • Smoke