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Inhibition of the Receptor for Advanced Glycation End‐products (RAGE) protects from secondhand smoke (SHS) induced intrauterine growth restriction (IUGR) in mice
Author(s) -
Lewis Joshua B,
Mejia Camilo A,
Jordan Clinton,
Monson Troy D,
Bodine Jared S,
Dunaway Todd M,
Egbert Kaleb M,
Wright Tanner J,
Ogden K Connor,
Broberg Dallin S,
Hall Parker D,
Nelson Shawn M,
Hirschi Kelsey M,
Reynolds Paul R,
Arroyo Juan A
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.978.18
Subject(s) - trophoblast , placenta , glycation , rage (emotion) , receptor , fetus , intrauterine growth restriction , medicine , endocrinology , andrology , chemistry , biology , pregnancy , genetics , neuroscience
Intrauterine growth restriction (IUGR) is a disease affecting 10% of all pregnancies. IUGR is associated with maternal, fetal, or placental abnormalities, but studies investigating the effects of secondhand smoke (SHS) exposure and IUGR are limited. Receptors for Advanced Glycation End‐products (RAGE) are pro‐inflammatory transmembrane receptors increased by SHS in the placenta. We tested the hypothesis that inhibition of RAGE during SHS exposure protects from smoke‐induced IUGR. C57Bl6 mice were exposed to SHS or SHS + semi‐synthetic glycosaminoglycan ethers (SAGEs) known to inhibit RAGE signaling. RAGE −/− mice were also exposed to SHS. Trophoblast cells were treated with cigarette smoke extract (CSE) with or without SAGEs in order to address the effects of RAGE inhibition during trophoblast invasion in vitro . SHS treated mice demonstrated a significant reduction in fetal weight (7.35‐fold; p ≤0.0001) and placental weight (1.13‐fold; p ≤0.0001) compared with controls. RAGE −/− mice were completely protected from fetal and placental weight deviations when exposed to SHS. Mice co‐treated with SHS and SAGEs were protected from SHS‐induced fetal weights decreases (4.22‐fold; p ≤0.0001). SHS treatment of C57Bl6 mice activated placental ERK (2.61‐fold, p ≤0.05), JNK (1.79‐fold, p ≤0.05), and p38 (2.44‐fold, p ≤0.05) and the expression of inflammatory mediators including TNF‐α (1.34‐fold p ≤0.05) and IL‐1β (1.03‐fold p ≤0.05). SHS‐mediated activation of these molecules was reduced to basal levels when SAGE was co‐administered. Invasion of trophoblast cells decreased 92% (p<0.002) when treated with CSE and CSE‐mediated invasion was completely reversed by SAGEs. We conclude that inhibition of RAGE protects against fetal weight loss during SHS‐induced IUGR. Our results further suggest that there is a direct correlation between RAGE activation and the development of IUGR during SHS. These studies provide insight into tobacco‐mediated IUGR development and clarify avenues that may be helpful in the alleviation of placental complications. Support or Funding Information This work was supported by a grant from the Flight Attendant's Medical Research Institute (FAMRI, PRR) and a BYU Mentoring Environment Grant (PRR).