Receptor for advanced glycation end-products signaling induction in the lung and placenta due to secondhand smoke and e-cigarette vapor

Project Summary
Placental complications affect up to 15% of all pregnancies and is a notable cause of preterm morbidity and mortality.
In addition to perinatal compromises including perinatal hypoxia and asphyxia, cerebral palsy, and persistent
pulmonary hypertension of the newborn, long-term sequelae of gestational complications include adult hypertension,
pulmonary complications, heart disease, stroke and diabetes. Involuntary exposure to tobacco smoke or electronic
cigarettes is assumed to be a notable causative factor of placental anomalies. Past studies identified the receptor for
advanced glycation end-products (RAGE) as a smoke-induced pattern recognition receptor with potent pro-
inflammatory characteristics. Further research demonstrated that RAGE is increased in the lung and placenta following
secondhand smoke or eCig exposure and that transgenic mice that conditionally up-regulate RAGE manifest aspects
of a smoker’s lung and hallmarks of placental insufficiency in the absence of smoke. SAGEs are semi-synthetic
glycosaminoglycan ethers that are potent modulators of inflammation in numerous animal models of human disease,
and are in preclinical development for periodontitis, oral mucositis, and bladder inflammation. Importantly, SAGEs
significantly inhibit interactions between RAGE and its many ligands necessary for signaling. The present proposal
aims to thoroughly assess the biology of RAGE as a molecular target in exposed placenta and to consider maternal
pulmonary and systemic inflammation during the orchestration of complications. A key innovation of this proposal is
a collection of animal models that control RAGE expression including RAGE null mice. This proposal also has
significant impact due to its clinical translational potential to ameliorate smokeor eCIG vapor-induced inflammation
and placental dysfunction. The central hypothesis is that inhibition of RAGE signaling improves lung and placental
growth/function and protects the offspring from the effects of exposure. Two specific aims are proposed, and each
uses advanced molecular methodologies employed by undergraduate students to test our hypotheses. The studies
outlined in this proposal will validate RAGE signaling as a target pathway for the translational prevention or
attenuation of placental defects in individuals unable or unwilling to remove tobacco exposure but may also help to
clarify RAGE-mediated pathogenesis in a number of physiological processes.

Grant Number: 1R15HD108743-01
NIH Institute/Center: NIH
Principal Investigator: JUAN ARROYO