Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB080

Poster Communications

RAGE and SAGE: Therapeutic Modalities for smoke-induced COPD

P. R. Reynolds1

1. Physiology and Dev Biology, Brigham Young University, Provo, Utah, United States.

Chronic obstructive pulmonary disease (COPD) is soon to be the third leading cause of death worldwide and it is characterized by debilitating inflammation and deleterious tissue loss in the respiratory compartment. Voluntary and involuntary exposure to tobacco smoke is the major cause of COPD. Past studies identified the receptor for advanced glycation end-products (RAGE) as a smoke-induced pattern recognition receptor with potent pro inflammatory characteristics. Our research demonstrated that RAGE is increased in the lung following first and secondhand smoke (SHS) exposure and that transgenic mice that conditionally up-regulate RAGE manifest characteristics of a smoker's lung 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. We have shown that SAGEs significantly inhibit interactions between RAGE and its many ligands necessary for signaling. The current research evaluated the in vivoeffects of short-term SHS exposure in RAGE null, conditional RAGE over-expressing, and control mice compared to identical animal groups exposed to room air only. Mice were subjected to daily SHS via a nose only inhalation system (Sireq Scientific, Montreal, Canada) as approved by institutional review boards. In short, mice were exposed to a 10 second computer-controlled puff of smoke generated every minute followed by 50 seconds of fresh air. Mice were exposed to SHS from two cigarettes over 10 minutes, allowed to breathe room air for 10 minutes, then exposed to smoke from one cigarette for an additional 10 minutes. This procedure was repeated five days a week for four weeks and compared to mice restrained and exposed to room air over the same period of time (n=8 per group). Select groups of mice were also co-treated with SAGEs via weekly ip injections. Molecular characterization of primary and SHS revealed significant pulmonary inflammation mediated at least in part by RAGE. Inflammatory cell behaviors were assessed by determining the activation of Ras, intracellular signaling kinases, and cytokine synthesis and secretion. Bronchoalveolar lavage fluid (BALF) was procured from our mouse models and assessed for inflammatory cells and secreted molecules. Lastly, pulmonary physiology tests revealed RAGE-mediated impairment. As a general theme, inflammation induced by tobacco smoke exposure was influenced by the availability of RAGE and significant amelioration of tobacco smoke-induced inflammation was observed in mice co-treated with SAGEs. These data reveal captivating information suggesting a role for RAGE signaling in lungs exposed to tobacco smoke and implicates plausible therapeutic modalities.

Where applicable, experiments conform with Society ethical requirements