RAGE and SAGE: Ameliorating COPD Pathogenesis via RAGE Abrogation

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease involving chronic airway inflammation and emphysema. While primary smoke poses the greatest risk, evidence suggests nearly half of the US population is also at risk due to exposure to second hand smoke (SHS). In the present study, we used control, RAGE null, and lung‐specific RAGE overexpressing transgenic (TG) mice to study the role of RAGE during responses to SHS. We evaluated inflammatory effects of SHS in these mice with and without the administration of semi‐synthetic glycosaminoglycan ethers (SAGEs), a family of anionic, partially lipophilic sulfated polysaccharide derivatives known to inhibit RAGE signaling. Mice were weaned and fed doxycycline to induce RAGE in TG mice at PN30. Select mice were exposed to SHS from three Kentucky 3R4F research cigarettes via a nose‐only delivery system (Sireq Scientific, Montreal, Canada) five days a week and ip injections of PBS or SAGE (a 30mg/kg body weight) occurred three times per week from PN40‐70 before all mice were sacrificed on PN70. RAGE mRNA and protein expression was elevated following SHS exposure of control and TG mice and no expression was detected in RAGE null mice. Bronchoalveolar lavage fluid (BALF) analysis revealed RAGE‐mediated influence of inflammatory cell diapedesis and BALF protein abundance. A multiplex cytokine array was performed in order to precisely determine the secretion of pro‐inflammatory modulators into BALF. Lung histological assessment revealed indistinguishable morphological changes following exposure, yet apoptosis was increased in lung parenchyma. Thematically, inflammatory signaling intermediates and downstream responses induced by SHS exposure were influenced by the availability of RAGE, as evidenced by RAGE nulls and SAGE treatment. These data reveal fascinating data suggesting therapeutic potential for the use of RAGE inhibitors in lungs exposed to SHS smoke.Support or Funding InformationThis work was supported by a grant from the Flight Attendant's Medical Research Institute (FAMRI, PRR and JAA) and a BYU Mentoring Environment Grant (JAA and PRR).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.