RAGE signaling influences tobacco smoke‐induced inflammation by pulmonary macrophages

Abstract

Receptors for advanced glycation end‐products (RAGE) are multi‐ligand cell surface receptors expressed by lung cells and expression increases following exposure to cigarette smoke (CS). The current study sought to characterize the pro‐inflammatory effects of RAGE in pulmonary macrophages (PMs) following CS exposure. Acute exposure to CS via nasal instillation revealed diminished bronchoalveolar lavage (BAL) cellularity and fewer macrophages in RAGE null mice compared to controls. Primary PMs were obtained from BAL, exposed to CS in vitro, and analyzed. CS significantly increased RAGE expression in wild type PMs. By ELISA, wild type PMs increased active Ras, a small GTPase that perpetuates pro‐inflammatory signaling, following CS exposure. Conversely, RAGE null PMs had less Ras activation compared to wild type PMs after exposure to CS. Assessment of signaling intermediates including p38 and NF‐kB revealed CS‐induced inflammation may occur in part via RAGE signaling. Lastly, qRT‐PCR and ELISA revealed that secretion of cytokines such as TNF‐α and IL‐1β were decreased in RAGE null PMs exposed to CS compared to CS‐exposed wild type PMs. These results show for the first time that primary PMs orchestrate CS‐induced inflammation, at least in part, via RAGE‐mediated mechanisms. This work was supported by the Flight Attendant's Medical Research Institute (FAMRI, PRR) and a BYU Mentoring Environment Grant (PRR).