Acute secondhand smoke-induced pulmonary inflammation is diminished in RAGE knockout mice

Abstract

The receptor for advanced glycation end-products (RAGE) has increasingly been demonstrated to be an important modulator of inflammation in cases of pulmonary disease. Published reports involving tobacco smoke exposure have demonstrated increased expression of RAGE, its participation in proinflammatory signaling, and its role in irreversible pulmonary remodeling. The current research evaluated the in vivo effects of short-term secondhand smoke (SHS) exposure in RAGE knockout and control mice compared with identical animals exposed to room air only. Quantitative PCR, immunoblotting, and immunohistochemistry revealed elevated RAGE expression in controls after 4 wk of SHS exposure and an anticipated absence of RAGE expression in RAGE knockout mice regardless of smoke exposure. Ras activation, NF-κB activity, and cytokine elaboration were assessed to characterize the molecular basis of SHS-induced inflammation in the mouse lung. Furthermore, bronchoalveolar lavage fluid was procured from RAGE knockout and control animals for the assessment of inflammatory cells and molecules. As a general theme, inflammation coincident with leukocyte recruitment was induced by SHS exposure and significantly influenced by the availability of RAGE. These data reveal captivating information suggesting a role for RAGE signaling in lungs exposed to SHS. However, ongoing research is still warranted to fully explain roles for RAGE and other receptors in cells coping with involuntary smoke exposure for prolonged periods of time.

Myocardial ischemic post-conditioning protects the lung against myocardial ischemia/reperfusion-induced damage by activating GSK-3β

“…mPTP is a nonspecific aperture on the mitochondrial inner membrane which allows entrance of active oxygen and free radicals when opening, resulting in organ damage. Inactivation of GSK-3β exacerbates ALI 16,17 .While activation of GSK-3β prevents mPTP opening and attenuates MIRI in cardiomyocytes 18 . In line with these results, in our current study, after MIRI, GSK-3β activation was significantly decreased in the lung that was associated with increased lung injury, suggesting that MIRI induced ALI by down-regulating p-GSK-3β.…”

Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke

“…In an elastase-induced emphysema-model, RAGE knockout mice were partly protected from structural lung changes and this effect was mainly attributed to the absence of RAGE in lung structural cells [22]. Mice exposed to acute secondhand smoke showed an increase in pulmonary RAGE protein expression [23]. Moreover, CS-induced release of proinflammatory cytokines and pulmonary recruitment of inflammatory cells were inhibited in RAGE -/- mice exposed to secondhand smoke [23] or cigarette smoke extract [24].…”

“…Mice exposed to acute secondhand smoke showed an increase in pulmonary RAGE protein expression [23]. Moreover, CS-induced release of proinflammatory cytokines and pulmonary recruitment of inflammatory cells were inhibited in RAGE -/- mice exposed to secondhand smoke [23] or cigarette smoke extract [24]. …”

Plausible Roles for RAGE in Conditions Exacerbated by Direct and Indirect (Secondhand) Smoke Exposure

“…An underlying mechanistic theme of the smoke-related disease states outlined in this review is chronic inflammation, in which RAGE is a key modulator. Essential to understanding the clear link between RAGE and disease progression is the key concept that RAGE expression is increased by exposure to tobacco smoke [5,209,210,211,212] and the induction of RAGE causes inflammatory disease symptoms similar or identical to the ones described herein [23,195,213,214,215,216,217]. …”