Pro-Inflammatory Profiling Of RAGE Targeted Mice Following Short-Term Tobacco Exposure.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology(2022)
Abstract
Inflammation underpins pulmonary disease progression during tobacco smoke exposure that may culminate in irreversdible pulmonary remodeling. While primary smoke poses notable risk, nearly half of the US population is also at risk due to exposure to secondhand smoke (SHS). In the present study, we assessed a potential role for RAGE, a cell-surface pattern recognition receptor implicated in pro-inflammatory signaling, following exposure to SHS. Specifically, we used wild type, RAGE null, and lung-specific RAGE overexpressing transgenic (TG) mice and evaluated the elaboration of inflammatory mediators in bronchoalveolar lavage fluid (BALF). Select mice were administered semi-synthetic glycosaminoglycan ethers (SAGEs), a family of anionic, partially lipophilic sulfated polysaccharide derivatives known to inhibit RAGE signaling. Mice were exposed to room air (RA) or 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 until sacrifice date on PN70. RAGE mRNA and protein expression was elevated in wild type and TG mice following SHS exposure and no expression was detected in RAGE nulls. BALF analyses revealed RAGE-mediated control of leukocyte extravasation and a multiplex cytokine array confirmed a role for RAGE in the coordination of pro-inflammatory chemokine/cytokine secretion. Among other mediators, TNF-a, MIP-2, and IL-1b were each differentially secreted by lung tissue following SHS exposure and concentrations were significantly decreased in BALF from exposed RAGE null or wild type mice concomitantly administered SAGEs. In summary, inflammatory 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 the utility of RAGE abrogation in lessening smoke-induced pulmonary exacerbations.
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Key words
tobacco,rage,mice
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