Abstract
BackgroundReceptors for advanced glycation end-products (RAGE) are multiligand cell-surface receptors expressed abundantly by distal pulmonary epithelium. Our lab has discovered RAGE-mediated effects in the orchestration of lung inflammation induced by tobacco smoke and environmental pollutants; however, the specific contribution of RAGE to the progression of proximal airway inflammation is still inadequately characterized.Methods and resultsWe generated a Tet-inducible transgenic mouse that conditionally overexpressed RAGE using the club cell (Clara) secretory protein (CCSP) promoter expressed by club (Clara) cells localized to the proximal airway. RAGE was induced for 40 days from weaning (20 days of age) until sacrifice date at 60 days. Immunohistochemistry, immunoblotting, and qPCR revealed significant RAGE up-regulation when compared to non-transgenic controls; however, H&E staining revealed no detectible morphological abnormalities and apoptosis was not enhanced during the 40 days of augmentation. Freshly procured bronchoalveolar lavage fluid (BALF) from CCSP-RAGE TG mice had significantly more total leukocytes and PMNs compared to age-matched control littermates. Furthermore, CCSP-RAGE TG mice expressed significantly more tumor necrosis factor alpha (TNF-α), interleukin 7 (IL-7), and interleukin 14 (IL-14) in whole lung homogenates compared to controls.ConclusionsThese data support the concept that RAGE up-regulation specifically in lung airways may function in the progression of proximal airway inflammation.
Highlights
Receptors for advanced glycation end-products (RAGE) propagate intracellular signaling programs following interaction with a diversity of ligands
These data support the concept that RAGE up-regulation in lung airways may function in the progression of proximal airway inflammation
cell (Clara) secretory protein (CCSP)-RAGE TG mice up-regulate RAGE expression in the proximal airways Double transgenic offspring (CCSP-RAGE TG) from CCSP-rtTA and TetO-RAGE transgenic mice were obtained and dox-mediated up-regulation of RAGE commenced on PN20, a period that coincided with the completion of lung morphogenesis
Summary
Receptors for advanced glycation end-products (RAGE) propagate intracellular signaling programs following interaction with a diversity of ligands. RAGE has increasingly been implicated as a progression factor in response to the availability of advanced glycation end-products (AGEs) that accumulate during oxidant stress and when endogenous ligands including S100/calgranulins, amyloid-β-peptide, and high mobility box protein 1 (HMGB1) are augmented [1,2,3]. A series of publications clearly outline discoveries that demonstrate elevated RAGE expression and signaling by pulmonary cell types when extrinsic particulates including tobacco smoke are present [7,8,9,10]. Receptors for advanced glycation end-products (RAGE) are multiligand cell-surface receptors expressed abundantly by distal pulmonary epithelium. Our lab has discovered RAGE-mediated effects in the orchestration of lung inflammation induced by tobacco smoke and environmental pollutants; the specific contribution of RAGE to the progression of proximal airway inflammation is still inadequately characterized
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