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.

Receptors for advanced glycation end‐products (RAGE) are multiligand cell‐surface receptors expressed abundantly by pulmonary epithelium. Our lab has discovered RAGE‐mediated effects in lung inflammation induced by tobacco smoke and environmental pollutants; however, the precise contribution of RAGE to proximal airway inflammation was yet unknown. We generated a Tet‐inducible transgenic mouse that conditionally over‐expresses RAGE using the Clara Cell Secretory Protein (CCSP) promoter active in proximal airway Clara cells. RAGE was induced for 40 days from weaning (20 days of age) until sacrifice date at 60 days. Compared to controls, immunohistochemistry, immunoblotting, and qPCR revealed significant RAGE up‐regulation; however, H&E staining revealed no detectible morphological disturbances. Freshly procured bronchoalveolar lavage fluid (BALF) from RAGE TG mice had significantly greater total protein content, total leukocyte quantity, PMN abundance, and cytokine concentration compared to age‐matched control littermates. These data support the concept that RAGE up‐regulation in lung airways may participate in inflammation of the proximal airway. Supported by the Flight Attendant's Medical Research Institute (FAMRI, PRR) and a BYU MEG (PRR).