title: Conditional overexpression of receptors for advanced glycation end-products in the adult murine lung causes airspace enlargement and induces inflammation.
abstract: Receptors for advanced glycation end-products (RAGE) are multiligand surface receptors detected abundantly in pulmonary tissue. Our previous work revealed increased RAGE expression in cells and lungs exposed to tobacco smoke and RAGE-mediated cytokine expression via proinflammatory mechanisms involving NF-κB. RAGE expression is elevated in various pathological states, including chronic obstructive pulmonary disease; however, precise contributions of RAGE to the progression of emphysema and pulmonary inflammation in the adult lung are unknown. In the current study, we generated a RAGE transgenic (RAGE TG) mouse and conditionally induced adult alveolar epithelium to overexpress RAGE. RAGE was induced after the period of alveologenesis, from weaning (20 d of age) until animals were killed at 50, 80, and 110 days (representing 30, 60, and 90 d of RAGE overexpression). Hematoxylin and eosin staining and mean chord length revealed incremental dilation of alveolar spaces as RAGE overexpression persisted. TUNEL staining and electron microscopy confirmed increased apoptosis and blebbing of alveolar epithelium in lungs from RAGE TG mice when compared with control mice. Immunohistochemistry for matrix metalloproteinase 9 revealed an overall increase in matrix metalloproteinase 9, which correlated with decreased elastin expression in RAGE TG mice. Furthermore, RAGE TG mice manifested significant inflammation measured by elevated bronchoalveolar lavage protein, leukocyte infiltration, and secreted cytokines. These data support the concept that innovative transgenic mice that overexpress RAGE may model pulmonary inflammation and alveolar destabilization independent of tobacco smoke and validate RAGE signaling as a target pathway in the prevention or attenuation of smoke-related inflammatory lung diseases.
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
authors.forename: Megan P
authors.initials: MP
authors.lastname: Stogsdill
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Stogsdill
authors.forename: B Garrett
authors.initials: BG
authors.lastname: Bodine
authors.forename: Ali C
authors.initials: AC
authors.lastname: Fredrickson
authors.forename: Tayler L
authors.initials: TL
authors.lastname: Sefcik
authors.forename: Tyler T
authors.initials: TT
authors.lastname: Wood
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Kasteler
authors.forename: Paul R
authors.initials: PR
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D017209:Apoptosis; D004318:Doxycycline / Q000494:pharmacology; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology*; D059748:Proteolysis; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000648:ultrastructure*; D011656:Pulmonary Emphysema / Q000473:pathology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D013194:Staining and Labeling; D015854:Up-Regulation; D014886:Weaning
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D004549:Elastin; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D004318:Doxycycline