title: Receptor for advanced glycation end products contributes to postnatal pulmonary development and adult lung maintenance program in mice.
abstract: The role of the receptor for advanced glycation end products (RAGE) in promoting the inflammatory response through activation of NF-κB pathway is well established. Recent findings indicate that RAGE may also have a regulative function in apoptosis, as well as in cellular proliferation, differentiation, and adhesion. Unlike other organs, lung tissue in adulthood and during organ development shows relatively high levels of RAGE expression. Thus a role for the receptor in lung organogenesis and homeostasis may be proposed. To evaluate the role of RAGE in lung development and adult lung homeostasis, we generated hemizygous and homozygous transgenic mice overexpressing human RAGE, and analyzed their lungs from the fourth postnatal day to adulthood. Moderate RAGE hyperexpression during lung development influenced secondary septation, resulting in an impairment of alveolar morphogenesis and leading to significant changes in morphometric parameters such as airspace number and the size of alveolar ducts. An increase in alveolar cell apoptosis and a decrease in cell proliferation were demonstrated by the terminal deoxy-nucleotidyltransferase-mediated dUTP nick end labeling reaction, active caspase-3, and Ki-67 immunohistochemistry. Alterations in elastin organization and deposition and in TGF-β expression were observed. In homozygous mice, the hyperexpression of RAGE resulted in histological changes resembling those changes characterizing human bronchopulmonary dysplasia (BPD). RAGE hyperexpression in the adult lung is associated with an increase of the alveolar destructive index and persistent inflammatory status leading to "destructive" emphysema. These results suggest an important role for RAGE in both alveolar development and lung homeostasis, and open new doors to working hypotheses on the pathogenesis of BPD and chronic obstructive pulmonary disease.
authors.affiliation: Department of Physiopathology, University of Siena, Via Aldo Moro 6, I-53100 Siena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fineschi
authors.forename: Giovanna
authors.initials: G
authors.lastname: De Cunto
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Facchinetti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Civelli
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Imbimbo
authors.forename: Chiara
authors.initials: C
authors.lastname: Carnini
authors.forename: Gino
authors.initials: G
authors.lastname: Villetti
authors.forename: Benedetta
authors.initials: B
authors.lastname: Lunghi
authors.forename: Stefania
authors.initials: S
authors.lastname: Stochino
authors.forename: Deena L
authors.initials: DL
authors.lastname: Gibbons
authors.forename: Adrian
authors.initials: A
authors.lastname: Hayday
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lungarella
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cavarra
mesh_terms: D000375:Aging; D000818:Animals; D001483:Base Sequence; D053148:Caspase 3 / Q000378:metabolism; D017931:DNA Primers; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D008168:Lung / Q000254:growth & development* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D017931:DNA Primers; D019394:Ki-67 Antigen; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D016212:Transforming Growth Factor beta; D053148:Caspase 3