title: Induction and regulation of murine emphysema by elastin peptides.
abstract: Emphysema is the major component of chronic obstructive pulmonary disease (COPD). During emphysema, elastin breakdown in the lung tissue originates from the release of large amounts of elastase by inflammatory cells. Elevated levels of elastin-derived peptides (EP) reflect massive pulmonary elastin breakdown in COPD patients. Only the EP containing the GXXPG conformational motif with a type VIII β-turn are elastin receptor ligands inducing biological activities. In addition, the COOH-terminal glycine residue of the GXXPG motif seems a prerequisite to the biological activity. In this study, we endotracheally instilled C57BL/6J mice with GXXPG EP and/or COOH-terminal glycine deleted-EP whose sequences were designed by molecular dynamics and docking simulations. We investigated their effect on all criteria associated with the progression of murine emphysema. Bronchoalveolar lavages were recovered to analyze cell profiles by flow cytometry and lungs were prepared to allow morphological and histological analysis by immunostaining and confocal microscopy. We observed that exposure of mice to EP elicited hallmark features of emphysema with inflammatory cell accumulation associated with increased matrix metalloproteinases and desmosine expression and of remodeling of parenchymal tissue. We also identified an inactive COOH-terminal glycine deleted-EP that retains its binding-activity to EBP and that is able to inhibit the in vitro and in vivo activities of emphysema-inducing EP. This study demonstrates that EP are key actors in the development of emphysema and that they represent pharmacological targets for an alternative treatment of emphysema based on the identification of EP analogous antagonists by molecular modeling studies.
authors.affiliation: EA4683, SFR CAP-Santé, Université de Reims Champagne-Ardenne, Reims, France;
authors.forename: Mehdi
authors.initials: M
authors.lastname: Sellami
authors.affiliation: EA4683, SFR CAP-Santé, Université de Reims Champagne-Ardenne, Reims, France;
authors.forename: Aïda
authors.initials: A
authors.lastname: Meghraoui-Kheddar
authors.affiliation: Plateforme d'Imagerie Cellulaire et Tissulaire, SFR CAP-Santé, URCA, Reims, France; and.
authors.forename: Christine
authors.initials: C
authors.lastname: Terryn
authors.affiliation: Laboratoire d'Anatomie et de Cytologie Pathologiques, CHU R. Debré, Reims, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Fichel
authors.affiliation: Laboratoire d'Anatomie et de Cytologie Pathologiques, CHU R. Debré, Reims, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bouland
authors.affiliation: Laboratoire d'Anatomie et de Cytologie Pathologiques, CHU R. Debré, Reims, France.
authors.forename: Marie-Daniele
authors.initials: MD
authors.lastname: Diebold
authors.affiliation: EA4683, SFR CAP-Santé, Université de Reims Champagne-Ardenne, Reims, France;
authors.forename: Moncef
authors.initials: M
authors.lastname: Guenounou
authors.affiliation: EA4683, SFR CAP-Santé, Université de Reims Champagne-Ardenne, Reims, France;
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Héry-Huynh
authors.affiliation: EA4683, SFR CAP-Santé, Université de Reims Champagne-Ardenne, Reims, France; richard.lenaour@univ-reims.fr.
authors.forename: Richard
authors.initials: R
authors.lastname: Le Naour
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors
chemical_list: D010455:Peptides; D011956:Receptors, Cell Surface; C054901:elastin-binding proteins; D003094:Collagen; D004549:Elastin; D010196:Pancreatic Elastase
keywords: elastin peptides; molecular modeling; murine model; parenchyma inflammation