title: Lack of Transcription Factor p53 Exacerbates Elastase-Induced Emphysema in Mice.
abstract: The transcription factor p53 is overexpressed in the lung of patients with emphysema, but it remains unclear if it has a deleterious or protective effect in disease progression. We investigated the role of p53 in the elastase-induced emphysema model and the molecular underlining mechanisms. Wild-type (WT) and p53(-/-) mice were instilled with pancreatic porcine elastase. We quantified emphysema (morphometric analysis), chemokine (C-C motif) ligand 2 (CCL2), and TNF-α in bronchoalveolar lavage (BAL) (ELISA), oxidative stress markers [heme oxygenase 1 (HO1), NAD(P)H dehydrogenase quinone 1 (NQO1), and quantitative RT-PCR], matrix metalloproteinase 12 (MMP12) expression, and macrophage apoptosis (cleaved caspase-3, immunofluorescence). p53 gene expression was up-regulated in the lung of elastase-instilled mice. p53 deletion aggravated elastase-induced emphysema severity, pulmonary inflammation (macrophage and neutrophil numbers and CCL2 and TNF-α levels in BAL), and lung oxidative stress. These findings, except for the increase in CCL2, were reproduced in WT mice transplanted with p53(-/-) bone marrow cells. The increased number of macrophages in p53(-/-) mice was not a consequence of reduced apoptosis or an excess of chemotaxis toward CCL2. Macrophage expression of MMP12 was higher in p53(-/-) mice compared with WT mice after elastase instillation. These findings provide evidence that p53(-/-) mice and WT mice grafted with p53(-/-) bone marrow cells are more prone to developing elastase-induced emphysema, supporting a protective role of p53, and more precisely p53 expressed in macrophages, against emphysema development. The pivotal role played by macrophages in this phenomenon may involve the MMP12-TNF-α pathway.
authors.affiliation: 1 Faculté de Médecine, Université Paris-Est, UMR S955, Créteil, France.|2 Inserm U955, Equipe 04, Créteil, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Chrusciel
authors.affiliation: 3 Département de Pneumologie, Hôpitaux de Brabois and.|4 Equipe d'accueil 7298 INGRES, CHU de Nancy, Vandoeuvre-les-Nancy, France.|5 Université de Lorraine, Nancy, France.
authors.forename: Maéva
authors.initials: M
authors.lastname: Zysman
authors.affiliation: 1 Faculté de Médecine, Université Paris-Est, UMR S955, Créteil, France.|2 Inserm U955, Equipe 04, Créteil, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Caramelle
authors.affiliation: 1 Faculté de Médecine, Université Paris-Est, UMR S955, Créteil, France.|2 Inserm U955, Equipe 04, Créteil, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Tiendrebeogo
authors.affiliation: 1 Faculté de Médecine, Université Paris-Est, UMR S955, Créteil, France.|2 Inserm U955, Equipe 04, Créteil, France.
authors.forename: Indoumady
authors.initials: I
authors.lastname: Baskara
authors.affiliation: 1 Faculté de Médecine, Université Paris-Est, UMR S955, Créteil, France.|2 Inserm U955, Equipe 04, Créteil, France.|6 Service d'Immunologie Biologique.
authors.forename: Sabine
authors.initials: S
authors.lastname: Le Gouvello
authors.affiliation: 3 Département de Pneumologie, Hôpitaux de Brabois and.|4 Equipe d'accueil 7298 INGRES, CHU de Nancy, Vandoeuvre-les-Nancy, France.|5 Université de Lorraine, Nancy, France.
authors.forename: François
authors.initials: F
authors.lastname: Chabot
authors.affiliation: 1 Faculté de Médecine, Université Paris-Est, UMR S955, Créteil, France.|7 Service d'Hématologie Biologique, and.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Giraudier
authors.affiliation: 1 Faculté de Médecine, Université Paris-Est, UMR S955, Créteil, France.|2 Inserm U955, Equipe 04, Créteil, France.|8 Centre Hospitalier Intercommunal, Service de Pneumologie et Pathologie Professionnelle, Créteil, France.
authors.forename: Jorge
authors.initials: J
authors.lastname: Boczkowski
authors.affiliation: 1 Faculté de Médecine, Université Paris-Est, UMR S955, Créteil, France.|2 Inserm U955, Equipe 04, Créteil, France.|9 Service de Physiologie Explorations Fonctionnelles, AP-HP, Hôpital Henri Mondor, DHU A-TVB, Créteil, France; and.
authors.forename: Laurent
authors.initials: L
authors.lastname: Boyer
mesh_terms: D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D018384:Oxidative Stress; D010196:Pancreatic Elastase; D010641:Phenotype; D011656:Pulmonary Emphysema / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D010196:Pancreatic Elastase; D053508:Matrix Metalloproteinase 12; C000602031:matrix metallopeptidase 12, mouse
keywords: TNF-α; emphysema; macrophages; p53