title: Characterization of spontaneous air space enlargement in mice lacking microfibrillar-associated protein 4.
abstract: Microfibrillar-associated protein 4 (MFAP4) is localized to elastic fibers in blood vessels and the interalveolar septa of the lungs and is further present in bronchoalveolar lavage. Mfap4 has been previously suggested to be involved in elastogenesis in the lung. We tested this prediction and aimed to characterize the pulmonary function changes and emphysematous changes that occur in Mfap4-deficient (Mfap4(-/-)) mice. Significant changes included increases in total lung capacity and compliance, which were evident in Mfap4(-/-) mice at 6 and 8 mo but not at 3 mo of age. Using in vivo breath-hold gated microcomputed tomography (micro-CT) in 8-mo-old Mfap4(-/-) mice, we found that the mean density of the lung parenchyma was decreased, and the low-attenuation area (LAA) was significantly increased by 14% compared with Mfap4(+/+) mice. Transmission electron microscopy (TEM) did not reveal differences in the organization of elastic fibers, and there was no difference in elastin content, but a borderline significant increase in elastin mRNA expression in 3-mo-old mice. Stereological analysis showed that alveolar surface density in relation to the lung parenchyma and total alveolar surface area inside of the lung were both significantly decreased in Mfap4(-/-) mice by 25 and 15%, respectively. The data did not support an essential role of MFAP4 in pulmonary elastic fiber organization or content but indicated increased turnover in young Mfap4(-/-) mice. However, Mfap4(-/-) mice developed a spontaneous loss of lung function, which was evident at 6 mo of age, and moderate air space enlargement, with emphysema-like changes.
authors.affiliation: Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark;
authors.forename: Anne Trommelholt
authors.initials: AT
authors.lastname: Holm
authors.affiliation: Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark;
authors.forename: Helle
authors.initials: H
authors.lastname: Wulf-Johansson
authors.affiliation: Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark;
authors.forename: Svend
authors.initials: S
authors.lastname: Hvidsten
authors.affiliation: Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark;
authors.forename: Patricia Troest
authors.initials: PT
authors.lastname: Jorgensen
authors.affiliation: Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark;
authors.forename: Anders
authors.initials: A
authors.lastname: Schlosser
authors.affiliation: Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark;
authors.forename: Bartosz
authors.initials: B
authors.lastname: Pilecki
authors.affiliation: Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark;
authors.forename: Maria
authors.initials: M
authors.lastname: Ormhøj
authors.affiliation: Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark;
authors.forename: Jesper Bonnet
authors.initials: JB
authors.lastname: Moeller
authors.affiliation: Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark;
authors.forename: Claus
authors.initials: C
authors.lastname: Johannsen
authors.affiliation: Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark;
authors.forename: Christina
authors.initials: C
authors.lastname: Baun
authors.affiliation: Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark;
authors.forename: Thomas
authors.initials: T
authors.lastname: Andersen
authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany; and REBIRTH Cluster of Excellence, Hannover, Germany;
authors.forename: Jan Philipp
authors.initials: JP
authors.lastname: Schneider
authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany; and REBIRTH Cluster of Excellence, Hannover, Germany;
authors.forename: Jan
authors.initials: J
authors.lastname: Hegermann
authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany; and REBIRTH Cluster of Excellence, Hannover, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Ochs
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, Germany;
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Götz
authors.affiliation: Institute of Lung Biology and Disease, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; and Member of the German Center for Lung Research (DZL), Hannover, Germany; Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany;
authors.forename: Holger
authors.initials: H
authors.lastname: Schulz
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; and.
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.affiliation: Department of Respiratory Medicine, Gentofte Hospital, Hellerup, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Vestbo
authors.affiliation: Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark;
authors.forename: Uffe
authors.initials: U
authors.lastname: Holmskov
authors.affiliation: Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; glsorensen@health.sdu.dk.
authors.forename: Grith Lykke
authors.identifier: http://orcid.org/0000-0002-5273-1097
authors.initials: GL
authors.lastname: Sorensen
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000235:genetics*; D005260:Female; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics*; D008168:Lung / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011656:Pulmonary Emphysema / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D012119:Respiration; D059467:Transcriptome
chemical_list: D002352:Carrier Proteins; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C000600072:MFAP4 protein, mouse; D004549:Elastin
keywords: MFAP4; air space enlargement; gene deficiency