title: Amine oxidase activity regulates the development of pulmonary fibrosis.
abstract: In pulmonary fibrosis, an inflammatory reaction and differentiation of myofibroblasts culminate in pathologic deposition of collagen. Amine oxidase copper containing-3 (AOC3) is a cell-surface-expressed oxidase that regulates leukocyte extravasation. Here we analyzed the potential role of AOC3 using gene-modified and inhibitor-treated mice in a bleomycin-induced pulmonary fibrosis model. Inflammation and fibrosis of lungs were assessed by histologic, flow cytometric, and quantitative PCR analysis. AOC3-deficient mice showed a 30-50% reduction in fibrosis, collagen synthesis, numbers of myofibroblasts, and accumulation of CD4+lymphocytes, NK T cells, macrophages, and type 2 innate lymphoid cells compared with wild-type control mice. AOC3-knock-in mice, which express a catalytically inactive form of AOC3, were also protected from lung fibrosis. In wild-type mice, a small-molecule AOC3 inhibitor treatment reduced leukocyte infiltration, myofibroblast differentiation, and fibrotic injury both in prophylactic and early therapeutic settings by about 50% but was unable to reverse the established fibrosis. AOC3 was also induced in myofibroblasts in human idiopathic pulmonary fibrosis. Thus, the oxidase activity of AOC3 contributes to the development of lung fibrosis mainly by regulating the accumulation of pathogenic leukocyte subtypes, which drive the fibrotic response.-Marttila-Ichihara, F., Elima, K., Auvinen, K., Veres, T. Z., Rantakari, P., Weston, C., Miyasaka, M., Adams, D., Jalkanen, S., Salmi, M. Amine oxidase activity regulates the development of pulmonary fibrosis.
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, Finland; fumiko.marttila@utu.fi.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Marttila-Ichihara
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, Finland.|Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Elima
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Auvinen
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Tibor Z
authors.initials: TZ
authors.lastname: Veres
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Rantakari
authors.affiliation: Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Unit, University of Birmingham, Birmingham, United Kingdom; and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Weston
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, Finland.|World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyasaka
authors.affiliation: Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Unit, University of Birmingham, Birmingham, United Kingdom; and.
authors.forename: David
authors.initials: D
authors.lastname: Adams
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, Finland.|Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: Sirpa
authors.initials: S
authors.lastname: Jalkanen
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, Finland.|Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Salmi
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D002264:Carboxylic Acids; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008214:Lymphocytes / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000378:metabolism; D011759:Pyrrolidines
chemical_list: D000903:Antibiotics, Antineoplastic; D002264:Carboxylic Acids; D015815:Cell Adhesion Molecules; D011759:Pyrrolidines; C479159:trans-4-hydroxy-N-methyl-L-proline(-)-(2S,4R)-4-hydroxy-1-methyl pyrrolidine-2-carboxylic acid; D001761:Bleomycin; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse
keywords: AOC3 enzyme; IPF; myofibroblasts; reactive oxygen species