The FASEB journal, 2017-06, Vol.31 (6), p.2477-2491
2017
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- Autor(en) / Beteiligte
- Titel
- Amine oxidase activity regulates the development of pulmonary fibrosis
- Ist Teil von
- The FASEB journal, 2017-06, Vol.31 (6), p.2477-2491
- Ort / Verlag
- United States: Federation of American Societies for Experimental Biology (FASEB)
- Erscheinungsjahr
- 2017
- Quelle
- Wiley-Blackwell Journals
- Beschreibungen/Notizen
- 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. FASEB J. 31, 2477–2491 (2017). www.fasebj.org
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0892-6638eISSN: 1530-6860DOI: 10.1096/fj.201600935RTitel-ID: cdi_proquest_miscellaneous_1911619487
- Format
- –
- Schlagworte
- Accumulation, Amine Oxidase (Copper-Containing) - genetics, Amine Oxidase (Copper-Containing) - metabolism, Animals, Antibiotics, Antineoplastic - toxicity, AOC3 enzyme, Bleomycin, Bleomycin - toxicity, Carboxylic Acids, CD4 antigen, Cell Adhesion Molecules - genetics, Cell Adhesion Molecules - metabolism, Cell surface, Collagen, Differentiation, Extravasation, Fibrosis, Flow cytometry, Gene Expression Regulation, Enzymologic - physiology, Humans, Infiltration, Inflammation, Inhibitors, Injury prevention, IPF, Leukocytes, Lung - enzymology, Lung - pathology, Lung diseases, Lungs, Lymphocytes, Lymphocytes - physiology, Lymphocytes T, Lymphoid cells, Macrophages, Mice, Mice, Knockout, myofibroblasts, Natural killer cells, Oxidase, Pulmonary fibrosis, Pulmonary Fibrosis - chemically induced, Pulmonary Fibrosis - enzymology, Pulmonary Fibrosis - metabolism, Pyrrolidines, reactive oxygen species, Rodents