Amine oxidase activity regulates the development of pulmonary fibrosis

Research output: Contribution to journalArticlepeer-review

Authors

  • Fumiko Marttila-Ichihara
  • Kati Elima
  • Kaisa Auvinen
  • Tibor Z Veres
  • Pia Rantakari
  • Masayuki Miyasaka
  • Sirpa Jalkanen
  • Marko Salmi

External organisations

  • MediCity Research Laboratory, University of Turku, Turku, Finland; fumiko.marttila@utu.fi.
  • MediCity Research Laboratory, University of Turku, Turku, Finland.
  • Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Unit, University of Birmingham, Birmingham, United Kingdom; and.

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.

Details

Original languageEnglish
JournalFASEB Journal
Early online date1 Mar 2017
Publication statusE-pub ahead of print - 1 Mar 2017

Keywords

  • Journal Article