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: Fumiko Marttila-Ichihara, Kati Elima, Kaisa Auvinen, Tibor Z Veres, Pia Rantakari, Christopher Weston, Masayuki Miyasaka, David Adams, Sirpa Jalkanen, Marko Salmi
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 31 Issue 6 Pg. 2477-2491 (06 2017) ISSN: 1530-6860 [Electronic] United States
• PMID: 28251930 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• Antibiotics, Antineoplastic
• Carboxylic Acids
• Cell Adhesion Molecules
• Pyrrolidines
• trans-4-hydroxy-N-methyl-L-proline(-)-(2S,4R)-4-hydroxy-1-methyl pyrrolidine-2-carboxylic acid
• Bleomycin
• AOC3 protein, human
• Amine Oxidase (Copper-Containing)
• semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse

Topics

• Amine Oxidase (Copper-Containing) (genetics, metabolism)
• Animals
• Antibiotics, Antineoplastic (toxicity)
• Bleomycin (toxicity)
• Carboxylic Acids
• Cell Adhesion Molecules (genetics, metabolism)
• Gene Expression Regulation, Enzymologic (physiology)
• Humans
• Lung (enzymology, pathology)
• Lymphocytes (physiology)
• Mice
• Mice, Knockout
• Pulmonary Fibrosis (chemically induced, enzymology, metabolism)
• Pyrrolidines