Amine oxidase activity regulates the development of pulmonary fibrosis

作者：Marttila Ichihara Fumiko; Elima Kati; Auvinen Kaisa; Veres Tibor Z; Rantakari Pia; Weston Christopher; Miyasaka Masayuki; Adams David; Jalkanen Sirpa; Salmi Marko

来源：The FASEB Journal, 2017, 31(6): 2477-2491.

DOI：10.1096/fj.201600935R

• IPF
• AOC3 enzyme
• myofibroblasts
• reactive oxygen species

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-treatedmice in a bleomycin-induced pulmonary fibrosis model. Inflammation and fibrosis of lungswere assessed by histologic, flow cytometric, and quantitative PCR analysis. AOC3-deficient mice showed a 30-50% reduction in fibrosis, collagen synthesis, numbers ofmyofibroblasts, and accumulation of CD4(+) lymphocytes, NK T cells, macrophages, andtype 2 innate lymphoidcells compared with wild-type controlmice. AOC3-knock-inmice, which express a catalytically inactive form of AOC3, were also protected from lung fibrosis. In wild-type mice, a small-moleculeAOC3inhibitor treatment reduced leukocyte infiltration, myofibroblast differentiation, andfibrotic 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.

• 出版日期2017-6