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.

Zinc-α2-glycoprotein as an inhibitor of amine oxidase copper-containing 3

“…On the other hand, inactivation of the enzyme by a single point mutation-which is critical for enzyme activity-renders AOC3 unable to promote leucocyte migration [81]. AOC3 has also been shown to play a role in liver, lung and kidney fibrosis [82][83][84]. Treatment with the AOC3 inhibitor semicarbazide significantly reduced kidney fibrosis in a unilateral ureteric obstruction model in mice.…”

Site-specific expression of amine oxidases in breast cancer metastases

“…It regulates the accumulation of pathogenic leukocytes and induces fibrosis, collagen synthesis, and proliferation of myofibroblasts and CD4+ lymphocytes. 44 Therefore, metastatic breast cancer of the lung may lead to proliferation of AOC3-positive myofibroblasts that serve as a tumor stroma and affect tumor biology, although this requires further study.…”

Vascular Adhesion Protein-1: A Cell Surface Amine Oxidase in Translation

“…In smooth muscle cells, VAP-1 is enriched in the caveolae of the plasma membrane (46). Also, pericytes lining the outer surface of blood vessels produce VAP-1 (85). In adipocytes, 25% of VAP-1 is found in GLUT4 + vesicles (95).…”

“…Notably, in a COPD model, a postponed SSAO treatment successfully reduces leukocyte infiltration and fibrosis, and improves lung compliance back to the control levels, although it does not affect emphysema-like alveolar enlargement (51). In addition, in bleomycin-induced lung damage, the fibrotic response is less severe in the VAP-1 knockout mice, in mice expressing the enzymatically inactive version of VAP-1, and in wild-type mice treated prophylactically or therapeutically with an SSAO inhibitor (85). Thus, VAP-1 function seems to contribute to fibrogenesis both by regulating the inflammatory response in the damaged organ and by directly modulating the myofibroblast responses to the insulting stimuli.…”