A novel NOX2 inhibitor attenuates human neutrophil oxidative stress and ameliorates inflammatory arthritis in mice

Fu-Chao Liu; Huang-Ping Yu; Po-Jen Chen; Hsuan-Wu Yang; Shih-Hsin Chang; Cherng-Chyi Tzeng; Wei-Jen Cheng; You-Ren Chen; Yeh-Long Chen; Tsong-Long Hwang

doi:10.1016/j.redox.2019.101273

A novel NOX2 inhibitor attenuates human neutrophil oxidative stress and ameliorates inflammatory arthritis in mice

Redox Biol. 2019 Sep:26:101273. doi: 10.1016/j.redox.2019.101273. Epub 2019 Jul 10.

Authors

Affiliations

¹ College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan.
² Department of Cosmetic Science, Providence University, Taichung, 433, Taiwan; Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan.
³ Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan.
⁴ Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, 333, Taiwan.
⁵ Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Department of Medical Research, Kaohsiung Medical University-Hospital, Kaohsiung, 807, Taiwan.
⁶ Graduate Institute of Clinical Medicine, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; Department of Traditional Chinese Medicine, Center of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan.
⁷ Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Department of Medical Research, Kaohsiung Medical University-Hospital, Kaohsiung, 807, Taiwan. Electronic address: yeloch@kmu.edu.tw.
⁸ Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan; Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, 333, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan, 333, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, 243, Taiwan. Electronic address: htl@mail.cgu.edu.tw.

Abstract

Neutrophil infiltration plays a significant pathological role in inflammatory diseases. NADPH oxidase type 2 (NOX2) is a respiratory burst oxidase that generates large amounts of superoxide anion (O₂^•-) and subsequent other reactive oxygen species (ROS). NOX2 is an emerging therapeutic target for treating neutrophilic inflammatory diseases. Herein, we show that 4-[(4-(dimethylamino)butoxy)imino]-1-methyl-1H-benzo[f]indol-9(4H)-one (CYR5099) acts as a NOX2 inhibitor and exerts a protective effect against complete Freund's adjuvant (CFA)-induced inflammatory arthritis in mice. CYR5099 restricted the production of O₂^•- and ROS, but not the elastase release, in human neutrophils activated with various stimulators. The upstream signaling pathways of NOX2 were not inhibited by CYR5099. Significantly, CYR5099 inhibited NOX2 activity in activated human neutrophils and in reconstituted subcellular assays. In addition, CYR5099 reduced ROS production, neutrophil infiltration, and edema in CFA-induced arthritis in mice. Our findings suggest that CYR5099 is a NOX2 inhibitor and has therapeutic potential for treating neutrophil-dominant oxidative inflammatory disorders.

Keywords: CYR5099; Inflammatory arthritis; NADPH oxidase 2; Neutrophil; Reactive oxygen species.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arthritis / drug therapy
Arthritis / etiology
Arthritis / metabolism*
Arthritis / pathology
Biomarkers
Calcium / metabolism
Endothelial Cells
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Extracellular Space / metabolism
Freund's Adjuvant
Humans
Male
Mice
Mitogen-Activated Protein Kinases / metabolism
NADPH Oxidase 2 / antagonists & inhibitors*
NADPH Oxidase 2 / chemistry
Neutrophils / drug effects*
Neutrophils / metabolism*
Oxidative Stress / drug effects*
Protein Binding
Proto-Oncogene Proteins c-akt / metabolism
Reactive Oxygen Species / metabolism
Structure-Activity Relationship

Substances

Biomarkers
Enzyme Inhibitors
Reactive Oxygen Species
Freund's Adjuvant
Cybb protein, mouse
NADPH Oxidase 2
Proto-Oncogene Proteins c-akt
Mitogen-Activated Protein Kinases
Calcium