Apremilast ameliorates acute respiratory distress syndrome by inhibiting neutrophil-induced oxidative stress

Yung-Fong Tsai; Chun-Yu Chen; Shun-Chin Yang; Yu-Ting Syu; Tsong-Long Hwang

Biomedical Journal (Aug 2023)

Apremilast ameliorates acute respiratory distress syndrome by inhibiting neutrophil-induced oxidative stress

Yung-Fong Tsai,
Chun-Yu Chen,
Shun-Chin Yang,
Yu-Ting Syu,
Tsong-Long Hwang

Affiliations

Yung-Fong Tsai: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital at Taoyuan, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Chun-Yu Chen: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital at Taoyuan, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Shun-Chin Yang: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan
Yu-Ting Syu: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital at Taoyuan, Taoyuan, Taiwan
Tsong-Long Hwang: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital at Taoyuan, Taoyuan, Taiwan; Research Center for Chinese Herbal Medicine and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei, Taiwan; Corresponding author. Graduate Institute of Natural Products, College of Medicine, Chang Gung University, 259 Wenhua 1st Rd., Gueishan, Taoyuan 333, Taiwan

Journal volume & issue: Vol. 46, no. 4
p. 100560

Abstract

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Background: The pathogenesis of acute respiratory distress syndrome (ARDS) is attributed to the dysregulation of oxidative stress and neutrophil recruitment. We aimed to investigate the anti-inflammatory effects of apremilast on human neutrophils and assess its efficacy for treating ARDS. Methods: We analysed superoxide anion generation, integrin expression, and adhesion in activated human neutrophils using spectrophotometry, flow cytometry, and immunofluorescence microscopy. Phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was determined using immunoblotting. A murine lipopolysaccharide (LPS)-induced ARDS model was used to evaluate the therapeutic effects of apremilast. Results: Apremilast significantly decreased superoxide anion production, reactive oxygen species (ROS) generation, cluster of differentiation (CD)11 b expression, and neutrophil adhesion in formyl-l-methionyl-l-leucyl-l-phenylalanine activated human neutrophils. Apremilast elevated cyclic 3′,5′-adenosine monophosphate (cAMP) and protein kinase A (PKA) activity in activated neutrophils. It reduced cellular cAMP-specific phosphodiesterase (PDE) activity and selectively inhibited enzymatic PDE4 activity. The activated cAMP/PKA pathway suppressed the phosphorylation of ERK and JNK as well as Ca2+ mobilization in activated neutrophils. All inhibitory effects of apremilast on activated neutrophils were reversed by a PKA inhibitor. In vivo examinations indicated that apremilast alleviated lung neutrophil infiltration, myeloperoxidase (MPO) activity, pulmonary oedema, and alveolar damage in LPS-induced ARDS. Conclusion: Apremilast inhibits inflammatory responses after neutrophil activation via cAMP/PKA-dependent inhibition of ERK and JNK activation. Our study revealed apremilast suppresses oxidative stress and chemotaxis by selectively inhibiting PDE4 in neutrophils and thus protects against endotoxin-induced ARDS in mice. Apremilast can be used as an alternative off-label drug in treating acute lung damage.

Published in Biomedical Journal

ISSN: 2319-4170 (Print); 2320-2890 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: https://www.sciencedirect.com/journal/biomedical-journal

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