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

doi:10.1016/j.bj.2022.09.001

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

Biomed J. 2023 Aug;46(4):100560. doi: 10.1016/j.bj.2022.09.001. Epub 2022 Sep 11.

Authors

Yung-Fong Tsai¹, Chun-Yu Chen¹, Shun-Chin Yang², Yu-Ting Syu³, Tsong-Long Hwang⁴

Affiliations

¹ 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.
² 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.
³ Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital at Taoyuan, Taoyuan, Taiwan.
⁴ 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. Electronic address: htl@mail.cgu.edu.tw.

Abstract

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.

Keywords: ARDS; Apremilast; Neutrophil; Oxidative stress; PDE4 inhibitor.

MeSH terms

Animals
Humans
Lipopolysaccharides / metabolism
Lipopolysaccharides / pharmacology
Mice
Neutrophils
Off-Label Use
Oxidative Stress
Respiratory Distress Syndrome* / drug therapy
Superoxides* / metabolism
Superoxides* / pharmacology

Substances

Superoxides
apremilast
Lipopolysaccharides