Ribociclib leverages phosphodiesterase 4 inhibition in the treatment of neutrophilic inflammation and acute respiratory distress syndrome

Po-Jen Chen; Shun-Hua Chen; Yu-Li Chen; Yi-Hsuan Wang; Cheng-Yu Lin; Chun-Hong Chen; Yung-Fong Tsai; Tsong-Long Hwang

doi:10.1016/j.jare.2024.03.019

Ribociclib leverages phosphodiesterase 4 inhibition in the treatment of neutrophilic inflammation and acute respiratory distress syndrome

J Adv Res. 2024 Mar 27:S2090-1232(24)00119-X. doi: 10.1016/j.jare.2024.03.019. Online ahead of print.

Authors

Po-Jen Chen¹, Shun-Hua Chen², Yu-Li Chen³, Yi-Hsuan Wang⁴, Cheng-Yu Lin⁵, Chun-Hong Chen⁶, Yung-Fong Tsai⁷, Tsong-Long Hwang⁸

Affiliations

¹ Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung 824410, Taiwan; Graduate Institute of Medicine, I-Shou University, Kaohsiung 824410, Taiwan.
² Departmentof Nursing, Fooyin University, Kaohsiung 831301, Taiwan.
³ 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 333324, Taiwan.
⁴ Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333324, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333324, Taiwan.
⁵ Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
⁶ Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung 824410, Taiwan.
⁷ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333324, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan.
⁸ 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 333324, Taiwan; Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333324, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333324, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City 24301, Taiwan. Electronic address: htl@mail.cgust.edu.tw.

PMID: 38548264
DOI: 10.1016/j.jare.2024.03.019

Abstract

Introduction: Overwhelming neutrophil activation and oxidative stress significantly contribute to acute respiratory distress syndrome (ARDS) pathogenesis. However, the potential of repurposing ribociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor used clinically in cancer treatment, for treating neutrophilic ARDS remains uncertain. This study illustrated the ability and underlying mechanism of ribociclib for treating ARDS and neutrophilic inflammation.

Methods: Primary human neutrophils were used to determine the therapeutic effects of ribociclib on respiratory bursts, chemotactic responses, and inflammatory signaling. In vitro and silico analyses were performed to determine the underlying molecular mechanisms. The potential of ribociclib repurposing was evaluated using an in vivo ARDS model in lipopolysaccharide (LPS)-primed mice.

Results: We found that treatment using ribociclib markedly limited overabundant oxidative stress (reactive oxygen species [ROS]) production and chemotactic responses (integrin levels and adhesion) in activated human neutrophils. Ribociclib was also shown to act as a selective inhibitor of phosphodiesterase 4 (PDE4), thereby promoting the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, leading to the inhibition of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) phosphorylation, and calcium influx. Notably, prophylactic administration and post-treatment with ribociclib ameliorated neutrophil infiltration, lung inflammation, accumulation of oxidative stress, pulmonary destruction, and mortality in mice with LPS-induced ARDS.

Conclusion: We demonstrated for the first time that ribociclib serves as a novel PDE4 inhibitor for treating neutrophilic inflammation and ARDS. The repurposing ribociclib and targeting neutrophilic PDE4 offer a potential off-label alternative for treating lung lesions and other inflammatory conditions.

Keywords: Acute respiratory distress syndrome; Neutrophilic inflammation; Phosphodiesterase 4; Ribociclib.