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Ribociclib leverages phosphodiesterase 4 inhibition in the treatment of neutrophilic inflammation and acute respiratory distress syndrome.
Chen, Po-Jen; Chen, Shun-Hua; Chen, Yu-Li; Wang, Yi-Hsuan; Lin, Cheng-Yu; Chen, Chun-Hong; Tsai, Yung-Fong; Hwang, Tsong-Long.
Afiliación
  • Chen PJ; Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung 824410, Taiwan; Graduate Institute of Medicine, I-Shou University, Kaohsiung 824410, Taiwan.
  • Chen SH; Departmentof Nursing, Fooyin University, Kaohsiung 831301, Taiwan.
  • Chen YL; 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.
  • Wang YH; 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.
  • Lin CY; Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
  • Chen CH; Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung 824410, Taiwan.
  • Tsai YF; 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.
  • Hwang TL; 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, Tai
J Adv Res ; 62: 229-243, 2024 Aug.
Article en En | MEDLINE | ID: mdl-38548264
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Purinas / Síndrome de Dificultad Respiratoria / Lipopolisacáridos / Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 / Inhibidores de Fosfodiesterasa 4 / Aminopiridinas / Inflamación / Neutrófilos Límite: Animals / Humans / Male Idioma: En Revista: J Adv Res Año: 2024 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Egipto
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Purinas / Síndrome de Dificultad Respiratoria / Lipopolisacáridos / Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 / Inhibidores de Fosfodiesterasa 4 / Aminopiridinas / Inflamación / Neutrófilos Límite: Animals / Humans / Male Idioma: En Revista: J Adv Res Año: 2024 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Egipto