2. Academic Validation
  3. A Potent Histone Deacetylase Inhibitor MPT0E028 Mitigates Emphysema Severity via Components of the Hippo Signaling Pathway in an Emphysematous Mouse Model

A Potent Histone Deacetylase Inhibitor MPT0E028 Mitigates Emphysema Severity via Components of the Hippo Signaling Pathway in an Emphysematous Mouse Model

  • Front Med (Lausanne). 2022 May 18:9:794025. doi: 10.3389/fmed.2022.794025.
Lu-Yang Yeh 1,  Yu-Ting Fang 2,  Hong-Sheng Lee 3,  Chia-Hao Liu 3,  You-Yin Chen 2,  Yu-Chun Lo 4,  Vincent Laiman 5 6,  Jing-Ping Liou 7,  Kian Fan Chung 8,  Hsiao-Chi Chuang 9 10 11,  Chien-Huang Lin 3
Affiliations

Affiliations

  • 1 School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 2 Department of Biomedical Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan.
  • 3 Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 4 PhD Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 5 International PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 6 Department of Anatomical Pathology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
  • 7 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 8 National Heart and Lung Institute, Imperial College London, London, United Kingdom.
  • 9 School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 10 Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
  • 11 Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
PMID: 35665319 DOI: 10.3389/fmed.2022.794025
Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a major cause of chronic mortality. The objective of this study was to investigate the therapeutic potential of a novel potent histone deacetylase (HDAC) inhibitor MPT0E028 on emphysema.

Materials and methods: A mouse model of porcine pancreatic Elastase (PPE)-induced emphysema was orally administered 0, 25, or 50 mg/kg body weight (BW) of the MPT0E028 five times/week for 3 weeks. Pulmonary function, mean linear intercept (MLI), chest CT, inflammation, yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), surfactant protein C (SPC), T1-α, p53, and Sirtuin 1 (SIRT1) levels were examined.

Results: 50 mg/kg BW of the MPT0E028 significantly decreased the tidal volume in emphysematous mice (p < 0.05). Emphysema severity was significantly reduced from 26.65% (PPE only) to 13.83% (50 mg/kg BW of the MPT0E028). Total cell counts, neutrophils, lymphocytes, and eosinophils significantly decreased with both 25 and 50 mg/kg BW of the MPT0E028 (p < 0.05). Also, 50 mg/kg BW of the MPT0E028 significantly decreased the levels of KC, TNF-α, and IL-6 in lung tissues and serum (p < 0.05). Expressions of p-TAZ/TAZ in lung tissues significantly decreased with 50 mg/kg BW of the MPT0E028 (p < 0.05). Expressions of p53 significantly decreased in alveolar regions with 50 mg/kg BW of the MPT0E028 (p < 0.05), and the expression of SPC increased in alveolar regions with 50 mg/kg BW of the MPT0E028 (p < 0.05).

Conclusions: Our study showed that the potent HDAC Inhibitor MPT0E028 reduced the severity and inflammation of emphysema with improvement in lung function, which could be regulated by Hippo signaling pathway. The MPT0E028 may have therapeutic potential for emphysema.

Keywords

COPD; HDAC; TAZ; alveolar; apoptosis; inflammation.

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