Inhibiting SIRT-2 by AK-7 restrains airway inflammation and oxidative damage promoting lung resurgence through NF-kB and MAP kinase signaling pathway

Front Immunol. 2024 Jun 24:15:1404122. doi: 10.3389/fimmu.2024.1404122. eCollection 2024.

Abstract

Introduction: Chronic obstructive pulmonary disease (COPD) is a major global cause of mortality with limited effective treatments. Sirtuins (SIRT) are histone deacetylases that are involved in the regulation of redox and inflammatory homeostasis. Hence, the present study aims to investigate the role of SIRT-2 in modulating inflammation in a murine model of COPD.

Methods: COPD in mice was established by cigarette smoke (CS) exposure for 60 days, and AK-7 was used as the specific SIRT-2 inhibitor. AK-7 (100 µg/kg and 200 µg/kg body weight) was administered intranasally 1 h before CS exposure. Molecular docking was performed to analyze the binding affinity of different inflammatory proteins with AK-7.

Results: Immune cell analysis showed a significantly increased number of macrophages (F4/80), neutrophils (Gr-1), and lymphocytes (CD4+, CD8+, and CD19+) in the COPD, group and their population was declined by AK-7 administration. Total reactive oxygen species, total inducible nitric oxide synthase, inflammatory mediators such as neutrophil elastase, C-reactive protein, histamine, and cytokines as IL4, IL-6, IL-17, and TNF-α were elevated in COPD and declined in the AK-7 group. However, IL-10 showed reverse results representing anti-inflammatory potency. AK-7 administration by inhibiting SIRT-2 decreased the expression of p-NF-κB, p-P38, p-Erk, and p-JNK and increased the expression of Nrf-2. Furthermore, AK-7 also declined the lung injury by inhibiting inflammation, parenchymal destruction, emphysema, collagen, club cells, and Kohn pores. AK-7 also showed good binding affinity with inflammatory proteins.

Discussion: The current study reveals that SIRT-2 inhibition mitigates COPD severity and enhances pulmonary therapeutic interventions, suggesting AK-7 as a potential therapeutic molecule for COPD medication development.

Keywords: MAP kinase; NF-kB; cytokines; inflammation; innate immunity.

MeSH terms

  • Animals
  • Carbazoles
  • Cytokines / metabolism
  • Disease Models, Animal
  • Lung / drug effects
  • Lung / immunology
  • Lung / metabolism
  • Lung / pathology
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B* / metabolism
  • Oxidative Stress* / drug effects
  • Pulmonary Disease, Chronic Obstructive* / etiology
  • Pulmonary Disease, Chronic Obstructive* / immunology
  • Pulmonary Disease, Chronic Obstructive* / metabolism
  • Signal Transduction
  • Sirtuin 2* / antagonists & inhibitors
  • Sirtuin 2* / metabolism

Substances

  • Sirtuin 2
  • NF-kappa B
  • Sirt2 protein, mouse
  • 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide
  • Cytokines
  • Carbazoles

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The funding provided was solely for the research and publication costs associated with the manuscript. The present study was financially supported by the Department of Science and Technology (P-07/694), Indian Council of Medical Research (P-14/0793) New Delhi, Institute of Eminence (R/Dev/IoE/Seed and Incentive Grant - III/2022–23/49239) Banaras Hindu University and Council of Scientific and Industrial Research (CSIR)- File No: 09/013(0907)/2019-EMR-1, India in the form of Senior Research fellowship.