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MPO-Mediated oxidative stress regulates lung tissue damage in T-COPD through activation of the NLRP3 inflammasome
Wen Li1, Kaican Zong1, E Jiang1
1Department of Respiratory and Critical Care Medicine, The Seventh People's Hospital of Chongqing, Affiliated Central Hospital of Chongqing University of Technology, Chongqing, China.
Purpose:
This study aimed to investigate the role of MPO in regulating the NLRP3 signaling pathway and its impact on lung injury in a Mycobacterium tuberculosis-induced chronic obstructive pulmonary disease (T-COPD) model.
Methods:
T-COPD was induced in mice by stimulating with Mycobacterium tuberculosis, and lung tissues were collected for histological analysis. ELISA, qPCR, and western blot assays were performed to assess the expression of pro-inflammatory cytokines and markers of lung injury, including Myeloperoxidase (MPO) and NOD-like receptor protein 3 (NLRP3). MPO-IN-5, an MPO inhibitor, was used to treat T-COPD mice, and its effects on inflammation and lung damage were evaluated. In vitro, murine lung epithelial MLE-12 cells were treated with LPS, CSE, and Mycobacterium tuberculosis with or without MPO treatment, followed by assessments of cell viability, apoptosis, ROS levels, and NLRP3 pathway activity.
Results:
Histological analysis of the M. tuberculosis/COPD group revealed significant pulmonary edema, inflammatory cell infiltration, and granuloma formation in the liver and spleen, compared with the COPD group. Pro-inflammatory cytokines TNF-α, IL-18, and IL-6 were elevated in the blood of the M. tuberculosis/COPD group. In the lungs, MPO expression and NLRP3 pathway activation were significantly increased. Treatment with MPO-IN-5 reduced the levels of LDH, CRP, and PCT, and reversed the morphological and inflammatory changes in lung tissue. Furthermore, MPO-IN-5 treatment also significantly decreased ROS production and the expression of inflammatory cytokines. In vitro, MPO treatment exacerbated NLRP3 activation in murine lung epithelial MLE-12 cells, while MPO inhibition (with MPO-IN-5) or NLRP3 knockdown mitigated these effects, enhancing cell proliferation and reducing apoptosis.
Conclusion:
Our results suggest that MPO plays a critical role in regulating the NLRP3 signaling pathway, contributing to lung injury in the T-COPD model. Inhibition of MPO with MPO-IN-5 effectively alleviates inflammation, reduces oxidative stress, and suppresses NLRP3 pathway activation, highlighting its potential as a therapeutic target for T-COPD.
Insights
Myeloperoxidase (MPO) drives lung injury in tuberculosis-induced COPD by activating the NLRP3 pathway. Inhibiting MPO with MPO-IN-5 reduces inflammation and oxidative stress, offering a potential therapy for T-COPD.
Area of Science:
- Pulmonary Medicine
- Immunology
- Molecular Biology
Background:
- Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung disease.
- Tuberculosis (TB) co-infection exacerbates COPD severity.
- The NLRP3 inflammasome pathway is implicated in inflammatory lung diseases.
Purpose of the Study:
- To investigate the role of Myeloperoxidase (MPO) in regulating the NLRP3 signaling pathway.
- To assess the impact of MPO on lung injury in a tuberculosis-induced COPD (T-COPD) mouse model.
- To evaluate the therapeutic potential of MPO inhibition in T-COPD.
Main Methods:
- Induction of T-COPD in mice using Mycobacterium tuberculosis.
- Histological, ELISA, qPCR, and Western blot analyses of lung tissues.
- Administration of MPO inhibitor (MPO-IN-5) and in vitro cell-based assays.
Main Results:
- T-COPD model showed increased pulmonary edema, inflammation, and elevated pro-inflammatory cytokines.
- MPO expression and NLRP3 pathway activation were significantly upregulated in T-COPD lungs.
- MPO-IN-5 treatment reduced inflammation, oxidative stress (ROS), and NLRP3 activation, improving lung injury markers.
Conclusions:
- MPO plays a key role in T-COPD pathogenesis by modulating the NLRP3 pathway.
- MPO inhibition effectively alleviates inflammation and oxidative stress in T-COPD.
- MPO inhibition represents a promising therapeutic strategy for T-COPD.
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