MPO-Mediated oxidative stress regulates lung tissue damage in T-COPD through activation of the NLRP3 inflammasome.

Abstract

PURPOSE: This study aimed to investigate the role of MPO in regulating the NLRP3 signaling pathway and its impact on lung injury in a-induced chronic obstructive pulmonary disease (T-COPD) model. METHODS: T-COPD was induced in mice by stimulating with, 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., murine lung epithelial MLE-12 cells were treated with LPS, CSE, andwith or without MPO treatment, followed by assessments of cell viability, apoptosis, ROS levels, and NLRP3 pathway activity. RESULTS: Histological analysis of the/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/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., 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.