Oxidative stress-driven dysregulation of the MMP-2/TIMP-2 axis in chronic obstructive pulmonary disease: Molecular...

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disorder characterized by persistent airflow limitation, airway remodeling, and irreversible destruction of alveolar structures. Increasing evidence suggests that oxidative stress plays a central role in COPD pathogenesis by disrupting the balance between proteolytic enzymes and their endogenous inhibitors, thereby promoting extracellular matrix degradation. Among these regulatory systems, the matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) axis has emerged as a critical determinant of lung tissue integrity and remodeling. This review provides a comprehensive overview of the molecular mechanisms linking environmental risk factors, including cigarette smoke and particulate matter exposure, to oxidative stress-mediated activation of inflammatory signaling pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and activator protein-1 (AP-1). These pathways contribute to the upregulation of MMP-2 expression and dysregulation of TIMP-2 activity, resulting in protease-antiprotease imbalance and progressive structural damage to the pulmonary extracellular matrix. In addition, the review summarizes current evidence regarding genetic polymorphisms in MMP-2 and TIMP-2 genes that may influence susceptibility to COPD and disease severity across different populations. Furthermore, emerging therapeutic strategies targeting oxidative stress and matrix remodeling pathways are discussed, highlighting their potential role in disease management. Despite advances in understanding COPD pathogenesis, significant gaps remain in elucidating the precise molecular regulation of the MMP-2/TIMP-2 axis and its clinical utility as a diagnostic or prognostic biomarker. Overall, this review emphasizes the importance of the MMP-2/TIMP-2 regulatory system as a central mechanistic link between oxidative stress and structural lung damage in COPD and underscores its potential as a promising target for future therapeutic intervention.