{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMMP‐12, a macrophage‐derived matrix metalloproteinase often termed macrophage elastase, plays a central role in lung pathophysiology. It is implicated in the proteolytic degradation of key extracellular matrix components—such as elastin and collagen—that underlie emphysema and chronic obstructive pulmonary disease (COPD). Genetic variants and promoter polymorphisms of MMP‐12 (and related MMPs) have been associated with a faster rate of lung function decline and smoking‐induced lung injury, reinforcing its relevance in the development and progression of COPD and emphysematous changes. Moreover, MMP‐12 appears to modulate the balance between proteolysis and anti‐proteolysis in the lung, and its aberrant activity is linked to both proteolytic attack on alveolar structures as well as dysregulated inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its extracellular matrix‐remodeling function, MMP‐12 exerts pivotal regulatory effects on inflammatory mediators. By precisely cleaving chemokines at receptor-binding motifs and processing chemotactic proteins, it modulates the recruitment and resolution of inflammatory cells during acute inflammatory responses. Intriguingly, MMP‐12 can be internalized and translocate to the nucleus of infected cells, where it upregulates genes (for example, IκBα) that facilitate the secretion of antiviral interferon‑α; failure to export IFN‑α in the absence of MMP‑12 has been linked to more severe viral infections. In addition, innovative fluorescence‐based enzymatic analyses have furthered our understanding of its kinetics, highlighting the potential for developing selective inhibitors that target its extracellular versus intracellular functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMMP‑12’s proteolytic activity is also critically involved in diverse tissue remodeling processes outside the lung. Its selective degradation of elastin and other substrates is linked to vascular remodeling in atherosclerosis and aneurysm formation, where MMP‑12–mediated elastolysis facilitates the initiation and progression of arterial and venous lesions. In the tumor microenvironment, enhanced MMP‑12 expression promotes invasiveness in gliomas, prostate, bladder, and other cancers by remodeling the extracellular matrix, and its genetic polymorphisms may influence cancer risk and metastatic potential. Furthermore, MMP‑12 modulates placental spiral artery remodeling under hypoxic conditions, contributes to corneal and skin wound repair by regulating epithelial cell proliferation and extracellular matrix turnover, and even influences metabolic processes by curbing adipose tissue expansion and modulating insulin sensitivity. Together, these multifaceted roles underscore MMP‑12 as not only a key mediator of inflammatory tissue destruction but also as a promising therapeutic target whose selective inhibition might ameliorate pathological remodeling in diseases as diverse as emphysema, vascular disorders, cancer, and wound healing disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "42"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "R Lang, A Kocourek, M Braun, et al. 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