{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAlpha‐1‐antitrypsin (AAT), the major circulating product of the SERPINA1 gene, is best known for its canonical role as a serine protease inhibitor that protects lung tissue by neutralizing neutrophil elastase and other proteolytic enzymes. By inhibiting destructive protease activity, AAT preserves extracellular matrix integrity and helps prevent conditions such as chronic obstructive pulmonary disease and elastin‐mediated vascular injury. In addition, AAT is found associated with high‐density lipoproteins, suggesting a protective role in maintaining vascular stability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its antiprotease function, SERPINA1 exerts significant anti‐inflammatory and immunomodulatory activities. Glycosylated AAT can bind chemokines such as interleukin-8, thereby modulating receptor engagement and curtailing excessive neutrophil chemotaxis. This regulatory function contributes to the suppression of proinflammatory cytokine synthesis and helps maintain a balanced immune response, as illustrated by the altered chemotactic profiles and cytokine production observed in individuals with AAT deficiency."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in SERPINA1—most notably the polymerogenic Z variant—disrupt normal protein folding and favor the formation of ordered polymers that accumulate within the endoplasmic reticulum. Interestingly, such intracellular retention does not elicit a classical unfolded protein response but rather activates distinct signaling pathways, including NF‑κB and caspase-mediated cascades, which contribute to hepatocellular injury and liver disease. Efficient clearance of these misfolded proteins through ER quality-control mechanisms (for example, via ER mannosidase I activity) is crucial for cellular proteostasis. Studies employing cell and animal models have further demonstrated that factors governing intracellular transport and degradation are key determinants of whether mutant AAT leads to clinical liver damage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRegulation of SERPINA1 expression and its post-translational modifications—such as variable glycosylation—affect the protein’s stability, half-life, and interaction with other plasma components. Detailed studies of the gene’s regulatory elements and the glycoform diversity of AAT indicate that such modifications can modify its anti-inflammatory and antiproteolytic capabilities, thereby influencing its utility as both a biomarker and a therapeutic target in inflammatory and malignant diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPopulation-based genetic and epidemiologic investigations have underscored the clinical importance of SERPINA1 allelic heterogeneity. Epidemiological data reveal a wide geographic distribution of both severe and intermediate deficiency alleles, with altered frequencies impacting susceptibility to lung, liver, and cardiovascular conditions. Furthermore, integrative genome-wide analyses have associated variation in SERPINA1 expression with metabolite networks and atherosclerotic plaque formation, emphasizing the systemic consequences of even modest deviations in AAT levels."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nLastly, emerging evidence points to a role for SERPINA1 in innate host defense mechanisms. Anomalous AAT forms not only undermine protease regulation but may also predispose to infections by impairing the control of neutrophil serine proteases and modulating extracellular trap formation. These insights widen the functional landscape of AAT, suggesting that its deficiency or structural alterations can contribute to increased infection susceptibility and influence systemic inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "C P Hersh, M Dahl, N P Ly, et al. 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