Unraveling the Pathogenesis of Chronic Obstructive Pulmonary Disease in Alpha-1 Antitrypsin Deficiency: Mechanisms, Biomarkers, and Therapeutic Implications

Abstract

Chronic obstructive pulmonary disease (COPD) represents a significant global disease burden, with progressive and irreversible airflow limitation and respiratory symptoms. While cigarette smoking is the primary COPD risk factor, genetic predisposition like alpha-1 antitrypsin deficiency (AATD) also confers risk, often resulting in early-onset disease. Understanding COPD mechanisms in AATD can inform disease pathogenesis overall, biomarker development for detection/prognosis, and targeted therapies. This review explores the interplay between AATD and COPD, integrating genetic, environmental, and molecular contributors to pathogenesis and disease progression. Additionally, we discuss emerging treatment strategies that may mitigate COPD severity in AATD patients. Specifically, AATD arises from mutations in the SERPINA1 gene, resulting in reduced alpha-1 antitrypsin (AAT) levels. General COPD mechanisms (protease-antiprotease imbalance, oxidative stress, aberrant inflammation) are understood, but specifics in AATD remain unclear, hindering precision medicine approaches for this high-risk population. Elucidating exact disease pathways could enable treatments beyond standard augmentation therapy. Reasons to prioritize this include arresting disease progression and reducing the substantial AATD-COPD burden. Recent omics studies have uncovered promising biomarkers for molecular phenotyping of COPD subtypes. Further inquiry into novel pathways and integrating multi-omics data with clinical outcomes can provide frameworks for elucidating AATD-COPD mechanisms and validating predictors. However, gaps remain in connecting putative biomarkers and mechanisms with clinical endpoints. These must be addressed to develop targeted therapies and improve outcomes for this early-onset, rapid COPD progression population.