The Role of Alpha-1 Antitrypsin in the Pathophysiology and Treatment of Inflammatory Lung Diseases

Daniella A Spittle,1 Alice M Turner2 1Department of Inflammation and Ageing, University of Birmingham, Birmingham, UK; 2Department of Applied Health Sciences, University of Birmingham, Birmingham, UKCorrespondence: Alice M Turner, Email a.m.turner@bham.ac.ukAbstract: Alpha-1 antitrypsin (AAT) is a serine protease inhibitor that plays a critical role in maintaining pulmonary homeostasis through regulation of the protease–antiprotease balance and modulation of inflammatory responses. AAT primarily protects lung tissue by inhibiting neutrophil elastase, thereby preventing excessive extracellular matrix degradation and alveolar destruction. Disruption of this balance, particularly in alpha-1 antitrypsin deficiency (AATD), results in unchecked proteolytic activity and progressive lung injury, most notably contributing to chronic obstructive pulmonary disease (COPD). Beyond its antiprotease function, AAT exerts broader anti-inflammatory, immunomodulatory and anti-apoptotic effects, influencing cytokine release, neutrophil recruitment and oxidative stress pathways. These properties highlight its translational relevance, positioning AAT as a potential therapeutic agent across a spectrum of inflammatory airway diseases, including bronchiectasis, cystic fibrosis and interstitial lung diseases. Clinical evidence supports AAT augmentation therapy in AATD-associated COPD, while emerging research explores its efficacy in non-deficiency states characterised by excessive inflammation and protease burden. Overall, AAT represents both a key pathogenic factor when deficient and a promising biologic therapy in inflammatory lung disease. This literature review explores its mechanisms and potential for expanded clinical application.Keywords: alpha-1 antitrypsin, inflammatory lung disease, protease inhibitor, chronic obstructive pulmonary disease, neutrophil elastase, augmentation therapy