Chymotrypsin-like Elastase-1 Mediates Progressive Emphysema in Alpha-1 Antitrypsin Deficiency.

Chymotrypsin-like elastase 1 (CELA1) is a serine protease that is neutralized by alpha-1antitrypsin (AAT) and prevents emphysema in a murine antisense oligonucleotide model of AAT-deficient emphysema. Mice with genetic ablation of do not have emphysema at baseline but develop emphysema with injury and aging. We tested the role of the gene in emphysema development in this genetic model of -deficiency following tracheal lipopolysaccharide (LPS), 10 months of cigarette smoke exposure, aging, and a low-dose tracheal porcine pancreatic elastase (LD-PPE) model we developed. In this last model, we performed proteomic analysis to understand differences in lung protein composition. We were unable to show that -deficient mice developed more emphysema than wild type with escalating doses of LPS. In the LD-PPE model, deficient mice developed significant and progressive emphysema from which & -deficient mice were protected. & deficient lungs had more matrix-associated proteins than deficientlungs but also had more leukocyte-associated proteases. With cigarette smoke exposure, -deficient mice had more emphysema than deficient mice but had less myeloperoxidase activity. -deficient mice had less age-related airspace simplification than AAT-deficient and were comparable to wild type. While CELA1 promotes inflammation-independent emphysema progression and its absence preserves the lung matrix in multiple models of AAT-deficient emphysema, for unclear reasons deficiency is associated with increased emphysema with cigarette smoke. While anti-CELA1 therapies could potentially be used to prevent emphysema progression in AAT deficiency after smoking cessation, an understanding of why and how cigarette smoke exacerbates emphysema in deficiency and whether AAT replacement therapy mitigates this effect is needed first.