PNNL

Abstract

Chymotrypsin-like elastase 1 (CELA1) is a serine protease that is neutralized by a1-antitrypsin (AAT) and prevents emphysema in a murine antisense oligonucleotide model of AAT-deficient emphysema. Mice with genetic ablation of AAT do not have emphysema at baseline but develop emphysema with injury and aging. We tested the role of CELA1 in emphysema development in this genetic model of AAT-deficiency following tracheal lipopolysacharide (LPS), 10 months of cigarette smoke (CS) 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 AAT-deficient mice developed more emphysema than wild type with escalating doses of LPS. In the LD-PPE model, AAT-deficient mice developed significant and progressive emphysema from which Cela1-/-&AAT-deficient mice were protected. Cela1-/-&AAT-deficient lungs had more matrix-associated proteins than AAT-deficient lungs, but also had more leukocyte-associated proteases. With CS exposure, Cela1-/-&AAT-deficient mice had more emphysema than AAT-deficient mice but had less myeloperoxidase activity. Cela1-/-&AAT-deficient mice had less age-related airspace simplification than AAT-deficient and was comparable to wildtype. While CELA1 promotes inflammation-independent emphysema progression and its absence preserves lung matrix in multiple models of AAT-deficient emphysema, for unclear reasons it is associated with increased emphysema with CS. While anti-CELA1 therapies could potentially be used to prevent emphysema progression in AAT deficiency after smoking cessation, an understanding of why and how CS exacerbates emphysema in Cela1 deficiency and whether AAT replacement therapy mitigates this effect is needed first.