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Automated Measurement of Pulmonary Emphysema and Small Airway Remodeling in Cigarette Smoke-exposed Mice
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Chymotrypsin-like Elastase-1 Mediates Progressive Emphysema in Alpha-1 Antitrypsin Deficiency
Andrew J Devine1, Noah J Smith2, Rashika Joshi1
1Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States.
Chronic Obstructive Pulmonary Diseases (Miami, Fla.)
|August 3, 2023
Summary
Chymotrypsin-like elastase 1 (CELA1) absence protects against emphysema in alpha-1-antitrypsin (AAT) deficient mice, except during cigarette smoke exposure. Further research is needed to understand this interaction for potential therapies.
Area of Science:
- Pulmonary Medicine
- Protease Biology
- Emphysema Pathogenesis
Background:
- Alpha-1-antitrypsin (AAT) deficiency is a genetic risk factor for emphysema.
- Chymotrypsin-like elastase 1 (CELA1) is a serine protease implicated in lung tissue degradation.
- Understanding factors influencing emphysema development in AAT deficiency is crucial for therapeutic development.
Purpose of the Study:
- To investigate the role of CELA1 in emphysema development in a murine model of AAT deficiency.
- To assess the impact of CELA1 deficiency on emphysema progression under various injury models, including LPS, cigarette smoke, aging, and a novel low-dose porcine pancreatic elastase (LD-PPE) model.
- To elucidate the mechanisms underlying CELA1's influence on lung matrix composition and inflammation.
Main Methods:
- Genetic ablation of AAT in mice to model AAT deficiency.
- Induction of emphysema using lipopolysaccharide (LPS), chronic cigarette smoke exposure, aging, and a newly developed low-dose porcine pancreatic elastase (LD-PPE) model.
- Proteomic analysis of lung tissue to compare protein composition between genotypes.
- Assessment of emphysema severity, airspace simplification, and inflammatory markers like myeloperoxidase activity.
Main Results:
- CELA1 and AAT double-deficient mice were protected from LD-PPE-induced emphysema, showing preserved lung matrix proteins.
- CELA1 deficiency did not exacerbate emphysema in response to LPS or aging.
- Surprisingly, CELA1-deficient mice exhibited increased emphysema with cigarette smoke exposure, despite reduced myeloperoxidase activity.
Conclusions:
- CELA1 promotes inflammation-independent emphysema progression and preserves lung matrix in several models of AAT deficiency.
- CELA1 deficiency exacerbates emphysema in response to cigarette smoke, a mechanism requiring further investigation.
- Targeting CELA1 may offer therapeutic potential for emphysema in AAT deficiency, particularly after smoking cessation, pending a clearer understanding of smoke-induced exacerbation.
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