The use of chymotrypsin-like elastase-1 (CELA1) may be a novel treatment for preventing emphysema in patients with alpha-1 antitrypsin deficiency (AATD), according to findings from a study conducted in mice and published in the journal Chronic Obstructive Pulmonary Diseases.
Approximately 10% of individuals with AATD develop lung disease associated with the disorder, in which progressive alveolar loss is observed despite the withdrawal of such triggering agents as cigarette smoke. Among patients who experience AATD-related pulmonary disease, progressive emphysema is reported and the disorder is known to be the fourth leading indication for lung transplantation.
Alpha-1 antitrypsin (AAT) is a protein manufactured in the liver that helps to protect a person’s lungs. The use of AAT augmentation treatments does not appear to prevent progression of the disease. Among those who do not produce sufficient levels of AAT, their lungs are more easily damaged from smoking, dust, or pollution in the environment.
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Recognizing that a critical need exists to develop new treatment options for patients with AATD, the researchers sought to test the role played by the serine protease CELA1 in the development of emphysema in a genetic model of AATD. CELA1 is synthesized and secreted by alveolar type 2 cells that are involved in postnatal lung elastance. It has been shown that CELA1 is neutralized by AAT and can prevent emphysema from developing in a “murine antisense oligonucleotide model of AAT-deficient emphysema.”
Read more about experimental therapies for patients with AATD
Mice in which a genetic ablation of AAT is present do not exhibit signs of emphysema at baseline; however, they do go on to develop emphysema with aging and injury. The researchers investigated the role played by CELA1 in the development of emphysema in genetic models of AAT deficiency based on the following protocols:
- Tracheal lipopolysaccharide (LPS) model of AAT-deficient emphysema: mice received escalating doses of LPS
- Low-dose tracheal porcine pancreatic elastase (LD-PPE) model: mice in whom 0.2 to 10 units of PPE was administered following anesthetization; proteomic analysis was performed to understand any differences in lung protein composition
- Cigarette smoke exposure model: mice that were exposed to 4 hours of whole-body cigarette smoke 5 days per week for 10 months, beginning at 10 to 12 weeks of age
- Aging model: female and male mice who were permitted to age to between 72 and 75 weeks of age
Results of the study demonstrated the following:
- A similar degree of emphysema was reported in wild-type and AAT-deficient mice in the LPS model.
- In the LD-PPE model, AAT-deficient mice went on to develop significant, progressive emphysema, thus demonstrating that CELA1 mediates protein-level differences in this AAT-deficient emphysema model, with possible differences in oxidative state and neutrophil activity. The role played by CELA1 in AAT-deficient emphysema seems to be more noticeable in male than in female mice.
- In the cigarette smoke exposure model, the lack of CELA1 was shown to enhance airspace destruction in AAT-deficient mice in response to sustained exposure to cigarette smoke.
- In the aging model, CELA1- and AAT-deficient mice experienced less age-related airspace simplification than AAT-deficient mice, which was comparable with that of wild-type mice.
“CELA1 mediates progressive airspace destruction in AAT-deficient emphysema and its inhibition may represent a novel therapy in AAT-related lung disease,” the researchers concluded.
Reference
Devine AJ, Smith NJ, Joshi R, et al. Chymotrypsin-like elastase-1 mediates progressive emphysema in alpha-1 antitrypsin deficiency. Chronic Obstr Pulm Dis. Published online August 1, 2023. doi:10.15326/jcopdf.2023.0416
