Role for Cela1 in Postnatal Lung Remodeling and Alpha-1 Antitrypsin-Deficient Emphysema

• Published in: American journal of respiratory cell and molecular biology Vol. 59; no. 2; pp. 167 - 178
• Main Authors: Joshi, Rashika, Heinz, Andrea, Fan, Qiang, Guo, Shuling, Monia, Brett, Schmelzer, Christian E H, Weiss, Anthony S, Batie, Matthew, Parameshwaran, Harikrishnan, Varisco, Brian M
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.08.2018
• Subjects: alpha 1-Antitrypsin - genetics; Animals; Antisense oligonucleotides; Biomechanical Phenomena; Chymotrypsin; CRISPR; Elastase; Elastin; Elastin - metabolism; Emphysema; Emphysema - genetics; Fibroblasts - metabolism; Gene expression; Gene Expression Regulation, Enzymologic - genetics; Humans; Lung - growth & development; Lung transplantation; Mass spectroscopy; Mice, Knockout; mRNA; Neutrophils; Original Research; Pancreas; Pancreatic elastase; Pancreatic Elastase - genetics; Pancreatic Elastase - metabolism; Pathogenesis; Phylogeny; Proteins; Rodents; Thorax; alpha-1 antitrypsin; lung matrix remodeling; elastin; lung development; emphysema
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2017-0361OC

Alpha-1 antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplant. Chymotrypsin-like elastase 1 (Cela1) is a digestive protease that is expressed during lung development in association with regions of elastin remodeling, exhibits stretch-dependent expression during lung regeneration, and binds lung elastin in a stretch-dependent manner. AAT covalently neutralizes Cela1 in vitro. We sought to determine the role of Cela1 in postnatal lung physiology, whether it interacted with AAT in vivo, and to detect any effects it may have in the context of AAT deficiency. The lungs of Cela1 mice had aberrant lung elastin structure and higher elastance as assessed with the flexiVent system. On the basis of in situ zymography with ex vivo lung stretch, Cela1 was solely responsible for stretch-inducible lung elastase activity. By mass spectrometry, Cela1 degraded mature elastin similarly to pancreatic elastase. Cela1 promoter and protein sequences were phylogenetically distinct in the placental mammal lineage, suggesting an adaptive role for lung-expressed Cela1 in this clade. A 6-week antisense oligonucleotide mouse model of AAT deficiency resulted in emphysema with increased Cela1 mRNA and reduction of approximately 70 kD Cela1, consistent with covalent binding of Cela1 by AAT. Cela1 mice were completely protected against emphysema in this model. Cela1 was increased in human AAT-deficient emphysema. Cela1 is important in physiologic and pathologic stretch-dependent remodeling processes in the postnatal lung. AAT is an important regulator of this process. Our findings provide proof of concept for the development of anti-Cela1 therapies to prevent and/or treat AAT-deficient emphysema.