The human lung continues to grow and develop postnatally with the formation of new alveolar septate to increase surface area and the remodeling of existing septae to improve the efficiency of gas exchange and increase lung compliance (i.e. reduce the work of breathing). We identified a novel protease, chymotrypsin-like elastase 1 (Cela1) which is expressed in the lung and plays a role in reducing postnatal lung compliance.
In collaboration with investigators from multiple different institutions, we have shown that:
- Cela1 is expressed in regions of lung elastin remodeling
- The lungs of Cela1-/- mice are stiffer and have smaller alveoli than those of wild type mice
- Cela1 degrades immature elastin and mature elastin without substantial specificity; however, elastin crosslinking domains inhibit its elastolytic activity in mature elastin
- Among three Cela isoforms (Cela1, Cela2, and Cela3), Cela1 is the only one universally present in placental mammals and both protein and promoter sequences are unique compared to mammalian Cela2 and Cela3 which are more similar to non-mammalian Cela isoforms suggesting that Cela1 plays a unique role in placental mammals
Current questions we are investigating include:
- What cell type is responsible for Cela1 remodeling activity?
- What are the transcriptional regulators of Cela1 activity?
- Can Cela1 activity be modulated to improve lung structure and function in bronchopulmonary dysplasia?
Joshi R, Heinz A, Fan Q, Guo S, Monia B, Schmelzer CEH, Weiss AS, Batie M, Parameshwaran H, Varisco BM. Role for Cela1 in Postnatal Lung Remodeling and AAT-deficient Emphysema. Am J Respir Cell Mol Biol. 2018 Feb 8.
Joshi R, Liu S, Brown MD, Young SM, Batie M, Kofron JM, Xu Y, Weaver TE, Apsley K, Varisco BM. Stretch regulates expression and binding of chymotrypsin-like elastase 1 in the postnatal lung. FASEB J. 2016 Feb;30(2):590-600.
Liu S, Young SM, Varisco BM. Dynamic Expression of Chymotrypsin Like Elastase-1 Over the Course of Lung Development. American Journal of Lung Cell and Molecular Physiology. 2014 Jun 15;306(12):L1104-16. PMID: 24793170