Abstract

1-antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplantation. We previously demonstrated that AAT covalently neutralizes chymotrypsin-like elastase 1 (Cela1) in vitro, that Cela1 is expressed during the alveolar stage of lung development in association with regions of lung elastin remodeling, and that lung stretch increases Cela1 expression and binding to lung elastin. Here we show that Cela1 is exclusively responsible for stretch-inducible lung elastase activity, reduces postnatal lung elastance, and is required for emphysema in an antisense oligo model of AAT deficiency. Cela1 mRNA is present in the human lung, and in the placental mammal lineage, Cela1 is more conserved than Cela2 or Cela3 with unique promoter and protein elements indicating a unique role for Cela1 in this lineage. These data demonstrate an adaptive role for Cela1 in placental mammal lung biology with physiologic relevance to AAT-deficient lung disease in humans.