Role of Chymotrypsin-like Elastase 1 in Lung Physiology and in α1-Antitrypsin Deficiency

Abstract

α1-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. α1-antitrypsin related lung disease (AAT-RLD) is the fourth leading indication for lung transplantation and is characterized by protease-mediated progressive emphysema that manifests in the 4th or 5th decade of life. Chymotrypsin-like elastase 1 (Cela1) is a digestive enzyme that binds to elastin in a stretch-dependent manner and is covalently neutralized by AAT. We hypothesized a role for Cela1 in AAT-RLD. Cela1-/- mice where phenotypically similar to wild type but had higher lung elastance and lacked stretch-inducible elastase activity. Wild-type mice administered anti-AAT oligo had reduced amounts of lung Cela1-AAT fusion protein in lung homogenate and spontaneously developed emphysema after 6 weeks. Cela1-/- mice administered anti-AAT oligo were completely protected from these emphysematous changes. Cela1 recombinant protein did not require propeptide cleavage for elastolysis, and its elastolytic profile was similar to that of other pancreatic elastases. Phylogenetic analysis of vertebrate Cela promoter and protein sequences showed that placental mammal Cela1 was distinct from other Cela’s, and that the placental mammal the Cela1 gene was invariantly conserved despite variable loss of other Cela genes in non-carnivores. These data demonstrate that the pancreatic enzyme Cela1 has been evolutionarily co-opted for a role in reducing lung elastance in the placental mammal lineage and that its stretch-regulated expression and elastolytic activity is responsible for emphysema in the absence of its anti-protease: AAT.