Granulocyte elastase‐mediated proteolysis of alpha1‐antitrypsin in cystic fibrosis bronchopulmonary secretions

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Abstract
Airway secretions of patients with cystic fibrosis (CF) contain large amounts of alpha1-antitrypsin (α1-AT), yet elastase activity is also often detectable, suggesting that airway α1-AT may not be functional in some CF patients. It is unknown whether in CF sputum α1-AT is inactivated by oxidants, neutrophil metalloproteinases, bacterial elastase, or neutrophil elastase. To investigate the mechanism(s) by which α1-AT may be inactivated in CF airway secretions, sputum samples were obtained from nine patients during respiratory physiotherapy. α1-AT was measured by radial immunodiffusion. Sputum-α1-AT was purified by antibody affinity chromatography. Electrophoresis of α1-AT from seven patients with acute infectious exacerbations revealed two distinct components: a minor band corresponding to an elastase/α1-AT complex and a major band typical of proteolysed α1-AT (Mr = 48 kD). Each patient had large amounts of sputum elastase activity. In contrast, two patients without free sputum elastase activity had intact sputum α1-AT; however, α1-AT was partially truncated by porcine pancreatic elastase suggesting that the α1-AT may have been partially oxidized. Adding α1-AT purified from normal serum to α1-AT-depleted sputum containing elastase activity resulted in a small α1-AT/elastase complex with most α1-AT being truncated. The serine proteinase inhibitor phenylmethylsulfonyl fluoride but not the metalloproteinase inhibitor EDTA prevented α1-AT proteolysis, thus granulocyte elastase can mediate α1-AT-AT degradation in CF. Apparently, the large granulocyte elastase burden in some acutely ill patients with cystic fibrosis can proteolytically inactivate α1-AT. Pediatr Pilmonol. 1989; 7:12–17.

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