Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema

Am J Respir Cell Mol Biol. 2002 Jun;26(6):723-30. doi: 10.1165/ajrcmb.26.6.4739.


Plasma deficiency of alpha(1)-antitrypsin is most commonly due to the Z mutation ((342)Glu--> Lys) and is associated with early-onset panlobular emphysema. The lung disease in these patients is attributed to the relative deficiency of circulating alpha(1)-antitrypsin resulting in uncontrolled neutrophil-derived proteolytic activity. We have previously demonstrated that the local deficiency of Z alpha(1)-antitrypsin is exacerbated by the formation of polymers within the lung and now show that this polymerization not only inactivates alpha(1)-antitrypsin but also converts the molecule to a chemoattractant for human neutrophils. The chemotactic action of polymeric alpha(1)-antitrypsin was substantially greater than that seen with other conformers, was of similar magnitude to C5a, and was apparent over a range of physiologically relevant concentrations (EC(50) 0.0045 +/- 0.002 mg/ml). The biologic activity of polymeric alpha(1)-antitrypsin was confirmed by the demonstration that polymers, but not native alpha(1)-antitrypsin, induced neutrophil shape change and stimulated myeloperoxidase release and neutrophil adhesion. Polymeric alpha(1)-antitrypsin had no effect on basal or N-formyl-Met-Leu-Phe- stimulated superoxide anion release or constitutive apoptosis. The chemotactic properties of polymeric alpha(1)-antitrypsin may provide an explanation for the excessive neutrophils found in the lungs of Z alpha(1)-antitrypsin homozygotes and suggests a new paradigm for the pathogenesis of emphysema in these patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Biopolymers / metabolism*
  • Cell Adhesion
  • Chemotaxis, Leukocyte*
  • Emphysema / etiology*
  • Humans
  • Neutrophils / cytology*
  • alpha 1-Antitrypsin / metabolism*


  • Biopolymers
  • alpha 1-Antitrypsin