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.