Am. J. Respir. Cell Mol. Biol., Volume 26, Number 6, June, 2002 723-730

Polymers of ₁-Antitrypsin Are Chemotactic for Human Neutrophils
A New Paradigm for the Pathogenesis of Emphysema

Jasvir S. Parmar, Ravi Mahadeva, Benjamin J. Reed, Neda Farahi, Karen A. Cadwallader, Mary T. Keogan, Diana Bilton, Edwin R. Chilvers,^* and David A. Lomas^*

Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom; Cambridge Institute for Medical Research, Cambridge, United Kingdom; Department of Immunology, Beaumont Hospital, Dublin, Republic of Ireland; and Cystic Fibrosis Unit, Papworth Hospital NHS Trust, Papworth Everard, Cambridge, United Kingdom

Plasma deficiency of ₁-antitrypsin is most commonly due to the Z mutation (³⁴²Glu Lys) and is associated with early-onset panlobular emphysema. The lung disease in these patients is attributed to the relative deficiency of circulating ₁-antitrypsin resulting in uncontrolled neutrophil-derived proteolytic activity. We have previously demonstrated that the local deficiency of Z ₁-antitrypsin is exacerbated by the formation of polymers within the lung and now show that this polymerization not only inactivates ₁-antitrypsin but also converts the molecule to a chemoattractant for human neutrophils. The chemotactic action of polymeric 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 (EC₅₀ 0.0045 ± 0.002 mg/ml). The biologic activity of polymeric ₁-antitrypsin was confirmed by the demonstration that polymers, but not native ₁-antitrypsin, induced neutrophil shape change and stimulated myeloperoxidase release and neutrophil adhesion. Polymeric 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 ₁-antitrypsin may provide an explanation for the excessive neutrophils found in the lungs of Z ₁-antitrypsin homozygotes and suggests a new paradigm for the pathogenesis of emphysema in these patients.

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