title: Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema.
abstract: 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.
authors.affiliation: Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, United Kingdom.
authors.forename: Jasvir S
authors.initials: JS
authors.lastname: Parmar
authors.forename: Ravi
authors.initials: R
authors.lastname: Mahadeva
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Reed
authors.forename: Neda
authors.initials: N
authors.lastname: Farahi
authors.forename: Karen A
authors.initials: KA
authors.lastname: Cadwallader
authors.forename: Mary T
authors.initials: MT
authors.lastname: Keogan
authors.forename: Diana
authors.initials: D
authors.lastname: Bilton
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
mesh_terms: D017209:Apoptosis; D001704:Biopolymers / Q000378:metabolism*; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D004646:Emphysema / Q000209:etiology*; D006801:Humans; D009504:Neutrophils / Q000166:cytology*; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
chemical_list: D001704:Biopolymers; D000515:alpha 1-Antitrypsin