Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema.
2002
Plasma deficiency of α1-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 α1-antitrypsin resulting in uncontrolled neutrophil-derived proteolytic activity. We have previously demonstrated that the local deficiency of Z α1-antitrypsin is exacerbated by the formation of polymers within the lung and now show that this polymerization not only inactivates α1-antitrypsin but also converts the molecule to a chemoattractant for human neutrophils. The chemotactic action of polymeric α1-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 α1-antitrypsin was confirmed by the demonstration that polymers, but not native α1-antitrypsin, induced neutrophil shape change ...
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