Polymers of α₁-Antitrypsin Are Chemotactic for Human Neutrophils

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.

Update on alpha-1 antitrypsin deficiency: New therapies

“…We have recently shown that circulating polymers of α 1 -antitrypsin are present in all individuals with ZZ α 1 -antitrypsin deficiency (mean 36.3+/-SD33.3µg/mL; n=517) and that the level is associated with COPD (OR 3.6, 95% CI 1.4-9.1) [45]. These observations provide a new paradigm for the pathogenesis of the emphysema associated with α 1 -antitrypsin deficiency -a combination of loss of anti-protease function combined with pro-inflammatory intrapulmonary polymers [44]. However it is still unknown whether the pro-inflammatory properties of polymers play an important role in the pathogenesis of the emphysema associated with α 1 -antitrypsin deficiency or whether the majority of the pathology is driven by the deficiency in the antiproteinase screen (Fig.…”

“…Polymers of α 1 -antitrypsin form within the lung as a result of local inflammation and exposure to cigarette smoke [39,40,42,43]. They are pro-inflammatory for human neutrophils in vitro [40,44] and in murine lungs in vivo [42]. Moreover cigarette smoke induces both intrapulmonary polymer formation and neutrophil influx in transgenic mice that express Z, but not M α 1 -antitrypsin [43].…”

“…Two randomised clinical trials have been undertaken but neither has shown that augmentation therapy reduces the rate of decline in lung function [62,63]. We have postulated that this is because the lung disease associated with α 1 -antitrypsin deficiency is caused by more than the deficiency of an important antiprotease; the pro-inflammatory intrapulmonary polymers may negate the antiprotease effect of intravenous replacement therapy [44,64]. Moreover, the relevance of decline in forced expiratory volume in 1 s (FEV 1 ) as an endpoint in respiratory disease is increasingly debated given recent data highlighting a developmental cause for reduced lung function [65].…”

Polymerization and Oxidation of Alpha-1-Antitrypsin in Pathogenesis of Emphysema

“…This conformational transition may further reduce the levels of functional proteinase inhibitor in the lungs, and consequently exacerbate lung tissue damage (Elliott et al, 1998). Studies of Parmar et al (Parmar et al, 2002) and Mulgrew et al (Mulgrew et al, 2004) showed that Z A1AT locally produced on the epithelial surface of the lung polymerizes and A1AT polymers demonstrate proapoptotic and proinflammatory effects. These studies also revealed that unlike M A1AT protein, Z A1AT protein polymerized at body temperature, and in addition of being an ineffective antiprotease inhibitor, might become a strong neutrophil chemoattractant, thus representing an ongoing source of inflammation in the lungs of individuals with A1ATD.…”

Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies

“…13 This conformational transition inactivates a 1 -antitrypsin as a proteinase inhibitor, thereby further reducing the already depleted levels of a 1 -antitrypsin that are available to protect the alveoli. (iii) Intrapulmonary polymers are chemotactic for human neutrophils in vitro, 14 and this may explain the finding that patients with Z a 1 -antitrypsin deficiency have an excess number of neutrophils in bronchoalveolar lavage 15 and in tissue sections of lung parenchyma. 6 The relative contribution of each of these pathways to lung damage in any given patient is unknown.…”