Polymers of Z α1-Antitrypsin Co-Localize with Neutrophils in Emphysematous Alveoli and Are Chemotactic in Vivo

Abstract

The molecular mechanisms that cause emphysema are complex but most theories suggest that an excess of proteinases is a crucial requirement. This paradigm is exemplified by severe deficiency of the key anti-elastase within the lung: alpha(1)-antitrypsin. The Z mutant of alpha(1)-antitrypsin has a point mutation Glu342Lys in the hinge region of the molecule that renders it prone to intermolecular linkage and loop-sheet polymerization. Polymers of Z alpha(1)-antitrypsin aggregate within the liver leading to juvenile liver cirrhosis and the resultant plasma deficiency predisposes to premature emphysema. We show here that polymeric alpha(1)-anti-trypsin co-localizes with neutrophils in the alveoli of individuals with Z alpha(1)-antitrypsin-related emphysema. The significance of this finding is underscored by the excess of neutrophils in these individuals and the demonstration that polymers cause an influx of neutrophils when instilled into murine lungs. Polymers exert their effect directly on neutrophils rather than via inflammatory cytokines. These data provide an explanation for the accelerated tissue destruction that is characteristic of Z alpha(1)-antitrypsin-related emphysema. The transition of native Z alpha(1)-antitrypsin to polymers inactivates its anti-proteinase function, and also converts it to a proinflammatory stimulus. These findings may also explain the progression of emphysema in some individuals despite alpha(1)-antitrypsin replacement therapy.

Update on alpha-1 antitrypsin deficiency: New therapies

“…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].…”

Le déficit en alpha-1-antitrypsine

“…Polymère trophiles dans les alvéoles pulmonaires des patients [40] ; d'autre part, ils sont chémo-attractants in vitro pour les neutrophiles et favorisent leur adhésion et stimulent leur dégranulation [9]. Enfin, l'environnement peut jouer un rôle important dans le déficit en 1AT, en particulier dans la formation des polymères Z.…”

Molecular mousetraps, α1-antitrypsin deficiency and the serpinopathies

“…The pro-inflammatory properties of polymers were further confirmed by the demonstration that they caused a neutrophil influx when instilled into the lungs of mice. 65 Therefore the chemoattractant properties of polymers may explain the excess number of neutrophils in bronchoalveolar lavage 66 and in tissue sections of lung parenchyma (Fig 3d) from individuals with Z α 1 -antitrypsin deficiency. Moreover, polymers may contribute to the excess inflammation that is apparent even in …”

“…For many years the emphysema associated with Z α 1 -antitrypsin deficiency has been a paradigm for emphysema seen in smokers who have normal levels of α 1 -antitrypsin. However, this is clearly an oversimplification as emphysema associated with Z α 1 -antitrypsin deficiency has a different distribution (upper rather than lower lobe), different pathology (panlobular rather than centrilobular emphysema), the presence of pro-inflammatory lung polymers [61][62][63]65 and different patterns of gene expression. 70 It seems likely that more differences will become apparent as we dissect the pathways of inflammation and tissue damage in individuals with α 1 -antitrypsin deficiency.…”