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(American Journal of Pathology. 2005;166:377-386.)
© 2005 American Society for Investigative Pathology

Polymers of Z ₁-Antitrypsin Co-Localize with Neutrophils in Emphysematous Alveoli and Are Chemotactic in Vivo

Ravi Mahadeva^*, Carl Atkinson, Zhenjun Li^*, Susan Stewart, Sabina Janciauskiene, Diane G. Kelley, Jasvir Parmar^*, Rebecca Pitman, Steven D. Shapiro^¶ and David A. Lomas^*

From the Department of Medicine,^* Division of Respiratory Medicine, University of Cambridge, United Kingdom; the Department of Histopathology, Papworth NHS Trust, Cambridge, United Kingdom; the Department of Medicine, University Hospital Malmo, Malmo, Sweden; the Division of Pulmonary and Critical Care, Washington University School of Medicine, St. Louis, Missouri; and the Division of Pulmonary and Critical Care Medicine,^¶ Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts

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: ₁-antitrypsin. The Z mutant of 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 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 ₁-anti-trypsin co-localizes with neutrophils in the alveoli of individuals with Z 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 ₁-antitrypsin-related emphysema. The transition of native Z 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 ₁-antitrypsin replacement therapy.

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