Polymers of Z alpha1-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo.
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.
Mahadeva
Ravi
R
Department of Medicine, Box 157, Level 5, Addenbrookes NHS Trust, Hills Road, Cambridge CB2 2QQ, UK. rm232@cam.ac.uk
Atkinson
Carl
C
Li
Zhenjun
Z
Stewart
Susan
S
Janciauskiene
Sabina
S
Kelley
Diane G
DG
Parmar
Jasvir
J
Pitman
Rebecca
R
Shapiro
Steven D
SD
Lomas
David A
DA
D000645:Ammonium Sulfate / Q000494:pharmacology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002633:Chemotaxis; D016207:Cytokines / Q000378:metabolism; D004646:Emphysema / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D019272:Leukocyte Elastase / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009504:Neutrophils / Q000378:metabolism*; D017354:Point Mutation; D011108:Polymers / Q000737:chemistry*; D011650:Pulmonary Alveoli / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000737:chemistry*
D016207:Cytokines; D011108:Polymers; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase; D000645:Ammonium Sulfate