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Polymers of Z alpha(1)-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo

Mahadeva, R; Atkinson, C; Li, ZJ; Stewart, S; Janciauskiene, Sabina LU ; Kelley, DG; Parmar, J; Pitman, R; Shapiro, SD and Lomas, DA (2005) In American Journal of Pathology 166(2). p.377-386
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 antielastase 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)-antitrypsin co-localizes with neutrophils in the alveoli of individuals with Z... (More)
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 antielastase 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)-antitrypsin 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 individual despite alpha(1)-antitrypsin replacement therapy. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
American Journal of Pathology
volume
166
issue
2
pages
377 - 386
publisher
American Society for Investigative Pathology
external identifiers
  • wos:000226743000005
  • pmid:15681822
  • scopus:19944430698
ISSN
1525-2191
language
English
LU publication?
yes
id
ad8c6480-58ec-437e-86f1-e2e8a1c6233d (old id 897602)
alternative location
http://ajp.amjpathol.org/cgi/content/abstract/166/2/377
date added to LUP
2008-01-16 14:01:08
date last changed
2017-11-12 03:22:06
@article{ad8c6480-58ec-437e-86f1-e2e8a1c6233d,
  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 antielastase 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)-antitrypsin 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 individual despite alpha(1)-antitrypsin replacement therapy.},
  author       = {Mahadeva, R and Atkinson, C and Li, ZJ and Stewart, S and Janciauskiene, Sabina and Kelley, DG and Parmar, J and Pitman, R and Shapiro, SD and Lomas, DA},
  issn         = {1525-2191},
  language     = {eng},
  number       = {2},
  pages        = {377--386},
  publisher    = {American Society for Investigative Pathology},
  series       = {American Journal of Pathology},
  title        = {Polymers of Z alpha(1)-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo},
  volume       = {166},
  year         = {2005},
}