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Polymers of Z alpha...
Polymers of Z alpha(1)-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo
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Mahadeva, R (author)
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Atkinson, C (author)
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Li, ZJ (author)
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Stewart, S (author)
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- Janciauskiene, Sabina (author)
- Lund University,Lunds universitet,Enheten för kroniska inflammatoriska och degenerativa sjukdomar,Forskargrupper vid Lunds universitet,Chronic Inflammatory and Degenerative Diseases Research Unit,Lund University Research Groups
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Kelley, DG (author)
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Parmar, J (author)
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Pitman, R (author)
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Shapiro, SD (author)
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Lomas, DA (author)
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(creator_code:org_t)
- 2005
- 2005
- English.
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In: American Journal of Pathology. - 1525-2191. ; 166:2, s. 377-386
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
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- art (subject category)
- ref (subject category)
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- By the author/editor
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Mahadeva, R
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Atkinson, C
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Li, ZJ
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Stewart, S
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Janciauskiene, S ...
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Kelley, DG
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show more...
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Parmar, J
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Pitman, R
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Shapiro, SD
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Lomas, DA
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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American Journal ...
- By the university
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Lund University