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

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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; Kelley, DG; Parmar, J; Pitman, R; Shapiro, SD; Lomas, DA.

I: American Journal of Pathology, Vol. 166, Nr. 2, 2005, s. 377-386.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Mahadeva, R, Atkinson, C, Li, ZJ, Stewart, S, Janciauskiene, S, Kelley, DG, Parmar, J, Pitman, R, Shapiro, SD & Lomas, DA 2005, 'Polymers of Z alpha(1)-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo', American Journal of Pathology, vol. 166, nr. 2, s. 377-386.

APA

CBE

Mahadeva R, Atkinson C, Li ZJ, Stewart S, Janciauskiene S, Kelley DG, Parmar J, Pitman R, Shapiro SD, Lomas DA. 2005. Polymers of Z alpha(1)-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo. American Journal of Pathology. 166(2):377-386.

MLA

Vancouver

Author

Mahadeva, R ; Atkinson, C ; Li, ZJ ; Stewart, S ; Janciauskiene, Sabina ; Kelley, DG ; Parmar, J ; Pitman, R ; Shapiro, SD ; Lomas, DA. / Polymers of Z alpha(1)-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo. I: American Journal of Pathology. 2005 ; Vol. 166, Nr. 2. s. 377-386.

RIS

TY - JOUR

T1 - Polymers of Z alpha(1)-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo

AU - Mahadeva, R

AU - Atkinson, C

AU - Li, ZJ

AU - Stewart, S

AU - Janciauskiene, Sabina

AU - Kelley, DG

AU - Parmar, J

AU - Pitman, R

AU - Shapiro, SD

AU - Lomas, DA

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

M3 - Article

VL - 166

SP - 377

EP - 386

JO - American Journal of Pathology

T2 - American Journal of Pathology

JF - American Journal of Pathology

SN - 1525-2191

IS - 2

ER -