Z alpha1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant.
BACKGROUND
Alpha1-antitrypsin (A1AT) is an abundant protein that is synthesized in the liver and is secreted into the plasma. From the plasma, A1AT diffuses into various body compartments, including the lung where it provides much of the antiprotease protection. The current understanding of the pathogenesis of emphysema in A1AT-deficient individuals focuses on the polymerization of mutant protein within the liver, which results in a deficiency of circulating A1AT and a protease-antiprotease imbalance in the lungs.


RESULTS
In this study, we evaluated BAL fluid samples from five healthy volunteers, five individuals with ZA1AT deficiency, and an individual with the PiZZ phenotype who had received a liver transplant. We show that the lung itself is a source of A1AT. In addition, the Z protein formed in the lung polymerizes, and these polymers are detectable in lung epithelial lining fluid by enzyme-linked immunosorbent assay and Western blot analysis. Finally, we show that polymeric ZA1AT is a potent neutrophil chemoattractant that is similar to polymerized MA1AT.


CONCLUSIONS
Our findings suggest that the polymerization of locally produced ZA1AT is a contributory factor to the lung inflammation experienced by those with A1AT deficiency and that standard antiprotease therapies may not address this problem.
Mulgrew
Alan T
AT
Department of Medicine, Respiratory Research Division, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
Taggart
Clifford C
CC
Lawless
Matthew W
MW
Greene
Catherine M
CM
Brantly
Mark L
ML
O'Neill
Shane J
SJ
McElvaney
Noel G
NG
D000328:Adult; D000368:Aged; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002630:Chemotactic Factors / Q000032:analysis / Q000502:physiology*; D006801:Humans; D008168:Lung; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000502:physiology*; D011108:Polymers; D000515:alpha 1-Antitrypsin / Q000032:analysis / Q000502:physiology*; D019896:alpha 1-Antitrypsin Deficiency / Q000378:metabolism
D002630:Chemotactic Factors; D011108:Polymers; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin