Chest
Volume 125, Issue 5, May 2004, Pages 1952-1957
Journal home page for Chest

Selected Reports
Z α1-Antitrypsin Polymerizes in the Lung and Acts as a Neutrophil Chemoattractant

https://doi.org/10.1378/chest.125.5.1952Get rights and content

Background

α1-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.

Methods and 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.

Section snippets

Study Population

Five patients with A1AT deficiency (PiZZ phenotype), five PiMM control subjects, and one patient with the PiZZ phenotype who had received a liver transplant were evaluated as part of this study. All patients were clinically stable at the time of the study and had been free of infection for the previous 6 weeks. All patients in the study had been phenotyped previously by standard isoelectric focusing techniques. The patient with the liver transplant had undergone transplantation 10 years

Patient Demographics

The study population included five PiZZ patients, whose conditions were confirmed by A1AT levels and isoelectric focusing. Four of the patients were ex-smokers with established lung disease (ie, FEV1, 43 ± 14% predicted; FEV1/FVC ratio, 38 ± 2% predicted; diffusing capacity of the lung for carbon monoxide [Dlco], 34± 12% predicted). One patient was a newly diagnosed nonsmoker (ie, FEV1, 99% predicted; FEV1/FVC ratio, 72% predicted; Dlco, 96% predicted). All patients were men, with an age range

Discussion

This study shows for the first time that A1AT is locally produced on the epithelial surface of the lung. The source of this A1AT could be respiratory epithelial cells, macrophages, or, less likely, neutrophils.910 In addition, unlike MA1AT protein, this ZA1AT protein polymerizes at body temperature, and, in addition to being an ineffective antiprotease inhibitor, may become a strong neutrophil chemoattractant, thus representing an ongoing source of inflammation in the lungs of individuals with

References (34)

  • ML Brantly et al.

    Clinical features and history of the destructive lung disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary symptoms

    Am Rev Respir Dis

    (1988)
  • S Errikson et al.

    Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency

    N Engl J Med

    (1986)
  • T Sveger

    Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants

    N Engl J Med

    (1976)
  • KC Smith et al.

    Alpha 1-antitrypsin deficiency panniculitis: a histopathologic and immunopathologic study of four cases

    Arch Dermatol

    (1987)
  • DY Mason et al.

    Alpha 1-antitrypsin is present within the primary granules of human polymorphonuclear leukocytes

    Am J Pathol

    (1991)
  • J Travis et al.

    The functional role of acute phase plasma proteinase inhibitors

    Tokai J Exp Clin Med

    (1988)
  • EP Molmenti et al.

    Cell-specific expression of alpha 1-antitrypsin in human intestinal epithelium

    J Clin Invest

    (1993)
  • Cited by (140)

    • Alpha-1 antitrypsin deficiency–associated panniculitis

      2021, Journal of the American Academy of Dermatology
      Citation Excerpt :

      Moreover, Z-AAT polymers are neutrophil chemoattractant30-32 and have been shown at skin biopsy alongside immunoglobulin M and complement C3.33 Studies have shown AAT polymers in the lungs of ZZ individuals34 and that AATD results in an increased influx of neutrophils into the lungs.30,35 These mechanisms may mirror the pathophysiology of AATD-associated panniculitis.

    • Alpha-1 Antitrypsin Deficiency Associated COPD

      2020, Clinics in Chest Medicine
    • Diagnostic evaluation of bronchiectasis

      2019, Respiratory Medicine: X
    View all citing articles on Scopus

    This research was funded by the American Alpha One Foundation and the Charitable Infirmary Charitable Trust, Health Research Board.

    View full text