Pneumology - Original Articles Open access

Z-alpha1-antitrypsin polymers and small airways disease: a new paradigm in alfa-1 anti-trypsin deficiency-related COPD development?

Authors

Published
8 June 2021
Section
Pneumology - Original Articles
DOI
10.4081/monaldi.2021.1883

Abstract

The presence of Alpha1-Antitrypsin (AAT) polymers, known to promote a sustained pro-inflammatory activity, has been previously demonstrated in bronchial biopsies of subjects with Z-AAT deficiency (AATD) suggesting a possible role in the development of COPD through a small airway disease impairment. The study aimed to assess the presence of small airways dysfunction and the potential correlation with the presence of Z-AAT polymers obtained by Exhaled Breath Condensate (EBC) collection in PiZZ subjects, as compared with matched healthy PiMM subjects. We enrolled 19 asymptomatic, never smoker subjects: 9 PiZZ and 10 PiMM as controls, without obstructive ventilatory defect (i.e., normal FEV1/VC% ratio). All subjects underwent complete pulmonary function tests (PFT). EBC was collected in all subjects. ELISA test was applied to search for Z-AAT polymers. The PiZZ subjects showed normal lung volumes and DLCO values. However, in comparison with PiMM subjects, the single breath test N2 wash-out revealed significant differences regarding the phase III slope (1.45±0.35 N2/L vs. 0.96±0.40 N2/L) (p<0.02) in the PiZZ subjects, while the closing volume/vital capacity ratio (14.3±4.5 % vs. 11.3±6.3 %) was not significantly increased. The ELISA test detected the presence of Z-AAT polymers in 44% of PiZZ patients. Asymptomatic, never smoker PiZZ subjects with normal spirometry and lung diffusion capacity showed airways impairment when compared to PiMM subjects. Although Z-AAT polymers were found only in 44% of PiZZ subjects, these findings suggest the possibility that chronic bronchiolitis can develop as a result of the long-term pro-inflammatory activity of Z-AAT polymers in subjects with Z-related AATD.

Keywords

Supporting Agencies

University of Brescia

References

  1. Blanco I, Bueno P, Diego I, et al. Alpha-1 anti-trypsin Pi? Z gene frequency and Pi?ZZ genotype numbers worldwide: an update. Int J Chron Obstruct Pulmon Dis 2017;12:561-69. DOI: https://doi.org/10.2147/COPD.S125389
  2. Strnad P, McElvaney NG, Lomas DA. Alpha1-antitrypsin deficiency. N Engl J Med 2020;382:1443-55. DOI: https://doi.org/10.1056/NEJMra1910234
  3. Franciosi AN, Carroll TP, McElvaney NG.Franciosi AN, et al. Pitfalls and caveats in alpha1- antitrypsin deficiency testing: a guide for clinicians. Lancet Respir Med 2019;7:1059-67. DOI: https://doi.org/10.1016/S2213-2600(19)30141-9
  4. Ferrarotti I, Ottaviani S, De Silvestri A, Corsico AG. Update on alpha(1)-antitrypsin deficiency. Breathe (Sheff) 2018;14:e17-e24. DOI: https://doi.org/10.1183/20734735.015018
  5. Janciauskiene S, Welte T. Well known and less well known functions of alpha-1 anti-trypsin: its role in chronic obstructive pulmonary disease and other disease developments. Ann Am Thorac Soc 2016;13:S280-8. DOI: https://doi.org/10.1513/AnnalsATS.201507-468KV
  6. Greene CM, Marciniak SJ, Teckman J, et al. α1-antitrypsin deficiency. Nat Rev Dis Primers 2016;2:16051. DOI: https://doi.org/10.1038/nrdp.2016.51
  7. Stoller JK, Aboussouan LS. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med 2011;185:246-59. DOI: https://doi.org/10.1164/rccm.201108-1428CI
  8. Eriksson S, Carlson J, Velez R. Risk of cirrhosis and primary liver cancer in alpha1-antitrypsin deficiency. N Engl J Med 1986;314:736-9. DOI: https://doi.org/10.1056/NEJM198603203141202
  9. Hussain M, Mieli-Vergani G, Mowat AP. Alpha1-antitrypsin deficiency and liver disease: clinical presentation, diagnosis and treatment. J Inherit Metab Dis 1991;14:497-511. DOI: https://doi.org/10.1007/BF01797920
  10. Pini L, Paoletti G, Heffler E, et al. Alpha1-antitrypsin deficiency and asthma. Curr Opin Allergy Clin Immunol 2021;21:46-51. DOI: https://doi.org/10.1097/ACI.0000000000000711
  11. Vizzardi E, Corda L, Sciatti E, et al. Echocardiographic evaluation in subjects with α1-antitrypsin deficiency. Eur J Clin Invest 2015;45:949-54. DOI: https://doi.org/10.1111/eci.12492
  12. Vizzardi E, Corda L, Pezzali N, et al. Elastic properties of theascending aorta in patients with ?1-antitrypsin deficiency (Z homozygotes). Heart 2012;98:1354-8. DOI: https://doi.org/10.1136/heartjnl-2012-302144
  13. Pini L, Peroni M, Zanotti C, et al. Investigating the link between Alpha-1 antitrypsin deficiency and abdominal aortic aneurysms. Ann Vasc Surg 2021;77:195-201. DOI: https://doi.org/10.1016/j.avsg.2021.05.064
  14. Lomas DA, Parfrey H. α1-Antitrypsin deficiency: Molecular pathophysiology. Thorax 2004;59:529-35. DOI: https://doi.org/10.1136/thx.2003.006528
  15. Gooptu B, Lomas DA. Polymers and inflammation: disease mechanisms of the serpinopathies; J Exp Med 2008;205:1529-34. DOI: https://doi.org/10.1084/jem.20072080
  16. Luisetti M, Seersholm N. α1-Antitrypsin deficiency: Epidemiology of α1-antitrypsin deficiency. Thorax 2004;59164-9. DOI: https://doi.org/10.1136/thorax.2003.006494
  17. Lomas DA, Mahadeva R. Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest 2002;110:1585-90. DOI: https://doi.org/10.1172/JCI0216782
  18. Lomas DA, Evans DL, Finch JT, Carrell RW. The mechanism of Z alpha1-antitrypsin accumulation in the liver. Nature 1992;357:605-7. DOI: https://doi.org/10.1038/357605a0
  19. Parmar JS, Mahadeva R, Reed BJ, et al. Polymers of alpha-1 anti-trypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema. Am J Respir Cell Mol Biol 2002;26:723-30. DOI: https://doi.org/10.1165/ajrcmb.26.6.4739
  20. Koo HK, Vasilescu DM, Booth S, et al. Small airways disease in mild and moderate chronic obstructive pulmonary disease: a cross-sectional study. Lancet Respir Med 2018;6:591-602. DOI: https://doi.org/10.1016/S2213-2600(18)30196-6
  21. Yanai M, Sekizawa K, Ohrui T, et al. Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure. J Appl Physiol 1992;72:1016-23. DOI: https://doi.org/10.1152/jappl.1992.72.3.1016
  22. Kim, Rogers TJ, Criner GJ. New concepts in the pathobiology of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008;5:478. DOI: https://doi.org/10.1513/pats.200802-014ET
  23. Taraseviciene-Stewart L, Voekel NF. Molecular pathogenesis of emphysema. J Clin Invest 2008;118:394. DOI: https://doi.org/10.1172/JCI31811
  24. Hogg JC, Timens W. The pathology of chronic obstructive pulmonary disease. Ann Rev Path Mech Dis 2009;4:435-59. DOI: https://doi.org/10.1146/annurev.pathol.4.110807.092145
  25. Tantucci C, Bottone D, Levi G, et al. Respiratory function, autonomic dysfunction, and systemic inflammation are closely linked in patients with COPD and tidal flow limitation: An exploratory study. Respir Physiol Neurobiol 2021;284:103565. DOI: https://doi.org/10.1016/j.resp.2020.103565
  26. Uccelli S, Pini L, Bottone D, et al. Dyspnea during night-time and at early morning in patients with stable COPD is associated with supine tidal expiratory flow limitation. Int J Chron Obstruct Pulmon Dis 2020;15:2549-58. DOI: https://doi.org/10.2147/COPD.S269346
  27. Burgel PR. The role of small airways in obstructive airway diseases. Eur Respir Rev 2011;20:23-33. DOI: https://doi.org/10.1183/09059180.00010410
  28. Stockley JA, Cooper BG, Stockley RA, Sapey E. Small airways disease: time for a revisit? Int J Chron Obstruct Pulmon Dis 2017;12:2343-53. DOI: https://doi.org/10.2147/COPD.S138540
  29. Tantucci C, Pini L. Inhaled corticosteroids in COPD: Trying to make a long story short. Int J Chron Obstruct Pulmon Dis 2020;15:821-9. DOI: https://doi.org/10.2147/COPD.S233462
  30. Bazzan E, Tin M, Biondini D, et al. Alpha1-Antitrypsin polymerizes in alveolar macrophages of smokers with and without alpha1-antitrypsin deficiency. Chest 2018;154:607-16. DOI: https://doi.org/10.1016/j.chest.2018.04.039
  31. Pini L, Tiberio L, Venkatesan N, et al. The role of bronchial epithelial cells in the pathogenesis of COPD in Z-alpha-1 antitrypsin deficiency. Respir Res 2014;15:112. DOI: https://doi.org/10.1186/s12931-014-0112-3
  32. Corda L, Bertella E, Pini L, et al. Diagnostic flow chart for targeted detection of alpha1- antitrypsin deficiency. Respir Med 2006;100:463-70. DOI: https://doi.org/10.1016/j.rmed.2005.06.009
  33. Pini L, Corda L, Malerba M, et al. Alpha 1-antitrypsin deficiency: the Brescia clinical study. Recent Prog Med 2000;91:352-61.
  34. Bayley DL, Abusriwil H, Ahmad A, Stockley RA. Validation of assays for inflammatory mediators in exhaled breath condensate. Eur Respir J 2008;31:943-8. DOI: https://doi.org/10.1183/09031936.00081707
  35. Koczulla AR, Noeske S, Herr C, et al. Alpha-1 anti-trypsin is elevated in exhaled breath condensate and serum in exacerbated COPD patients. Respir Med 2012;106:120-6. DOI: https://doi.org/10.1016/j.rmed.2011.06.015

Metrics

Citations and online attention from Dimensions, Altmetric and PlumX.

PlumX Metrics

License

Copyright (c) 2021 The Author(s)

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.