Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Jun 1;22(11):5996.
doi: 10.3390/ijms22115996.

Protease-Antiprotease Imbalance in Bronchiectasis

Martina Oriano  1   2 , Francesco Amati  1 , Andrea Gramegna  1   2 , Anthony De Soyza  3 , Marco Mantero  1   2 , Oriol Sibila  4 , Sanjay H Chotirmall  5 , Antonio Voza  6 , Paola Marchisio  1   7 , Francesco Blasi  1   2 , Stefano Aliberti  1   2
Affiliations
Review

Protease-Antiprotease Imbalance in Bronchiectasis

Martina Oriano et al. Int J Mol Sci. .

Abstract

Airway inflammation plays a central role in bronchiectasis. Protease-antiprotease balance is crucial in bronchiectasis pathophysiology and increased presence of unopposed proteases activity may contribute to bronchiectasis onset and progression. Proteases' over-reactivity and antiprotease deficiency may have a role in increasing inflammation in bronchiectasis airways and may lead to extracellular matrix degradation and tissue damage. Imbalances in serine proteases and matrix-metallo proteinases (MMPs) have been associated to bronchiectasis. Active neutrophil elastase has been associated with disease severity and poor long-term outcomes in this disease. Moreover, high levels of MMPs have been associated with radiological and disease severity. Finally, severe deficiency of α1-antitrypsin (AAT), as PiSZ and PiZZ (proteinase inhibitor SZ and ZZ) phenotype, have been associated with bronchiectasis development. Several treatments are under study to reduce protease activity in lungs. Molecules to inhibit neutrophil elastase activity have been developed in both oral or inhaled form, along with compounds inhibiting dipeptydil-peptidase 1, enzyme responsible for the activation of serine proteases. Finally, supplementation with AAT is in use for patients with severe deficiency. The identification of different targets of therapy within the protease-antiprotease balance contributes to a precision medicine approach in bronchiectasis and eventually interrupts and disrupts the vicious vortex which characterizes the disease.

Keywords: bronchiectasis; neutrophilic inflammation; proteases.

PubMed Disclaimer

Conflict of interest statement

M.O., F.A., A.G., M.M., O.S., S.H.C., A.V. and P.M. declare no conflict of interest. F.B. reports grants and personal fees from AstraZeneca, grants from Bayer, grants and personal fees from Chiesi, grants and personal fees from GlaxoSmithKline, personal fees from Grifols, personal fees from Guidotti, personal fees from Insmed, grants and personal fees from Menarini, personal fees from Novartis, grants and personal fees from Pfizer, personal fees from Zambon, personal fees from Vertex, outside the submitted work. S.A. reports personal fees from Bayer Healthcare, personal fees from Grifols, personal fees from AstraZeneca, personal fees from Zambon, grants and personal fees from Chiesi, grants and personal fees from Insmed, personal fees from GlaxoSmithKline, personal fees from Menarini, personal fees from ZetaCube Srl, grants from Fisher & Paykel, outside the submitted work. A.D.S. reports grants, speakers fees and travel support from AstraZeneca, Bayer, Chiesi, Forest labs, GSK, Insmed, Pfizer, Medimmune, Novartis and Zambon outside the submitted work.

Figures

Figure 1
Figure 1
Mechanism of action of proteases and antiproteases, along with their potential treatments. DPP1: Dipeptidyl peptidase 1; AAT: α1 antitrypsin; TMPs: tissue inhibitors of metalloproteinases; MMPs: Matrix metalloproteinases; IL: interleukin; TNF: tumour necrosis factor.
Figure 2
Figure 2
AAT mechanism of inhibition. (A) AAT binds NE, the reactive central loop is cleaved in a high energy state followed by a change of conformation (B) and the formation of an AAT-NE complex.
Figure 3
Figure 3
Structure of DPP1 (A), brensocatib (B) and GSK2793660 (C).
See this image and copyright information in PMC

References

    1. Polverino E., Goeminne P.C., McDonnell M.J., Aliberti S., Marshall S.E., Loebinger M.R., Murris M., Cantón R., Torres A., Dimakou K., et al. European Respiratory Society guidelines for the management of adult bronchiectasis. Eur. Respir. J. 2017;50:1700629. doi: 10.1183/13993003.00629-2017. - DOI - PubMed
    1. Aliberti S., Sotgiu G., Lapi F., Gramegna A., Cricelli C., Blasi F. Prevalence and incidence of bronchiectasis in Italy. BMC Pulm. Med. 2020;20:15. doi: 10.1186/s12890-020-1050-0. - DOI - PMC - PubMed
    1. Quint J.K., Millett E.R.C., Joshi M., Navaratnam V., Thomas S.L., Hurst J.R., Smeeth L., Brown J.S. Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: A population-based cohort study. Eur. Respir. J. 2016;47:186–193. doi: 10.1183/13993003.01033-2015. - DOI - PMC - PubMed
    1. Monteagudo M., Rodríguez-Blanco T., Barrecheguren M., Simonet P., Miravitlles M. Prevalence and incidence of bronchiectasis in Catalonia, Spain: A population-based study. Respir. Med. 2016;121:26–31. doi: 10.1016/j.rmed.2016.10.014. - DOI - PubMed
    1. Lonni S., Chalmers J.D., Goeminne P.C., McDonnell M.J., Dimakou K., De Soyza A., Polverino E., Van de Kerkhove C., Rutherford R., Davison J., et al. Etiology of Non-Cystic Fibrosis Bronchiectasis in Adults and Its Correlation to Disease Severity. Ann. Am. Thorac. Soc. 2015;12:1764–1770. doi: 10.1513/AnnalsATS.201507-472OC. - DOI - PMC - PubMed

MeSH terms