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Role of Proteases and Associated Inhibitors in Chronic Airways Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 April 2021) | Viewed by 23274

Special Issue Editor

School of Pharmacy, Queen’s University Belfast, Belfast, UK
Interests: chronic airway diseases; proteases and their inhibitors; infection and inflammation

Special Issue Information

Dear Colleagues,

Within the airways, a protease–antiprotease imbalance plays a major role in the pathophysiology and progression of diseases such as cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis. Aberrant proteolysis, particularly associated with members of the serine, cysteine and metalloproteases families, has been implicated in the destruction of airway tissue, the inactivation of endogeneous inhibitors, cleavage of immune proteins and the activation of inflammatory mediators. Proteases are also involved in the propagation of a muco-obstructive phenotype through their role as activators of the epithelial sodium channel (ENaC), leading to defects in epithelial ion–fluid transport, resulting in airway dehydration and dysfunctional mucociliary clearance mechanisms which increase the risk of infection. More recently, host proteases have been highlighted as playing a critical role in SARS-CoV-2 infectivity. Proteases are therefore attractive targets for therapeutic intervention. Target proteases with active drug development programmes include neutrophil elastase and cathepsin C (dipeptidyl peptidase I).

Authors are invited to submit original research and review articles which address the progress and current understanding of the proteolytic environment of the airways, how aberrant proteolysis contributes to disease pathophysiology or how advances in the field may aid the identification of novel biomarkers and patient stratification, therapeutic targets or the development of targeted therapies.

Topics include but are not limited to:

  • Protease–antiprotease imbalance in chronic airway diseases including but not limited to cystic fibrosis, COPD, bronchiectasis and COVID-19;
  • The role of host and potentially viral or bacterial proteases in pathways related to airway infection and inflammation;
  • Proteases involved in airways hydration and mucociliary clearance mechanisms, i.e., channel-activating proteases (CAPs) of the epithelial sodium channel (ENaC);
  • Proteases as therapeutic targets for chronic airway diseases, including COVID-19;
  • Protease and/or protease inhibitors as novel biomarkers of airway disease to aid patient stratification and/or disease management;
  • Report of novel protease inhibitors as potential candidates for drug development and/or research tools.

Prof. S. Lorraine Martin
Guest Editor

Manuscript Submission Information

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Keywords

  • Proteases
  • Protease inhibitors
  • Cystic fibrosis
  • Chronic obstructive airways disease
  • Bronchiectasis
  • COVID-19

Published Papers (6 papers)

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Research

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13 pages, 4102 KiB  
Article
Genetic Deletion of Mmp9 Does Not Reduce Airway Inflammation and Structural Lung Damage in Mice with Cystic Fibrosis-like Lung Disease
by Claudius Wagner, Anita Balázs, Jolanthe Schatterny, Zhe Zhou-Suckow, Julia Duerr, Carsten Schultz and Marcus A. Mall
Int. J. Mol. Sci. 2022, 23(21), 13405; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113405 - 02 Nov 2022
Cited by 3 | Viewed by 1554
Abstract
Elevated levels of matrix metalloprotease 9 (MMP-9) and neutrophil elastase (NE) are associated with bronchiectasis and lung function decline in patients with cystic fibrosis (CF). MMP-9 is a potent extracellular matrix-degrading enzyme which is activated by NE and has been implicated in structural [...] Read more.
Elevated levels of matrix metalloprotease 9 (MMP-9) and neutrophil elastase (NE) are associated with bronchiectasis and lung function decline in patients with cystic fibrosis (CF). MMP-9 is a potent extracellular matrix-degrading enzyme which is activated by NE and has been implicated in structural lung damage in CF. However, the role of MMP-9 in the in vivo pathogenesis of CF lung disease is not well understood. Therefore, we used β-epithelial Na+ channel-overexpressing transgenic (βENaC-Tg) mice as a model of CF-like lung disease and determined the effect of genetic deletion of Mmp9 (Mmp9-/-) on key aspects of the pulmonary phenotype. We found that MMP-9 levels were elevated in the lungs of βENaC-Tg mice compared with wild-type littermates. Deletion of Mmp9 had no effect on spontaneous mortality, inflammatory markers in bronchoalveolar lavage, goblet cell metaplasia, mucus hypersecretion and emphysema-like structural lung damage, while it partially reduced mucus obstruction in βENaC-Tg mice. Further, lack of Mmp9 had no effect on increased inspiratory capacity and increased lung compliance in βENaC-Tg mice, whereas both lung function parameters were improved with genetic deletion of NE. We conclude that MMP-9 does not play a major role in the in vivo pathogenesis of CF-like lung disease in mice. Full article
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13 pages, 2076 KiB  
Article
The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients
by Iris G. M. Schouten, Richard A. Mumford, Dirk Jan A. R. Moes, Pieter S. Hiemstra and Jan Stolk
Int. J. Mol. Sci. 2021, 22(15), 8031; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158031 - 27 Jul 2021
Cited by 1 | Viewed by 1749
Abstract
In alpha-1-antitrypsin deficiency (AATD), neutrophil serine proteases such as elastase and proteinase 3 (PR3) are insufficiently inhibited. A previous study in AATD patients showed a higher plasma level of the specific PR3-generated fibrinogen-derived peptide AαVal541, compared with healthy controls. Here, we analyzed the [...] Read more.
In alpha-1-antitrypsin deficiency (AATD), neutrophil serine proteases such as elastase and proteinase 3 (PR3) are insufficiently inhibited. A previous study in AATD patients showed a higher plasma level of the specific PR3-generated fibrinogen-derived peptide AαVal541, compared with healthy controls. Here, we analyzed the course of AαVal541 plasma levels during 4 weeks after a single iv dose of 240 mg/kg AAT in ten patients with genotype Z/Rare or Rare/Rare. To this end, we developed an immunoassay to measure AαVal541 in plasma and applied population pharmacokinetic modeling for AAT. The median AαVal541 plasma level before treatment was 140.2 nM (IQR 51.5–234.8 nM)). In five patients who received AAT for the first time, AαVal541 levels decreased to 20.6 nM (IQR 5.8–88.9 nM), and in five patients who already had received multiple infusions before, it decreased to 26.2 nM (IQR 22.31–35.0 nM). In 9 of 10 patients, AαVal541 levels were reduced to the median level of healthy controls (21.4 nM; IQR 16.7–30.1 nM). At 7–14 days after treatment, AαVal541 levels started to increase again in all patients. Our results show that fibrinopeptide AαVal541 may serve as a biochemical footprint to assess the efficacy of in vivo inhibition of PR3 activity in patients receiving intravenous AAT augmentation therapy. Full article
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Review

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22 pages, 21141 KiB  
Review
The Serpin Superfamily and Their Role in the Regulation and Dysfunction of Serine Protease Activity in COPD and Other Chronic Lung Diseases
by Gillian A. Kelly-Robinson, James A. Reihill, Fionnuala T. Lundy, Lorcan P. McGarvey, John C. Lockhart, Gary J. Litherland, Keith D. Thornbury and S. Lorraine Martin
Int. J. Mol. Sci. 2021, 22(12), 6351; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126351 - 14 Jun 2021
Cited by 31 | Viewed by 5327
Abstract
Chronic obstructive pulmonary disease (COPD) is a debilitating heterogeneous disease characterised by unregulated proteolytic destruction of lung tissue mediated via a protease-antiprotease imbalance. In COPD, the relationship between the neutrophil serine protease, neutrophil elastase, and its endogenous inhibitor, alpha-1-antitrypsin (AAT) is the best [...] Read more.
Chronic obstructive pulmonary disease (COPD) is a debilitating heterogeneous disease characterised by unregulated proteolytic destruction of lung tissue mediated via a protease-antiprotease imbalance. In COPD, the relationship between the neutrophil serine protease, neutrophil elastase, and its endogenous inhibitor, alpha-1-antitrypsin (AAT) is the best characterised. AAT belongs to a superfamily of serine protease inhibitors known as serpins. Advances in screening technologies have, however, resulted in many members of the serpin superfamily being identified as having differential expression across a multitude of chronic lung diseases compared to healthy individuals. Serpins exhibit a unique suicide-substrate mechanism of inhibition during which they undergo a dramatic conformational change to a more stable form. A limitation is that this also renders them susceptible to disease-causing mutations. Identification of the extent of their physiological/pathological role in the airways would allow further expansion of knowledge regarding the complexity of protease regulation in the lung and may provide wider opportunity for their use as therapeutics to aid the management of COPD and other chronic airways diseases. Full article
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15 pages, 1146 KiB  
Review
Protease–Antiprotease Imbalance in Bronchiectasis
by Martina Oriano, Francesco Amati, Andrea Gramegna, Anthony De Soyza, Marco Mantero, Oriol Sibila, Sanjay H. Chotirmall, Antonio Voza, Paola Marchisio, Francesco Blasi and Stefano Aliberti
Int. J. Mol. Sci. 2021, 22(11), 5996; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115996 - 01 Jun 2021
Cited by 16 | Viewed by 4759
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 [...] Read more.
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. Full article
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22 pages, 1879 KiB  
Review
Trypsin-Like Proteases and Their Role in Muco-Obstructive Lung Diseases
by Emma L. Carroll, Mariarca Bailo, James A. Reihill, Anne Crilly, John C. Lockhart, Gary J. Litherland, Fionnuala T. Lundy, Lorcan P. McGarvey, Mark A. Hollywood and S. Lorraine Martin
Int. J. Mol. Sci. 2021, 22(11), 5817; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115817 - 29 May 2021
Cited by 12 | Viewed by 4812
Abstract
Trypsin-like proteases (TLPs) belong to a family of serine enzymes with primary substrate specificities for the basic residues, lysine and arginine, in the P1 position. Whilst initially perceived as soluble enzymes that are extracellularly secreted, a number of novel TLPs that are anchored [...] Read more.
Trypsin-like proteases (TLPs) belong to a family of serine enzymes with primary substrate specificities for the basic residues, lysine and arginine, in the P1 position. Whilst initially perceived as soluble enzymes that are extracellularly secreted, a number of novel TLPs that are anchored in the cell membrane have since been discovered. Muco-obstructive lung diseases (MucOLDs) are characterised by the accumulation of hyper-concentrated mucus in the small airways, leading to persistent inflammation, infection and dysregulated protease activity. Although neutrophilic serine proteases, particularly neutrophil elastase, have been implicated in the propagation of inflammation and local tissue destruction, it is likely that the serine TLPs also contribute to various disease-relevant processes given the roles that a number of these enzymes play in the activation of both the epithelial sodium channel (ENaC) and protease-activated receptor 2 (PAR2). More recently, significant attention has focused on the activation of viruses such as SARS-CoV-2 by host TLPs. The purpose of this review was to highlight key TLPs linked to the activation of ENaC and PAR2 and their association with airway dehydration and inflammatory signalling pathways, respectively. The role of TLPs in viral infectivity will also be discussed in the context of the inhibition of TLP activities and the potential of these proteases as therapeutic targets. Full article
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21 pages, 700 KiB  
Review
Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease
by Michael C. McKelvey, Ryan Brown, Sinéad Ryan, Marcus A. Mall, Sinéad Weldon and Clifford C. Taggart
Int. J. Mol. Sci. 2021, 22(9), 5018; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22095018 - 09 May 2021
Cited by 15 | Viewed by 4229
Abstract
Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in [...] Read more.
Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in various aspects of such diseases continues to grow. Patients with muco-obstructive lung disease experience progressive spirals of inflammation, mucostasis, airway infection and lung function decline. Some therapies exist for the treatment of these symptoms, but they are unable to halt disease progression and patients may benefit from novel adjunct therapies. In this review, we highlight how proteases act as multifunctional enzymes that are vital for normal airway homeostasis but, when their activity becomes immoderate, also directly contribute to airway dysfunction, and impair the processes that could resolve disease. We focus on how proteases regulate the state of mucus at the airway surface, impair mucociliary clearance and ultimately, promote mucostasis. We discuss how, in parallel, proteases are able to promote an inflammatory environment in the airways by mediating proinflammatory signalling, compromising host defence mechanisms and perpetuating their own proteolytic activity causing structural lung damage. Finally, we discuss some possible reasons for the clinical inefficacy of protease inhibitors to date and propose that, especially in a combination therapy approach, proteases represent attractive therapeutic targets for muco-obstructive lung diseases. Full article
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