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Review
. 2025 Jan 2;65(1):2401050.
doi: 10.1183/13993003.01050-2024. Print 2025 Jan.

Targeting neutrophil serine proteases in bronchiectasis

James D Chalmers  1   2 , Marcus A Mall  3   4   5   2 , Sanjay H Chotirmall  6   7 , Anne E O'Donnell  8 , Patrick A Flume  9 , Naoki Hasegawa  10 , Felix C Ringshausen  11   12   13 , Henrik Watz  14 , Jin-Fu Xu  15 , Michal Shteinberg  16   17   18 , Pamela J McShane  19   18
Affiliations
Review

Targeting neutrophil serine proteases in bronchiectasis

James D Chalmers et al. Eur Respir J. .

Abstract

Persistent neutrophilic inflammation is a central feature in both the pathogenesis and progression of bronchiectasis. Neutrophils release neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), cathepsin G and proteinase 3. When chronically high levels of free NSP activity exceed those of protective antiproteases, structural lung destruction, mucosal-related defects, further susceptibility to infection and worsening of clinical outcomes can occur. Despite the defined role of prolonged, high levels of NSPs in bronchiectasis, no drug that controls neutrophilic inflammation is licensed for the treatment of bronchiectasis. Previous methods of suppressing neutrophilic inflammation (such as direct inhibition of NE) have not been successful; however, an emerging therapy designed to address neutrophil-mediated pathology, inhibition of the cysteine protease cathepsin C (CatC, also known as dipeptidyl peptidase 1), is a promising approach to ameliorate neutrophilic inflammation, since this may reduce the activity of all NSPs implicated in bronchiectasis pathogenesis, and not just NE. Current data suggest that CatC inhibition may effectively restore the protease-antiprotease balance in bronchiectasis and improve disease outcomes as a result. Clinical trials for CatC inhibitors in bronchiectasis have reported positive phase III results. In this narrative review, we discuss the role of high NSP activity in bronchiectasis, and how this feature drives the associated morbidity and mortality seen in bronchiectasis. This review discusses therapeutic approaches aimed at treating neutrophilic inflammation in the bronchiectasis lung, summarising clinical trial outcomes and highlighting the need for more treatment strategies that effectively address chronic neutrophilic inflammation in bronchiectasis.

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Conflict of interest statement

Conflict of interest: J.D. Chalmers reports support for the present manuscript from Boehringer Ingelheim, grants or contracts from AstraZeneca, Boehringer Ingelheim, Genentech, Gilead Sciences, GlaxoSmithKline, Grifols, Insmed, Trudell and Novartis, consulting fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Grifols, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon, and is the current Chief Editor of the European Respiratory Journal. M.A. Mall reports support for the present manuscript from Boehringer Ingelheim, grants from Boehringer Ingelheim, the German Research Foundation (DFG), German Federal Ministry of Education and Research (BMBF), German Innovation Fund, and an independent medical grant from Vertex Pharmaceuticals with payments made to the institution, consultancy fees from AbbVie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Santhera, Splisense and Vertex Pharmaceuticals, personal fees for advisory board participation or consulting from AbbVie, Antabio, Arrowhead Pharmaceuticals, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Pari, Splisense and Vertex Pharmaceuticals, lecture honoraria from Vertex Pharmaceuticals, and travel support from Boehringer Ingelheim and Vertex Pharmaceuticals; M.A. Mall also reports that he is inventor on an issued patent filed by the University of North Carolina at Chapel Hill, describing the Scnn1b-transgenic mouse, and holds a leadership position as Fellow of the ERS (FERS). S.H. Chotirmall reports support for the present manuscript from Boehringer Ingelheim, grants from Singapore Ministry of Health's National Medical Research Council (Clinician Scientist Individual Research Grant (MOH-001356), Clinician Scientist Award (MOH-000710) and Open Fund Individual Research Grant (MOH-000955), and Singapore Ministry of Education under its AcRF Tier 1 Grant (RT1/22), serves on advisory boards for CSL Behring, Pneumagen Ltd and Boehringer Ingelheim, has received lecture fees from AstraZeneca and Chiesi Farmaceutici, and has served on data and safety monitoring boards for Inovio Pharmaceuticals Ltd and Imam Abdulrahman Bin Faisal University. A.E. O'Donnell reports support for the present study from Boehringer Ingelheim and Nucleus Global, grants from Boehringer Ingelheim, Insmed, Zambon, Paratek, AN2, Armata, Renovian and Spero, payment or honoraria for lectures, presentations, manuscript writing or educational events from New York University School of Medicine, Academic CME, Vinidico and Peer View Institute, and a leadership role with the US Bronchiectasis Research Registry. P.A. Flume reports support for the present study from Boehringer Ingelheim, grants or contracts from Boehringer Ingelheim, Insmed and Synchrony, consultancy fees from Insmed, and serves on advisory boards and is a site principal investigator for Insmed and Boehringer Ingelheim. N. Hasegawa reports support for the present manuscript from Boehringer Ingelheim, grants from Insmed, consulting fees from Boehringer Ingelheim and Insmed, royalties or licences from Boehringer Ingelheim, patents planned, issued or pending for Boehringer Ingelheim, and payment or honoraria for lectures from Insmed. F.C. Ringshausen reports support for the present manuscript from Boehringer Ingelheim, grants from the German Center for Lung Research (DZL), German Center for Infection Research (DZIF), IMI (EU/EFPIA) and iABC Consortium (including Alaxia, Basilea, Novartis and Polyphor), Mukoviszidose Institute, Novartis and Insmed Germany, with payments made to the institution, consulting fees from Parion Sciences, Grifols, Zambon, Insmed, Helmholtz-Zentrum für Infektionsforschung and Boehringer Ingelheim, payment or honoraria for lectures, presentations, manuscript writing or educational events from I!DE Werbeagentur GmbH, Interkongress GmbH, AstraZeneca, Insmed, Grifols and Universitätsklinikum Frankfurt am Main, payment for expert testimony from the Social Court Cologne, with payments made to the institution, support for attending meetings from Mukoviszidose eV, participation on a data and safety monitoring board or advisory board with Insmed, Grifols, Shionogi and Parion, leadership roles as PI of the German Center for Lung Research and Co-PI of the ECFS-CTN, and other financial interests from AstraZeneca, Boehringer Ingelheim, Celtaxsys, Corbus, Insmed, Novartis, Parion, University of Dundee, Vertex and Zambon, for clinical trial participation with fees paid to the institution. H. Watz reports support for the present manuscript from Boehringer Ingelheim, consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Sanofi, payment or honoraria for lectures, presentations or educational events from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Sanofi, support for attending meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Sanofi, and leadership roles as Chair, COPD guideline of the German Respiratory Society and Chair, disease area COPD of the German Center for Lung Research (DZL). J-F. Xu reports support for the present manuscript from Boehringer Ingelheim. M. Shteinberg reports support for the present manuscript from Boehringer Ingelheim, grants/research support from GlaxoSmithKline, Insmed, Novartis, Trudell Pharma and Tel Aviv League for Lung Diseases, consultation fees from AstraZeneca, Boehringer Ingelheim, Dexcel, GlaxoSmithKline, Kamada, Synchrony Medical, Trumed, Vertex and Zambon, payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Insmed, Kamada, Novartis, PhysioAssist, Sanofi and Teva, participation on a data and safety monitoring board for AstraZeneca, Boehringer Ingelheim and Bonus Biotherapeutics, support for attending meetings from AstraZeneca Israel, Novartis, Actelion, Kamada, Boehringer Ingelheim, GlaxoSmithKline and Rafa, leadership roles with AJRCCM, EMBARC, the Israel Pulmonology Society and the Israel Society for TB and Mycobacterial Diseases, is an editorial board member of ERJ and Chest, and taskforce member for ERS bronchiectasis guidelines, and receipt of equipment from Trudell Medical. P.J. McShane reports support for the present manuscript from Boehringer Ingelheim, consultancy fees from Boehringer Ingelheim, payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from from Insmed, participation on a data safety monitoring board or advisory board with Boehringer Ingelheim (AIRLEAF trial), Spero and Insmed (Aspen trial), and the following financial or non-financial interests: principal investigator for Insmed (Aspen trial), Boehringer Ingelheim (AIRLEAF), Paratek (oral omadacycline), AN2 Therapeutics (Epetraborole), Renovian (ARINA-1), Spero, Armata, Electromed and MannKind.

Figures

None
The imbalance between neutrophil serine proteases (NSPs) (neutrophil elastase (NE), proteinase 3 (PR3) and cathepsin G (CatG)) and their antiproteases, as caused by neutrophilic inflammation, can promote and maintain a pathogenic environment in the bronchiectasis lung. High NSP activity can affect multiple components of the “vicious vortex” in bronchiectasis, impairing mucociliary clearance, promoting infection and degrading functional lung tissue in the process. Sustained and unresolved, these effects are known to contribute to pulmonary exacerbations, which are critical events in bronchiectasis that are highly associated with mortality. In turn, worsened disease promotes more inflammation, forming a cycle of health deterioration with associated morbidity and mortality. Cathepsin C (CatC) inhibition may be the most appropriate intervention point in this cycle, since inhibition of CatC may suppress NSP activity, thereby suppressing the persistent neutrophilic inflammation seen in bronchiectasis.
FIGURE 1
FIGURE 1
Protease–antiprotease imbalance under instances of healthy versus diseased states. #: acute inflammation as an event can be observed during infection with a pathogen, for example. In this scenario, inflammation is swift and ensures that the threat (the pathogen, in this case) is dealt with quickly. : chronic inflammation can be a long-lasting event that arises from multiple sources, such as abnormal immune reactions to normal tissues or even unresolved infection/injury from initial acute inflammatory events. In this scenario, although the initial threat may be resolved, the inflammation persists and then causes damage to healthy surrounding tissues. ECM: extracellular matrix.
FIGURE 2
FIGURE 2
Endotypes in bronchiectasis affect treatment plans. CatC: cathepsin C; CF: cystic fibrosis; MCC: mucociliary clearance; NET: neutrophil extracellular trap; NSP: neutrophil serine protease; PCD: primary ciliary dyskinesia; Th2: T-helper 2.
FIGURE 3
FIGURE 3
The neutrophilic inflammatory environment of the bronchiectasis lung and associated clinical outcomes. CatG: cathepsin G; ECM: extracellular matrix; NE: neutrophil elastase; NSP: neutrophil serine protease; PR3: proteinase 3.
FIGURE 4
FIGURE 4
Potential therapeutic approaches to counteract neutrophilic inflammation in bronchiectasis. CatC: cathepsin C; CatG: cathepsin G; NE: neutrophil elastase; NSP: neutrophil serine protease; PR3: proteinase 3.
See this image and copyright information in PMC

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