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New Pathogenic Mechanism of Proteases in Inflammatory Lung Diseases
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New Pathogenic Mechanism of Proteases in Inflammatory Lung 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 (30 December 2023) | Viewed by 5927

Special Issue Editor

Dr. Xin Xu

E-Mail Website
Guest Editor
Division of Pulmonary, Allergy, and Critical Care Medicine UAB, Program in Protease and Matrix Biology, The University of Alabama at Birmingham, 845 19th Street South, Birmingham, AL 35205, USA
Interests: protease; matrikin; neutrophil; epithelial cell; tissue remodeling in inflammatory lung diseases; COPD; cystic fibrosis; acute respiratory distress syndrome; autoimmune disease

Special Issue Information

Dear Colleagues, 

Proteases are involved in respiratory homeostasis. The expression of proteases and their inhibitors play an important role in various lung diseases, such as pulmonary emphysema, chronic bronchitis, cystic fibrosis, asthma, acute respiratory distress syndrome, and infectious diseases. Studies suggest that specific inhibitors against these enzymes have a potential role to be disease-modifying. This Special Issue will focus on the pathophysiological mechanisms and clinical implications of airway proteases in inflammatory lung disease, both chronic and acute. The elucidation of these pathways may provide novel biomarkers and therapeutic targets for lung diseases.

We would like to extend our sincerest gratitude to Prof. Dr. Kristopher Ruben Genschmer from the University of Alabama at Birmingham for his contribution in editing this Special Issue.

Dr. Xin Xu
Guest Editor

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Keywords

  • protease
  • antiprotease
  • matrikine
  • extracellular matrix (ECM)
  • tissue remodeling
  • tissue degradation
  • cellular signaling
  • extracellular vesicles (EV)
  • inflammatory lung diseases
  • COPD
  • cystic fibrosis
  • asthma
  • idiopathic pulmonary fibrosis (IPF)
  • acute respiratory distress syndrome

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Published Papers (4 papers)

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Research

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13 pages, 3839 KiB  
Article
Neutrophil Elastase Degrades Histone Deacetylases and Sirtuin 1 in Primary Human Monocyte Derived Macrophages
by Shuo Zheng, Gamze B. Bulut, Apparao B. Kummarapurugu, Jonathan Ma and Judith A. Voynow
Int. J. Mol. Sci. 2024, 25(8), 4265; https://doi.org/10.3390/ijms25084265 - 12 Apr 2024
Cited by 2 | Viewed by 1049
Abstract
Neutrophil elastase (NE) is taken up by macrophages, retains intracellular protease activity, and induces a pro-inflammatory phenotype. However, the mechanism of NE-induced pro-inflammatory polarization of macrophages is not well understood. We hypothesized that intracellular NE degrades histone deacetylases (HDAC) and Sirtuins, disrupting the [...] Read more.
Neutrophil elastase (NE) is taken up by macrophages, retains intracellular protease activity, and induces a pro-inflammatory phenotype. However, the mechanism of NE-induced pro-inflammatory polarization of macrophages is not well understood. We hypothesized that intracellular NE degrades histone deacetylases (HDAC) and Sirtuins, disrupting the balance of lysine acetylation and deacetylation and resulting in nuclear to cytoplasmic translocation of a major alarmin, High Mobility Group Box 1 (HMGB1), a pro-inflammatory response in macrophages. Human blood monocytes were obtained from healthy donors or from subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Monocytes were differentiated into blood monocyte derived macrophages (BMDMs) in vitro. Human BMDMs were exposed to NE or control vehicle, and the abundance of HDACs and Sirtuins was determined by Western blotting of total cell lysates or nuclear extracts or determined by ELISA. HDAC, Sirtuin, and Histone acetyltransferase (HAT) activities were measured. NE degraded most HDACs and Sirtuin (Sirt)1, resulting in decreased HDAC and sirtuin activities, with minimal change in HAT activity. We then evaluated whether the NE-induced loss of Sirt activity or loss of HDAC activities would alter the cellular localization of HMGB1. NE treatment or treatment with Trichostatin A (TSA), a global HDAC inhibitor, both increased HMGB1 translocation from the nucleus to the cytoplasm, consistent with HMGB1 activation. NE significantly degraded Class I and II HDAC family members and Sirt 1, which shifted BMDMs to a pro-inflammatory phenotype. Full article
(This article belongs to the Special Issue New Pathogenic Mechanism of Proteases in Inflammatory Lung Diseases)
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19 pages, 3741 KiB  
Article
Could the Oxidation of α1-Antitrypsin Prevent the Binding of Human Neutrophil Elastase in COVID-19 Patients?
by Maura D’Amato, Monica Campagnoli, Paolo Iadarola, Paola Margherita Bignami, Marco Fumagalli, Laurent Roberto Chiarelli, Giovanni Stelitano, Federica Meloni, Pasquale Linciano, Simona Collina, Giampiero Pietrocola, Valentina Vertui, Anna Aliberti, Tommaso Fossali and Simona Viglio
Int. J. Mol. Sci. 2023, 24(17), 13533; https://doi.org/10.3390/ijms241713533 - 31 Aug 2023
Viewed by 1126
Abstract
Human neutrophil elastase (HNE) is involved in SARS-CoV-2 virulence and plays a pivotal role in lung infection of patients infected by COVID-19. In healthy individuals, HNE activity is balanced by α1-antitrypsin (AAT). This is a 52 kDa glycoprotein, mainly produced and secreted by [...] Read more.
Human neutrophil elastase (HNE) is involved in SARS-CoV-2 virulence and plays a pivotal role in lung infection of patients infected by COVID-19. In healthy individuals, HNE activity is balanced by α1-antitrypsin (AAT). This is a 52 kDa glycoprotein, mainly produced and secreted by hepatocytes, that specifically inhibits HNE by blocking its activity through the formation of a stable complex (HNE–AAT) in which the two proteins are covalently bound. The lack of this complex, together with the detection of HNE activity in BALf/plasma samples of COVID-19 patients, leads us to hypothesize that potential functional deficiencies should necessarily be attributed to possible structural modifications of AAT. These could greatly diminish its ability to inhibit neutrophil elastase, thus reducing lung protection. The aim of this work was to explore the oxidation state of AAT in BALf/plasma samples from these patients so as to understand whether the deficient inhibitory activity of AAT was somehow related to possible conformational changes caused by the presence of abnormally oxidized residues. Full article
(This article belongs to the Special Issue New Pathogenic Mechanism of Proteases in Inflammatory Lung Diseases)
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Review

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23 pages, 692 KiB  
Review
Neutrophil-Derived Proteases in Lung Inflammation: Old Players and New Prospects
by Coby J. Cheetham, Michael C. McKelvey, Daniel F. McAuley and Clifford C. Taggart
Int. J. Mol. Sci. 2024, 25(10), 5492; https://doi.org/10.3390/ijms25105492 - 17 May 2024
Cited by 1 | Viewed by 1510
Abstract
Neutrophil-derived proteases are critical to the pathology of many inflammatory lung diseases, both chronic and acute. These abundant enzymes play roles in key neutrophil functions, such as neutrophil extracellular trap formation and reactive oxygen species release. They may also be released, inducing tissue [...] Read more.
Neutrophil-derived proteases are critical to the pathology of many inflammatory lung diseases, both chronic and acute. These abundant enzymes play roles in key neutrophil functions, such as neutrophil extracellular trap formation and reactive oxygen species release. They may also be released, inducing tissue damage and loss of tissue function. Historically, the neutrophil serine proteases (NSPs) have been the main subject of neutrophil protease research. Despite highly promising cell-based and animal model work, clinical trials involving the inhibition of NSPs have shown mixed results in lung disease patients. As such, the cutting edge of neutrophil-derived protease research has shifted to proteases that have had little-to-no research in neutrophils to date. These include the cysteine and serine cathepsins, the metzincins and the calpains, among others. This review aims to outline the previous work carried out on NSPs, including the shortcomings of some of the inhibitor-orientated clinical trials. Our growing understanding of other proteases involved in neutrophil function and neutrophilic lung inflammation will then be discussed. Additionally, the potential of targeting these more obscure neutrophil proteases will be highlighted, as they may represent new targets for inhibitor-based treatments of neutrophil-mediated lung inflammation. Full article
(This article belongs to the Special Issue New Pathogenic Mechanism of Proteases in Inflammatory Lung Diseases)
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13 pages, 1488 KiB  
Review
Eosinophilic Chronic Rhinosinusitis and Pathogenic Role of Protease
by Jaehyeong Kim, Sooun Kwak, Juhyun Lee, Il-Ho Park, Seung Hoon Lee, Jae Min Shin and Tae Hoon Kim
Int. J. Mol. Sci. 2023, 24(24), 17372; https://doi.org/10.3390/ijms242417372 - 12 Dec 2023
Cited by 1 | Viewed by 1612
Abstract
Chronic rhinosinusitis (CRS) is an inflammation of the nasal and paranasal sinus mucosa, and eosinophilic CRS (eCRS) is a subtype characterized by significant eosinophil infiltration and immune response by T-helper-2 cells. The pathogenesis of eCRS is heterogeneous and involves various environmental and host [...] Read more.
Chronic rhinosinusitis (CRS) is an inflammation of the nasal and paranasal sinus mucosa, and eosinophilic CRS (eCRS) is a subtype characterized by significant eosinophil infiltration and immune response by T-helper-2 cells. The pathogenesis of eCRS is heterogeneous and involves various environmental and host factors. Proteases from external sources, such as mites, fungi, and bacteria, have been implicated in inducing type 2 inflammatory reactions. The balance between these proteases and endogenous protease inhibitors (EPIs) is considered important, and their imbalance can potentially lead to type 2 inflammatory reactions, such as eCRS. In this review, we discuss various mechanisms by which exogenous proteases influence eCRS and highlight the emerging role of endogenous protease inhibitors in eCRS pathogenesis. Full article
(This article belongs to the Special Issue New Pathogenic Mechanism of Proteases in Inflammatory Lung Diseases)
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