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      Proteases and Their Inhibitors in Chronic Obstructive Pulmonary Disease

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          Abstract

          In the context of respiratory disease, chronic obstructive pulmonary disease (COPD) is the leading cause of mortality worldwide. Despite much development in the area of drug development, currently there are no effective medicines available for the treatment of this disease. An imbalance in the protease: Antiprotease ratio in the COPD lung remains an important aspect of COPD pathophysiology and several studies have shown the efficacy of antiprotease therapy in both in vitro and in vivo COPD models. However more in-depth studies will be required to validate the efficacy of lead drug molecules targeting these proteases. This review discusses the current status of protease-directed drugs used for treating COPD and explores the future prospects of utilizing the potential of antiprotease-based therapeutics as a treatment for this disease.

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          Neutrophil serine proteases: specific regulators of inflammation.

          Christine Pham (2006)
          Neutrophils are essential for host defence against invading pathogens. They engulf and degrade microorganisms using an array of weapons that include reactive oxygen species, antimicrobial peptides, and proteases such as cathepsin G, neutrophil elastase and proteinase 3. As discussed in this Review, the generation of mice deficient in these proteases has established a role for these enzymes as intracellular microbicidal agents. However, I focus mainly on emerging data indicating that, after release, these proteases also contribute to the extracellular killing of microorganisms, and regulate non-infectious inflammatory processes by activating specific receptors and modulating the levels of cytokines.
          Article 0 comments Cited 294 times – based on 0 reviews     Review now
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            Chronic obstructive pulmonary disease: molecular and cellular mechanisms.

            P Barnes, S Shapiro, R A Pauwels (2003)
            Chronic obstructive pulmonary disease is a leading cause of death and disability, but has only recently been extensively explored from a cellular and molecular perspective. There is a chronic inflammation that leads to fixed narrowing of small airways and alveolar wall destruction (emphysema). This is characterised by increased numbers of alveolar macrophages, neutrophils and cytotoxic T-lymphocytes, and the release of multiple inflammatory mediators (lipids, chemokines, cytokines, growth factors). A high level of oxidative stress may amplify this inflammation. There is also increased elastolysis and evidence for involvement of several elastolytic enzymes, including serine proteases, cathepsins and matrix metalloproteinases. The inflammation and proteolysis in chronic obstructive pulmonary disease is an amplification of the normal inflammatory response to cigarette smoke. This inflammation, in marked contrast to asthma, appears to be resistant to corticosteroids, prompting a search for novel anti-inflammatory therapies that may prevent the relentless progression of the disease.
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              Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3.

              O Sørensen, P Follin, A H Johnsen … (2001)
              Cathelicidins are a family of antimicrobial proteins found in the peroxidase-negative granules of neutrophils. The known biologic functions reside in the C-terminus, which must be cleaved from the holoprotein to become active. Bovine and porcine cathelicidins are cleaved by elastase from the azurophil granules to yield the active antimicrobial peptides. The aim of this study was to identify the physiological setting for cleavage of the only human cathelicidin, hCAP-18, to liberate the antibacterial and cytotoxic peptide LL-37 and to identify the protease responsible for this cleavage. Immunoelectron microscopy demonstrated that both hCAP-18 and azurophil granule proteins were present in the phagolysosome. Immunoblotting revealed no detectable cleavage of hCAP-18 in cells after phagocytosis. In contrast, hCAP-18 was cleaved to generate LL-37 in exocytosed material. Of the 3 known serine proteases from azurophil granules, proteinase 3 was solely responsible for cleavage of hCAP-18 after exocytosis. This is the first detailed study describing the generation of a human antimicrobial peptide from a promicrobicidal protein, and it demonstrates that the generation of active antimicrobial peptides from common proproteins occurs differently in related species. (Blood. 2001;97:3951-3959)
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Clin Med
                Journal ID (iso-abbrev): J Clin Med
                Journal ID (publisher-id): jcm
                Title: Journal of Clinical Medicine
                Publisher: MDPI
                ISSN (Electronic): 2077-0383
                Publication date (Electronic): 28 August 2018
                Publication date Collection: September 2018
                Volume: 7
                Issue: 9
                Electronic Location Identifier: 244
                Affiliations
                [1 ]Biological Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam, India; rs_tapandey@ 123456dibru.ac.in (T.D.); kalitajk74@ 123456gmail.com (J.K.)
                [2 ]Centre for Biotechnology and Bioinformatics, Dibrugarh University, Dibrugarh 786004, Assam, India
                [3 ]Airway Innate Immunity Research Group, Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, Northern Ireland BT9 7BL, UK; s.weldon@ 123456qub.ac.uk
                Author notes
                [* ]Correspondence: c.taggart@ 123456qub.ac.uk ; Tel.: +44-28-9024-5133
                Author information
                https://orcid.org/0000-0003-3497-8624
                https://orcid.org/0000-0001-5628-6624
                Article
                Publisher ID: jcm-07-00244
                DOI: 10.3390/jcm7090244
                PMC ID: 6162857
                PubMed ID: 30154365
                SO-VID: 25da1816-e392-4cfe-ba5e-44f3095073ca
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 30 July 2018
                Date accepted : 25 August 2018
                Categories
                Subject: Review

                Keywords: chronic obstructive pulmonary disease,protease,antiprotease
                Data availability:
                Keywords: chronic obstructive pulmonary disease, protease, antiprotease

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