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Review ArticleReview Article

Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases

Brice Korkmaz, Marshall S. Horwitz, Dieter E. Jenne and Francis Gauthier
David Sibley, ASSOCIATE EDITOR
Pharmacological Reviews December 2010, 62 (4) 726-759; DOI: https://doi.org/10.1124/pr.110.002733
Brice Korkmaz
Institut National de la Santé et de la Recherche Médicale U-618 “Protéases et Vectorisation Pulmonaires,” Tours, France (B.K., F.G.); Université François Rabelais, Tours, France (B.K., F.G.); Department of Pathology, University of Washington, Seattle, Washington (M.S.H.); and Max-Planck Institute of Neurobiology, Martinsried, Germany (D.E.J.)
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Marshall S. Horwitz
Institut National de la Santé et de la Recherche Médicale U-618 “Protéases et Vectorisation Pulmonaires,” Tours, France (B.K., F.G.); Université François Rabelais, Tours, France (B.K., F.G.); Department of Pathology, University of Washington, Seattle, Washington (M.S.H.); and Max-Planck Institute of Neurobiology, Martinsried, Germany (D.E.J.)
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Dieter E. Jenne
Institut National de la Santé et de la Recherche Médicale U-618 “Protéases et Vectorisation Pulmonaires,” Tours, France (B.K., F.G.); Université François Rabelais, Tours, France (B.K., F.G.); Department of Pathology, University of Washington, Seattle, Washington (M.S.H.); and Max-Planck Institute of Neurobiology, Martinsried, Germany (D.E.J.)
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Francis Gauthier
Institut National de la Santé et de la Recherche Médicale U-618 “Protéases et Vectorisation Pulmonaires,” Tours, France (B.K., F.G.); Université François Rabelais, Tours, France (B.K., F.G.); Department of Pathology, University of Washington, Seattle, Washington (M.S.H.); and Max-Planck Institute of Neurobiology, Martinsried, Germany (D.E.J.)
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David Sibley
Institut National de la Santé et de la Recherche Médicale U-618 “Protéases et Vectorisation Pulmonaires,” Tours, France (B.K., F.G.); Université François Rabelais, Tours, France (B.K., F.G.); Department of Pathology, University of Washington, Seattle, Washington (M.S.H.); and Max-Planck Institute of Neurobiology, Martinsried, Germany (D.E.J.)
Roles: ASSOCIATE EDITOR
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Abstract

Polymorphonuclear neutrophils are the first cells recruited to inflammatory sites and form the earliest line of defense against invading microorganisms. Neutrophil elastase, proteinase 3, and cathepsin G are three hematopoietic serine proteases stored in large quantities in neutrophil cytoplasmic azurophilic granules. They act in combination with reactive oxygen species to help degrade engulfed microorganisms inside phagolysosomes. These proteases are also externalized in an active form during neutrophil activation at inflammatory sites, thus contributing to the regulation of inflammatory and immune responses. As multifunctional proteases, they also play a regulatory role in noninfectious inflammatory diseases. Mutations in the ELA2/ELANE gene, encoding neutrophil elastase, are the cause of human congenital neutropenia. Neutrophil membrane-bound proteinase 3 serves as an autoantigen in Wegener granulomatosis, a systemic autoimmune vasculitis. All three proteases are affected by mutations of the gene (CTSC) encoding dipeptidyl peptidase I, a protease required for activation of their proform before storage in cytoplasmic granules. Mutations of CTSC cause Papillon-Lefèvre syndrome. Because of their roles in host defense and disease, elastase, proteinase 3, and cathepsin G are of interest as potential therapeutic targets. In this review, we describe the physicochemical functions of these proteases, toward a goal of better delineating their role in human diseases and identifying new therapeutic strategies based on the modulation of their bioavailability and activity. We also describe how nonhuman primate experimental models could assist with testing the efficacy of proposed therapeutic strategies.

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  • This article is available online at http://pharmrev.aspetjournals.org.

    doi:10.1124/pr.110.002733.

  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 62 (4)
Pharmacological Reviews
Vol. 62, Issue 4
1 Dec 2010
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Review ArticleReview Article

Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases

Brice Korkmaz, Marshall S. Horwitz, Dieter E. Jenne and Francis Gauthier
Pharmacological Reviews December 1, 2010, 62 (4) 726-759; DOI: https://doi.org/10.1124/pr.110.002733

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Review ArticleReview Article

Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases

Brice Korkmaz, Marshall S. Horwitz, Dieter E. Jenne and Francis Gauthier
Pharmacological Reviews December 1, 2010, 62 (4) 726-759; DOI: https://doi.org/10.1124/pr.110.002733
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  • Article
    • Abstract
    • I. Introduction
    • II. Neutrophil Elastase, Proteinase 3, and Cathepsin G
    • III. Biological Functions of Elastase, Proteinase 3, and Cathepsin G
    • IV. Physiological Inhibitors of Elastase, Proteinase 3, and Cathepsin G
    • V. Pathophysiology of Elastase, Proteinase 3 and Cathepsin G in Human Diseases
    • VI. New Strategies for Fighting Neutrophil Serine Protease-Related Human Diseases
    • VII. Concluding Remarks
    • Acknowledgments.
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