scholarly journals Inhibitors of Serine Proteases as Potential Therapeutic Agents:  The Road from Thrombin to Tryptase to Cathepsin G.

2004 ◽  
Vol 47 (10) ◽  
pp. 2716-2716 ◽  
Author(s):  
Bruce E. Maryanoff
Keyword(s):  
Serine Proteases ◽  
Therapeutic Agents ◽  
Cathepsin G ◽  
The Road

SLPI and trappin-2 as therapeutic agents to target airway serine proteases in inflammatory lung diseases: current and future directions

2011 ◽  
Vol 39 (5) ◽  
pp. 1441-1446 ◽  
Author(s):  
Marie-Louise Zani ◽  
Annabelle Tanga ◽  
Ahlame Saidi ◽  
Hélène Serrano ◽  
Sandrine Dallet-Choisy ◽  
...  
Keyword(s):  
Serine Proteases ◽  
Lung Diseases ◽  
Therapeutic Potential ◽  
Therapeutic Agents ◽  
Cathepsin G ◽  
Chronic Obstructive ◽  
Inhaled Drugs ◽  
Future Directions ◽  
Obstructive Pulmonary Disease ◽  
Chronic Lung Diseases

It is now clear that NSPs (neutrophil serine proteases), including elastase, Pr3 (proteinase 3) and CatG (cathepsin G) are major pathogenic determinants in chronic inflammatory disorders of the lungs. Two unglycosylated natural protease inhibitors, SLPI (secretory leucocyte protease inhibitor) and elafin, and its precursor trappin-2 that are found in the lungs, have therapeutic potential for reducing the protease-induced inflammatory response. This review examines the multifaceted roles of SLPI and elafin/trappin-2 in the context of their possible use as inhaled drugs for treating chronic lung diseases such as CF (cystic fibrosis) and COPD (chronic obstructive pulmonary disease).

scholarly journals The Evolutionary History of the Chymase Locus -a Locus Encoding Several of the Major Hematopoietic Serine Proteases

2021 ◽  
Vol 22 (20) ◽  
pp. 10975
Author(s):  
Srinivas Akula ◽  
Zhirong Fu ◽  
Sara Wernersson ◽  
Lars Hellman
Keyword(s):  
Mast Cell ◽  
T Cell ◽  
Serine Proteases ◽  
Phylogenetic Trees ◽  
Granzyme B ◽  
Large Family ◽  
Cathepsin G ◽  
Immune Functions ◽  
New Class ◽  
History Of

Several hematopoietic cells of the immune system store large amounts of proteases in cytoplasmic granules. The absolute majority of these proteases belong to the large family of chymotrypsin-related serine proteases. The chymase locus is one of four loci encoding these granule-associated serine proteases in mammals. The chymase locus encodes only four genes in primates, (1) the gene for a mast-cell-specific chymotryptic enzyme, the chymase; (2) a T-cell-expressed asp-ase, granzyme B; (3) a neutrophil-expressed chymotryptic enzyme, cathepsin G; and (4) a T-cell-expressed chymotryptic enzyme named granzyme H. Interestingly, this locus has experienced a number of quite dramatic expansions during mammalian evolution. This is illustrated by the very large number of functional protease genes found in the chymase locus of mice (15 genes) and rats (18 genes). A separate expansion has also occurred in ruminants, where we find a new class of protease genes, the duodenases, which are expressed in the intestinal region. In contrast, the opossum has only two functional genes in this locus, the mast cell (MC) chymase and granzyme B. This low number of genes may be the result of an inversion, which may have hindered unequal crossing over, a mechanism which may have been a major factor in the expansion within the rodent lineage. The chymase locus can be traced back to early tetrapods as genes that cluster with the mammalian genes in phylogenetic trees can be found in frogs, alligators and turtles, but appear to have been lost in birds. We here present the collected data concerning the evolution of this rapidly evolving locus, and how these changes in gene numbers and specificities may have affected the immune functions in the various tetrapod species.

Hemopoietic Progenitor Cells from the Bone Marrow of Serpinb3A-/- Mice Are Radioresistant

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2680-2680
Author(s):  
Stephanie Thermozier ◽  
Michael W. Epperly ◽  
Darcy Franicola ◽  
Xichen Zhang ◽  
Renee Fisher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Survival ◽  
Progenitor Cells ◽  
Serine Proteases ◽  
Cathepsin G ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
University Of Pittsburgh ◽  
Significant Difference ◽  
The University

Abstract Introduction: Serpins are a superfamily of serine proteases that regulate proteolytic pathways by utilizing a conformational change to bind to and inhibit multiple peptidases. Currently 36 human serpins have been identified, but the roles of most are not fully understood (Silverman et al., J Biol Chem. 285(32):24299-305, 2010). A majority of serpins inhibit serine proteases but serpins that inhibit lysosomal cytosine peptidases, granzymes, serine protease and calpains. Previous studies have shown that serpins play a critical role in cell survival by blocking lysosomal induced necrosis injury. Serpinb3A (Antichymotrypsin) has been identified as an inhibitor of the serine peptidases, chymotrypsin and cathepsin G. We now report that hematopoietic progenitor cells in the bone marrow of Serpinb3A-/- mice are radioresistant. Materials & Methods: Serpinb3A-/- and control Balb/c mice were obtained from Charles River and were housed five per cage according to University of Pittsburgh Institutional Animal Care and Use Committee (IACUC) regulations. All protocols were approved by the University of Pittsburgh IACUC. Veterinary care was provided by the Division of Laboratory Animal Research of the University of Pittsburgh. Whole bone marrow was obtained by flushing the marrow from the femurs of sacrificed Serpinb3A-/- and Balb/c mice. Single cell suspensions were irradiated to doses ranging from 0 to 8 Gy using a at 70 cGy/min using a Shepherd Mark 1 137Cs γ-ray source (J.L. Shepherd, San Fernando, CA, USA). The cells were plated in 0.8% methylcellulose containing hematopoietic growth supportive medium (StemCell Technology product #3134) at varying densities in quadruplicate in Linbro plates (Fisher Scientific, Pittsburgh, PA, USA) and incubated at 37°C and 5% CO2 for 9-11 days at which time the number of colony forming unit granulocyte-macrophage (CFU-GM) colonies of 50 cells or greater were counted. The data from 5 experiments was analyzed using linear quadratic and single-hit, multi-target models. Results: CFU-GM from Serpinb3A-/- mouse marrow showed an increase in radiation resistance with an increase in the shoulder of the irradiation survival curve compared to Balb/c marrow (ň = 4.9 ± 1.4 and 1.4 ± 0.1, p = 0.0451, respectively). There was no significant difference in the Do for CFU-GM of the two mouse strains (Do = 1.48 ± 0.19 Gy for Serapinb3A-/- mice and 1.56 ± 0.06 Gy for Balb/c mice, p = 0.0997. Conclusions: The data support a possible role for the loss of Serpinb3a in providing a cell survival advantage for hematopoietic progenitor cells exposed to lethal doses of ionizing irradiation. This would suggest that the Serpinb3a target protease helps repair the cellular injury induced by ionizing radiation. Alternatively, the germ line loss of Serpinb3a may up-regulate the expression of other clade B serpins known to protect cells from injury. Ongoing studies will help determine the nature of this protective effect against radiation-induced cell death. Disclosures No relevant conflicts of interest to declare.

scholarly journals A tick salivary protein targets cathepsin G and chymase and inhibits host inflammation and platelet aggregation

Blood ◽  
2011 ◽  
Vol 117 (2) ◽  
pp. 736-744 ◽  
Author(s):  
Jindrich Chmelar ◽  
Carlo J. Oliveira ◽  
Pavlina Rezacova ◽  
Ivo M. B. Francischetti ◽  
Zuzana Kovarova ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Serine Proteases ◽  
Acute Inflammation ◽  
Biological Activities ◽  
Salivary Protein ◽  
Cathepsin G ◽  
Skin Injury ◽  
Edema Formation ◽  
Protein Targets ◽  
First Time

Abstract Platelet aggregation and acute inflammation are key processes in vertebrate defense to a skin injury. Recent studies uncovered the mediation of 2 serine proteases, cathepsin G and chymase, in both mechanisms. Working with a mouse model of acute inflammation, we revealed that an exogenous salivary protein of Ixodes ricinus, the vector of Lyme disease pathogens in Europe, extensively inhibits edema formation and influx of neutrophils in the inflamed tissue. We named this tick salivary gland secreted effector as I ricinus serpin-2 (IRS-2), and we show that it primarily inhibits cathepsin G and chymase, while in higher molar excess, it affects thrombin activity as well. The inhibitory specificity was explained using the crystal structure, determined at a resolution of 1.8 Å. Moreover, we disclosed the ability of IRS-2 to inhibit cathepsin G-induced and thrombin-induced platelet aggregation. For the first time, an ectoparasite protein is shown to exhibit such pharmacological effects and target specificity. The stringent specificity and biological activities of IRS-2 combined with the knowledge of its structure can be the basis for the development of future pharmaceutical applications.

scholarly journals Neutrophil Cathepsin G Proteolysis of Protease Activated Receptor 4 Generates a Novel, Functional Tethered Ligand

2021 ◽  
Author(s):  
Michelle L. Stoller ◽  
Indranil Basak ◽  
Frederik Denorme ◽  
Jesse W Rowley ◽  
James Alsobrooks ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Synthetic Peptide ◽  
Cleavage Site ◽  
Serine Proteases ◽  
Cathepsin G ◽  
Mass Spectrometry Analysis ◽  
Calcium Flux ◽  
Spectrometry Analysis ◽  
Thrombin Cleavage ◽  
Tethered Ligand

Platelet-neutrophil interactions regulate ischemic vascular injury. Platelets are activated by serine proteases that cleave protease activated receptor (PAR) amino-termini, resulting in an activating tethered ligand. Neutrophils release cathepsin G (CatG) at sites of injury and inflammation, which activates PAR4 but not PAR1, although the molecular mechanism of CatG-induced PAR4 activation is unknown. We show that blockade of the canonical PAR4 thrombin cleavage site did not alter CatG-induced platelet aggregation, suggesting CatG cleaves a different site than thrombin. Mass spectrometry analysis using PAR4 N-terminus peptides revealed CatG cleavage at Ser67-Arg68. A synthetic peptide, RALLLGWVPTR, representing the tethered ligand resulting from CatG proteolyzed PAR4, induced PAR4-dependent calcium flux and greater platelet aggregation than the thrombin-generated GYPGQV peptide. Mutating PAR4 Ser67 or Arg68 reduced CatG-induced calcium flux without affecting thrombin-induced calcium flux. Dog platelets, which contain a conserved CatG PAR4 Ser-Arg cleavage site, aggregated in response to human CatG and RALLLGWVPTR, while mouse (Ser-Gln) and rat (Ser-Glu) platelets, were unresponsive. Thus, CatG amputates the PAR4 thrombin cleavage site by cleavage at Ser67-Arg68 and activates PAR4 by generating a new functional tethered ligand. These findings support PAR4 as an important CatG signaling receptor and suggest a novel therapeutic approach for blocking platelet-neutrophil-mediated pathophysiologies.

Abstract 126: Gene Deletion of Dipeptidyl Peptidase I Reduces Myocyte Loss and Preserves Cardiac Function After Myocardial Ischemia-Reperfusion Injury

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Zhao Qi ◽  
Mikhail Kolpakov ◽  
Bahman Hooshdaran ◽  
Khadija Rafiq ◽  
Xinji Guo ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Cardiac Function ◽  
Reperfusion Injury ◽  
Cardiac Remodeling ◽  
Serine Proteases ◽  
Gene Deletion ◽  
Cathepsin G ◽  
Wild Type ◽  
Myocyte Apoptosis

Introduction and Hypothesis: Chronic inflammation predisposes tissue to adverse cardiac remodeling and contributes to heart failure (HF) progression. The mechanisms whereby inflammation contributes to cardiac remodeling after cardiac injury has largely focused on action of reactive oxygen species and cytokines/chemokines and their role on myocyte growth and extracellular matrix (ECM) remodeling. However, the role of inflammatory proteases on myocyte loss and adverse cardiac remodeling has not been studied and are the focus of this study. Methods and Results: We subjected wild type and mice lacking Dipeptidyl peptidase I (DPPI), a lysosomal enzyme involved in the cleavage and activation of major inflammatory serine proteases, to myocardial ischemia for 30 min followed by reperfusion for 24hrs (IRI) and assessed the role of DPPI gene deletion on inflammatory proteases activation, myocyte apoptosis and cardiac remodeling and function. DPPI KO mice show markedly reduced inflammatory serine protease activity in response to myocardial IRI compared to wild type mice. DPPI deletion also markedly reduced myocyte apoptosis, limited infarct size and improved cardiac function in response to IRI. The role of inflammatory serine proteases in cardiac remodeling was further demonstrated after in-vivo cardiac transfer of cathepsin G, a neutrophil derived serine protease that has been shown to induce myocyte death in-vitro. Mice with cathepsin G injection for 5 days show increased interstitial collagen degradation and myocyte apoptosis and presented cardiac dilatation and contractile dysfunction. Conclusions: These findings reveal the role of DPPI as a key mediator of postischemic/reperfusion injury and show that inflammatory derived proteases contribute to the pathological cardiac remodeling and dysfunction.

scholarly journals The neutrophil serine protease inhibitor serpinb1 preserves lung defense functions in Pseudomonas aeruginosa infection

2007 ◽  
Vol 204 (8) ◽  
pp. 1901-1909 ◽  
Author(s):  
Charaf Benarafa ◽  
Gregory P. Priebe ◽  
Eileen Remold-O'Donnell
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Serine Proteases ◽  
Late Onset ◽  
Surfactant Protein ◽  
Cathepsin G ◽  
Intrinsic Defect ◽  
Surfactant Protein D ◽  
Bacterial Clearance ◽  
Cytokines And Chemokines ◽  
Molecular Components

Neutrophil serine proteases (NSPs; elastase, cathepsin G, and proteinase-3) directly kill invading microbes. However, excess NSPs in the lungs play a central role in the pathology of inflammatory pulmonary disease. We show that serpinb1, an efficient inhibitor of the three NSPs, preserves cell and molecular components responsible for host defense against Pseudomonas aeruginosa. On infection, wild-type (WT) and serpinb1-deficient mice mount similar early responses, including robust production of cytokines and chemokines, recruitment of neutrophils, and initial containment of bacteria. However, serpinb1−/− mice have considerably increased mortality relative to WT mice in association with late-onset failed bacterial clearance. We found that serpinb1-deficient neutrophils recruited to the lungs have an intrinsic defect in survival accompanied by release of neutrophil protease activity, sustained inflammatory cytokine production, and proteolysis of the collectin surfactant protein–D (SP-D). Coadministration of recombinant SERPINB1 with the P. aeruginosa inoculum normalized bacterial clearance in serpinb1−/− mice. Thus, regulation of pulmonary innate immunity by serpinb1 is nonredundant and is required to protect two key components, the neutrophil and SP-D, from NSP damage during the host response to infection.

scholarly journals In situ localization by double-labeling immunoelectron microscopy of anti-neutrophil cytoplasmic autoantibodies in neutrophils and monocytes

Blood ◽  
1990 ◽  
Vol 75 (1) ◽  
pp. 242-250 ◽  
Author(s):  
J Calafat ◽  
R Goldschmeding ◽  
PL Ringeling ◽  
H Janssen ◽  
CE van der Schoot
Keyword(s):  
Immunoelectron Microscopy ◽  
Serine Proteases ◽  
Cytochalasin B ◽  
Cathepsin G ◽  
Human Neutrophils ◽  
Double Labeling ◽  
Specific Granules ◽  
Normal Human ◽  
Myeloid Leukocytes

Abstract Anti-neutrophil cytoplasmic autoantibodies (ANCA) associated with active Wegener's granulomatosis are directed against a soluble 29-Kd protein present in human neutrophils and monocytes. Affinity labeling with tritiated diisopropylfluorophosphate (3H-DFP) suggested that ANCA- antigen is a serine protease. We used immunoelectron microscopy to study the in situ localization of the ANCA-antigen in normal human neutrophils and monocytes using immunoglobulin G (IgG) from ANCA- positive patients and a mouse monoclonal antibody against the ANCA- antigen. Label was observed on the large granules of the neutrophils and in granules of monocytes. Double-labeling, using anti- myeloperoxidase or the peroxidase reaction as markers for azurophil granules and anti-lactoferrin as marker for specific granules, showed that ANCA is colocalized with markers of azurophil granules but not with lactoferrin. Furthermore, elastase and cathepsin G were found in the azurophil granules of neutrophils and in the peroxidase-positive granules of monocytes, colocalized with ANCA-antigen. Cytochalasin-B- treated neutrophils stimulated with N-formyl-methionyl-leucyl- phenylalanine (fMLP) formed large intracellular vacuoles and were partially degranulated. Some vacuoles contained ANCA-antigen, as well as myeloperoxidase, elastase, and cathepsin G, demonstrating release of these enzymes from the azurophil granules into vacuoles. Our results demonstrate that ANCA-antigen is located in myeloperoxidase-containing granules of neutrophils and monocytes, and is packaged in the same granules as elastase and cathepsin G, the two previously identified serine proteases of myeloid leukocytes.

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