Novel roles of protease inhibitors in infection and inflammation

2002 ◽  
Vol 30 (2) ◽  
pp. 116-120 ◽  
Author(s):  
P. S. Hiemstra
Keyword(s):  
Extracellular Matrix ◽  
Protease Inhibitors ◽  
Neutrophil Elastase ◽  
Proteinase Inhibitor ◽  
Tissue Repair ◽  
Proteinase Inhibitors ◽  
Serine Proteinase ◽  
Serine Proteinases ◽  
Matrix Synthesis ◽  
Infection And Inflammation

The local balance between proteinase inhibitors and proteinases determines local proteolytic activity. Various studies have demonstrated the importance of serine proteinase inhibitors in regulating the activity of serine proteinases that are released by leucocytes during inflammation. Recently it has been shown that these inhibitors may also display functions that are distinct from those associated with the inhibition of leucocyte-derived proteinases. In this review the results of selected studies focusing on three inhibitors of neutrophil elastase, i.e. α1-proteinase inhibitor, secretory leucocyte proteinase inhibitor and elafin, are presented, with the aim of illustrating their possible involvement in the regulation of inflammation, host defence against infection, tissue repair and extracellular matrix synthesis.

scholarly journals Proteinase inhibitors in rat serum. Purification and partial characterization of three functionally distinct trypsin inhibitors

1984 ◽  
Vol 218 (3) ◽  
pp. 953-959 ◽  
Author(s):  
L Kuehn ◽  
M Rutschmann ◽  
B Dahlmann ◽  
H Reinauer
Keyword(s):  
Proteinase Inhibitor ◽  
Proteinase Inhibitors ◽  
Serine Proteinase ◽  
The Other ◽  
Serine Proteinases ◽  
Rat Serum ◽  
Apparent Homogeneity ◽  
Human Counterpart ◽  
Proteinase Inhibitor Ii

Three different serine proteinase inhibitors were isolated from rat serum and purified to apparent homogeneity. One of the inhibitors appears to be homologous to alpha 1-proteinase inhibitor isolated from man and other species, but the other two, designated rat proteinase inhibitor I and rat proteinase inhibitor II, seem to have no human counterpart. alpha 1-Proteinase inhibitor (Mr 55000) inhibits trypsin, chymotrypsin and elastase, the three serine proteinases tested. Rat proteinase inhibitor I (Mr 66000) is active towards trypsin and chymotrypsin, but is inactive towards elastase. Rat proteinase inhibitor II (Mr 65000) is an effective inhibitor of trypsin only. Their contributions to the trypsin-inhibitory capacity of rat serum are about 68, 14 and 18% for alpha 1-proteinase inhibitor, rat proteinase inhibitor I and rat proteinase inhibitor II respectively.

scholarly journals The Mouse Testis Is the Source of Various Serine Proteases and Serine Proteinase Inhibitors (SERPINs): Serine Proteases and SERPINs Identified in Leydig Cells Are under Gonadotropin Regulation

Endocrinology ◽  
2006 ◽  
Vol 147 (9) ◽  
pp. 4374-4383 ◽  
Author(s):  
Fanny Odet ◽  
Adélie Verot ◽  
Brigitte Le Magueresse-Battistoni
Keyword(s):  
Extracellular Matrix ◽  
Plasminogen Activator ◽  
Serine Proteases ◽  
Leydig Cells ◽  
Proteinase Inhibitors ◽  
Primary Cultures ◽  
Serine Proteinases ◽  
Rt Pcr ◽  
Positive Effects ◽  
Extracellular Matrix Components

The occurrence of various serine proteinases and serine proteinases inhibitors (SERPINs) was investigated by RT-PCR in whole testes of 1-, 3-, and 8-wk-old mice in crude and enriched germ cell fractions, mouse Leydig tumor cells (mLTC-1), and primary cultures of 3- and 8-wk-old enriched fractions of Leydig cells and 3-wk-old Sertoli cells. New members were identified in the testis protease repertoire. Within the Leydig repertoire, a PCR product was found for plasminogen activators urokinase plasminogen activator (uPA) and tissue plasminogen activator (8-wk-old cells), matriptase-2 (mLTC-1), kallikrein-21, SERPINA5, SERPINB2 (primary cultures), and serine peptidase inhibitor Kunitz type 2 (SPINT2). The gonadotropin regulation was explored by semiquantitative RT-PCR, using steroidogenic acute regulatory protein (StAR) as a positive control. Matriptase-2, kallikrein-21, SPINT2, and SERPINA5 were down-regulated, whereas uPA and its receptor were up-regulated by human chorionic gonadotropin (hCG) via cAMP in the mLTC-1 cells. Positive effects were observed transiently after 1–8 h of hCG exposure, and negative effects, first evidenced after 6 h, lasted 48 h. The hCG-induced effects were confirmed in primary cultures. In addition, SERPINB2 was augmented by hCG in primary cultures. Addition of either trypsin or protease inhibitors did not alter the hCG-induced surge of StAR. Because hCG regulated proteases and SERPINs (whereas testosterone did not), it could alter the proteolytic balance of Leydig cells and consequently the metabolism of extracellular matrix components. Therefore, even though a direct interplay between the early hCG-induced surge of uPA and StAR is unlikely, our data together with the literature suggest that extracellular matrix proteins alter Leydig cell steroidogenesis.

Influence of a Cysteine Proteinase Inhibitor on Alfalfa Weevil (Coleoptera: Curculionidae) Growth and Development Over Successive Generations

2000 ◽  
Vol 35 (1) ◽  
pp. 70-76 ◽  
Author(s):  
T. C. Elden
Keyword(s):  
Proteinase Inhibitor ◽  
Growth And Development ◽  
Proteinase Inhibitors ◽  
Cysteine Proteinase ◽  
Serine Proteinase ◽  
Adult Survival ◽  
Cysteine Proteinase Inhibitor ◽  
Alfalfa Weevil ◽  
Hypera Postica ◽  
Successive Generations

The influence of leupeptin, a cysteine and serine proteinase inhibitor, on alfalfa weevil, Hypera postica (Gyllenhal), growth and development was investigated over nine successive generations. Concern that ingestion of proteinase inhibitors by phytophagous insects could induce production of inhibitor-insensitive proteinase activity initiated this investigation. The percent alfalfa weevil larval, pupal and adult survival, and defoliation was significantly lower on alfalfa foliage treated with leupeptin than on untreated foliage in all nine generations tested. Main effects for generations and treatment times generation were nonsignificant for all variables. This study demonstrates that after nine generations leupeptin, when compared to an untreated control, does not lose its ability to significantly inhibit alfalfa weevil growth and development. This suggests that the alfalfa weevil did not utilize or induce other proteinases (digestive enzymes) to compensate for inhibition of one of its major proteinases.

Involvement of cysteine proteinases in excystment of Paragonimus ohirai metacercariae induced by sodium cholate and A23187

2003 ◽  
Vol 77 (1) ◽  
pp. 21-26 ◽  
Author(s):  
T. Ikeda
Keyword(s):  
Proteinase Inhibitor ◽  
Proteinase Inhibitors ◽  
Cysteine Proteinase ◽  
Serine Proteinase ◽  
Sodium Cholate ◽  
Cysteine Proteinase Inhibitor ◽  
Cysteine Proteinases ◽  
Serine Proteinase Inhibitor ◽  
Similar Activity

AbstractThe involvement of intrinsic proteinases in the excystment of Paragonimus ohirai metacercariae was studied in in vitro excystment induced by sodium (Na) cholate, a bile salt and A23187, a Ca2+ ionophore. The effects of various proteinase inhibitors on the in vitro excystment were examined and similar inhibitory profiles were obtained. Benzyloxycarbonyl-L-leucyl-L-leucinal (Z-Leu-Leu-H), a cysteine proteinase inhibitor and 4-(2-aminoethyl)-benzenesulfonyl fluoride (Pefabloc SC), a serine proteinase inhibitor completely inhibited excystment, while L-3-carboxy-2,3-trans-epoxypropionyl-leucylamido (4-guanidino)-butane (E-64), a cysteine proteinase inhibitor and leupeptin, a cysteine/serine proteinase inhibitor permitted partial excystment at a lower rate, but inhibited it from proceeding from the partial excystment stage. In secretions released from metacercariae during excystment, proteinase activities detected towards various fluorogenic peptidyl substrates were almost completely inhibited by Z-Leu-Leu-H and E-64, but not by Pefabloc SC. Sodium cholate induced a higher secretion of cysteine proteinases and a higher rate of excystment than A23187. Profiles of cysteine proteinase activities towards five peptidyl substrates detected were markedly different among the two secretions and the lysate of newly excysted juveniles. Newly excysted juveniles released cysteine proteinases with similar activity profiles and levels to metacercariae induced by Na cholate-incubation, whereas the release of cysteine proteinases was reduced compared with metacercariae induced by A23187-incubation. These results provide valuable information about the involvement of intrinsic proteinases in metacercarial excystment.

scholarly journals Serpins in cartilage and osteoarthritis: what do we know?

2021 ◽  
Author(s):  
David J. Wilkinson
Keyword(s):  
Proteinase Inhibitors ◽  
Serine Proteinase ◽  
Cartilage Destruction ◽  
Inhibition Mechanism ◽  
Serine Proteinases ◽  
Surface Receptors ◽  
Monogenic Disorders ◽  
Joint Disorder ◽  
Proteinase Inhibition ◽  
First Time

Serpins (serine proteinase inhibitors) are an ancient superfamily of structurally similar proteins, the majority of which use an elegant suicide inhibition mechanism to target serine proteinases. Despite likely evolving from a single common ancestor, the 36 human serpins have established roles regulating diverse biological processes, such as blood coagulation, embryonic development and extracellular matrix (ECM) turnover. Genetic mutations in serpin genes underpin a host of monogenic disorders — collectively termed the ‘serpinopathies’ — but serpin dysregulation has also been shown to drive pathological mechanisms in many common diseases. Osteoarthritis is a degenerative joint disorder, characterised by the progressive destruction of articular cartilage. This breakdown of the cartilage is driven by the metalloproteinases, and it has long been established that an imbalance of metalloproteinases to their inhibitors is of critical importance. More recently, a role for serine proteinases in cartilage destruction is emerging; including the activation of latent matrix metalloproteinases and cell-surface receptors, or direct proteolysis of the ECM. Serpins likely regulate these processes, as well as having roles beyond serine proteinase inhibition. Indeed, serpins are routinely observed to be highly modulated in osteoarthritic tissues and fluids by ‘omic analysis, but despite this, they are largely ignored. Confusing nomenclature and an underappreciation for the role of serine proteinases in osteoarthritis (OA) being the likely causes. In this narrative review, serpin structure, biochemistry and nomenclature are introduced, and for the first time, their putative importance in maintaining joint tissues — as well as their dysregulation in OA — are explored.

scholarly journals Protease–Antiprotease Imbalance in Bronchiectasis

2021 ◽  
Vol 22 (11) ◽  
pp. 5996
Author(s):  
Martina Oriano ◽  
Francesco Amati ◽  
Andrea Gramegna ◽  
Anthony De Soyza ◽  
Marco Mantero ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Disease Severity ◽  
Neutrophil Elastase ◽  
Proteinase Inhibitor ◽  
Serine Proteases ◽  
Matrix Degradation ◽  
Long Term Outcomes ◽  
Elastase Activity ◽  
Severe Deficiency

Airway inflammation plays a central role in bronchiectasis. Protease–antiprotease balance is crucial in bronchiectasis pathophysiology and increased presence of unopposed proteases activity may contribute to bronchiectasis onset and progression. Proteases’ over-reactivity and antiprotease deficiency may have a role in increasing inflammation in bronchiectasis airways and may lead to extracellular matrix degradation and tissue damage. Imbalances in serine proteases and matrix-metallo proteinases (MMPs) have been associated to bronchiectasis. Active neutrophil elastase has been associated with disease severity and poor long-term outcomes in this disease. Moreover, high levels of MMPs have been associated with radiological and disease severity. Finally, severe deficiency of α1-antitrypsin (AAT), as PiSZ and PiZZ (proteinase inhibitor SZ and ZZ) phenotype, have been associated with bronchiectasis development. Several treatments are under study to reduce protease activity in lungs. Molecules to inhibit neutrophil elastase activity have been developed in both oral or inhaled form, along with compounds inhibiting dipeptydil-peptidase 1, enzyme responsible for the activation of serine proteases. Finally, supplementation with AAT is in use for patients with severe deficiency. The identification of different targets of therapy within the protease–antiprotease balance contributes to a precision medicine approach in bronchiectasis and eventually interrupts and disrupts the vicious vortex which characterizes the disease.

Functional proteomics of kallikrein-related peptidases in ovarian cancer ascites fluid

2010 ◽  
Vol 391 (4) ◽  
Author(s):  
Katerina Oikonomopoulou ◽  
Ihor Batruch ◽  
Chris R. Smith ◽  
Antoninus Soosaipillai ◽  
Eleftherios P. Diamandis ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Proteinase Inhibitors ◽  
Serine Proteinase ◽  
Cancer Cell Line ◽  
Malignant Ascites ◽  
Ascites Fluid ◽  
Clinical Samples ◽  
Serine Proteinases ◽  
Α2 Macroglobulin

Abstract Kallikrein-related peptidases (KLKs) are secreted serine proteinases with trypsin or chymotrypsin-like activity. Several family members, such as KLKs 6 and 10, are potential ovarian cancer biomarkers. Recently, using a newly developed assay for active KLK6, we found that only a very small proportion of immunoreactive KLK6 in tumor-derived clinical samples (malignant ascites fluid), in cerebrospinal fluid, and in cancer cell line supernatants is enzymatically active. We therefore hypothesized that a proportion of other immunoreactive KLKs in such samples could be present, but might be partly complexed to endogenous serine proteinase inhibitors. Using a combination of immunological isolation of the enzymes, activity-based probe analysis and proteomics, we identified active KLK10 in ovarian cancer ascites and we provide preliminary data that the activity of other KLKs present in these samples can be decreased by known proteinase inhibitors (e.g., α2-macroglobulin, α1-antitrypsin). Our data suggest that the enzymatic activity of ovarian cancer-released KLKs that are detected by regular immunoassays is low in vivo and very likely regulated by proteinase inhibitors.

A serine proteinase inhibitor isolated from Tamarindus indica seeds and its effects on the release of human neutrophil elastase

Life Sciences ◽  
2005 ◽  
Vol 76 (25) ◽  
pp. 2881-2891 ◽  
Author(s):  
J.M.S.L.L. Fook ◽  
L.L.P. Macedo ◽  
G.E.D.D. Moura ◽  
F.M. Teixeira ◽  
A.S. Oliveira ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Proteinase Inhibitor ◽  
Serine Proteinase ◽  
Human Neutrophil Elastase ◽  
Tamarindus Indica ◽  
Serine Proteinase Inhibitor
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