Journal articles: 'Human neutrophil elastase inhibitors'

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Mendez, Deena, Prasad SR, and Kutty AVM. "Differential Inhibition of Human Neutrophil Elastase and Bacterial Elastase by endogenous Protease Inhibitors." JOURNAL OF CLINICAL AND BIOMEDICAL SCIENCES 08, no. 1 (March 15, 2018): 10–13. http://dx.doi.org/10.58739/jcbs/v08i1.2.

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Human Neutrophil Elastase (HNE) is released from neutrophils when foreign substances are encoun-tered. Elastase is also released by invasive pathogenic microorganisms and is an important virulence factor. Serine protease inhibitors counter the elastase released in excess to prevent the damage of tissues. Aim: The aim of this study was to assess the specificity of the endogenous protease inhibitors α1 Anti trypsin( α1AT) and α2 Macroglobulin( α2MG) on Human Neutrophil Elastase and elastase released by Pseudomonas aeruginosa. Result: It was observed that Pseudomonal elastase exhibited resistance to inhibition in com-parison to Human Neutrophil Elastase particularly by α1 Anti trypsin. However, the inhibition patterns of these enzymes were more or less similar in both the cases by α2 Macroglobulin. Conclusion; α1AT is a less potent inhibitor of Pseudonomas aeruginosa elastase and might require exogenous inhibitory substances to control the damaging effects of this enzyme. Keywords: α1 Anti trypsin, α2 Macroglobulin, Human Neutrophil Elastase, Pseudomonas aeruginosa

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Dubin, A., J. Potempa, and J. Travis. "Structural and functional characterization of elastases from horse neutrophils." Biochemical Journal 300, no. 2 (June 1, 1994): 401–6. http://dx.doi.org/10.1042/bj3000401.

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In order better to understand the pathophysiology of the equine form of emphysema, two elastinolytic enzymes from horse neutrophils, referred to as proteinases 2A and 2B, have been extensively characterized and compared with the human neutrophil proteinases, proteinase-3 and elastase. Specificity studies using both the oxidized insulin B-chain and synthetic peptides revealed that cleavage of peptide bonds with P1 alanine or valine residues was preferred. Further characterization of the two horse elastases by N-terminal sequence and reactive-site analyses indicated that proteinases 2A and 2B have considerable sequence similarity to each other, to proteinase-3 from human neutrophils (proteinase 2A), to human neutrophil elastase (proteinase 2B) and to a lesser extent to pig pancreatic elastase. Horse and human elastases differed somewhat in their interaction with some natural protein proteinase inhibitors. For example, in contrast with its action on human neutrophil elastase, aprotinin did not inhibit either of the horse proteinases. However, the Val15, alpha-aminobutyric acid-15 (Abu15), alpha-aminovaleric acid-15 (Nva15) and Ala15 reactive-site variants of aprotinin were good inhibitors of proteinase 2B (Ki < 10(-9) M) but only weak inhibitors of proteinase 2A (Ki > 10(-7) M). In summary, despite these differences, the horse neutrophil elastases were found to resemble closely their human counterparts, thus implicating them in the pathological degradation of connective tissue in chronic lung diseases in the equine species.

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Janusz, M. J., and N. S. Doherty. "Degradation of cartilage matrix proteoglycan by human neutrophils involves both elastase and cathepsin G." Journal of Immunology 146, no. 11 (June 1, 1991): 3922–28. http://dx.doi.org/10.4049/jimmunol.146.11.3922.

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Abstract The granule proteases of human neutrophils are thought to be responsible for the connective tissue destruction associated with certain inflammatory diseases. Using a model system for the degradation of a macromolecular connective tissue substrate, purified neutrophil elastase and cathepsin G were both individually able to degrade cartilage matrix proteoglycan and this degradation was blocked by the appropriate specific inhibitors. Neutrophil granule lysate also produced cartilage matrix degradation but little inhibition of degradation occurred when either elastase or cathepsin G inhibitor was used alone. However, a combination of elastase and cathepsin G inhibitors each at 100 microM or each at 10 microM blocked cartilage matrix degradation by 89% +/- 1 and 65% +/- 9 (mean +/- SEM, n = 3), respectively. The magnitude of the cartilage degradation mediated by neutrophil lysate, and its sensitivity to specific inhibitors, was reproduced using purified elastase and cathepsin G at the concentrations at which they are present in neutrophil lysate. Human neutrophils stimulated with opsonized zymosan degraded cartilage matrix in a dose-dependent manner in the presence of serum antiproteases. Supernatants from stimulated neutrophils cultured in the presence of serum did not degrade cartilage matrix, indicating that neutrophil mediated degradation in the presence of serum was confined to the protected subjacent region between the inflammatory cell and the substratum. A combination of elastase and cathepsin G inhibitors each at 500 microM or each at 100 microM blocked subjacent cartilage matrix degradation by stimulated human neutrophils by 91% +/- 3 and 54% +/- 8 (mean +/- SEM, n = 5), respectively, whereas either the elastase or cathepsin G inhibitor alone was much less effective. These studies demonstrate that neutrophil-mediated cartilage matrix degradation is produced primarily by elastase and cathepsin G. Furthermore, these results support the hypothesis that inflammatory neutrophils form zones of close contact with substratum that exclude serum antiproteases and that this subjacent degradation of cartilage matrix by stimulated neutrophils can be blocked by a combination of synthetic elastase and cathepsin G inhibitors.

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Potempa, J., J. J. Enghild, and J. Travis. "The primary elastase inhibitor (elastasin) and trypsin inhibitor (contrapsin) in the goat are serpins related to human α1-anti-chymotrypsin." Biochemical Journal 306, no. 1 (February 15, 1995): 191–97. http://dx.doi.org/10.1042/bj3060191.

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Two primary serine proteinase inhibitors in goat plasma have been isolated and characterized. The N-terminal sequence analysis of the purified proteins revealed that they are closely related to each other and are highly homologous to human alpha 1-anti-chymotrypsin rather than alpha 1-proteinase inhibitor. However, despite structural similarities the inhibitory specificity of the goat inhibitors differed from each other and from that of anti-chymotrypsin. In contrast with human anti-chymotrypsin, one of the goat inhibitors was shown to be a strong and specific inhibitor of trypsin (k(ass.) = 1.9 x 10(6) M-1.s-1), whereas the other was an efficient inhibitor of neutrophil elastase (k(ass.) = 1.5 x 10(6) M-1.S-1). Differences in the inhibitory specificity of each protein could readily be attributed to the amino acid sequence within the reactive site region. The trypsin inhibitor with an assumed arginine residue at the P1 position of the reactive-site peptide bond is referred to as ‘contrapsin’, and indicates that the occurrence of contrapsins is not restricted to rodents. In contrast, the inhibitory specificity, resistance to oxidative and proteolytic inactivation and the presence of a P1 leucine residue in the elastase inhibitor is unique among inhibitory serpins that have been characterized to date. Because this serpin is apparently the major elastase inhibitor in goat plasma, it is likely to be involved in the control of goat neutrophil elastase. Therefore, we suggest the name ‘elastasin’, and extend it to any other anti-chymotrypsin related serpins possessing neutrophil-elastase- inhibitory activity.

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Marinaccio, Lorenza, Azzurra Stefanucci, Giuseppe Scioli, Alice Della Valle, Gokhan Zengin, Angelo Cichelli, and Adriano Mollica. "Peptide Human Neutrophil Elastase Inhibitors from Natural Sources: An Overview." International Journal of Molecular Sciences 23, no. 6 (March 8, 2022): 2924. http://dx.doi.org/10.3390/ijms23062924.

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Elastases are a broad group of enzymes involved in the lysis of elastin, the main component of elastic fibres. They are produced and released in the human body, mainly by neutrophils and the pancreas. The imbalance between elastase activity and its endogenous inhibitors can cause different illnesses due to their excessive activity. The main aim of this review is to provide an overview of the latest advancements on the identification, structures and mechanisms of action of peptide human neutrophil elastase inhibitors isolated from natural sources, such as plants, animals, fungi, bacteria and sponges. The discovery of new elastase inhibitors could have a great impact on the pharmaceutical development of novel drugs through the optimization of the natural lead compounds. Bacteria produce mainly cyclic peptides, while animals provide for long and linear amino acid sequences. Despite their diverse natural sources, these elastase inhibitors show remarkable IC50 values in a range from nM to μM values, thus representing an interesting starting point for the further development of potent bioactive compounds on human elastase enzymes.

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Inauen, W., D. N. Granger, C. J. Meininger, M. E. Schelling, H. J. Granger, and P. R. Kvietys. "Anoxia-reoxygenation-induced, neutrophil-mediated endothelial cell injury: role of elastase." American Journal of Physiology-Heart and Circulatory Physiology 259, no. 3 (September 1, 1990): H925—H931. http://dx.doi.org/10.1152/ajpheart.1990.259.3.h925.

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The aim of this study was to assess the role of neutrophilic elastase in anoxia-reoxygenation-induced, neutrophil-mediated injury to microvascular endothelium. Cultured bovine microvascular endothelial cells were grown to confluence and labeled with 51Cr. The endothelial cells were exposed to a 30-min period of anoxia and subsequently reoxygenated. Endothelial cell injury, quantitated as 51Cr release and cell detachment, was determined 8 h after reoxygenation. Addition of neutrophils upon reoxygenation enhanced the anoxia-reoxygenation-induced increase in 51Cr release and cell detachment. The neutrophil-mediated injury was associated with elastase release from the neutrophils. Four agents were used to inhibit neutrophilic elastase activity: Eglin C, methoxysuccunyl-Ala2-Pro-Val-CH2Cl, L658,758, and a monoclonal antibody against neutrophilic elastase. All elastase inhibitors attenuated the neutrophil-mediated endothelial cell detachment but not 51Cr release. Addition of purified human neutrophilic elastase, at a level that mimicked the release from neutrophils, increased cell detachment in endothelial cells exposed to anoxia-reoxygenation but did not affect 51Cr release. Our results indicate that elastase plays an important role in anoxia-reoxygenation-induced, neutrophil-mediated endothelial cell dysfunction.

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Rosengren, S., and K. E. Arfors. "Neutrophil-mediated vascular leakage is not suppressed by leukocyte elastase inhibitors." American Journal of Physiology-Heart and Circulatory Physiology 259, no. 4 (October 1, 1990): H1288—H1294. http://dx.doi.org/10.1152/ajpheart.1990.259.4.h1288.

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Application of leukotriene B4 (LTB4) to hamster cheek pouches induces neutrophil-dependent vascular leakage of macromolecules as well as leukocyte intravascular adherence and emigration. The effect of inhibitors of neutrophil elastase on these reactions was studied with intravital microscopy. Anesthetized hamsters were pretreated with the elastase inhibitors L 658,758, Eglin C, or dextran sulfate, and LTB4 (10 nM) was superfused over the cheek pouches. Neither Eglin C nor L 658,758 had any effect on the resulting vascular leakage of a macromolecular marker; in contrast, dextran sulfate suppressed this leakage by 85%. None of the compounds affected LTB4-induced leukocyte adherence or neutrophil diapedesis. The inhibitors were able to inhibit both hamster and human neutrophil elastase as estimated in crude neutrophil extracts. These results suggest that neutrophils extravasate and generate vascular leakage without the use of their elastase activity. The inhibitory effect of dextran sulfate on macromolecular leakage may be due to interaction with cationic proteins released from the neutrophils.

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Edwards, Philip D., and Chris A. Veale. "Inhibitors of human neutrophil elastase." Expert Opinion on Therapeutic Patents 7, no. 1 (January 1997): 17–28. http://dx.doi.org/10.1517/13543776.7.1.17.

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Filep, Janos G., Natalie Edner, Everton de Oliveira Lima Dos Santos, Meriem Sekheri, and Driss El Kebir. "TLR9 activation impairs phagocytosis-induced neutrophil apoptosis and prolongs E. coli-induced acute lung injury." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 129.1. http://dx.doi.org/10.4049/jimmunol.198.supp.129.1.

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Abstract Neutrophil dysfunction, resulting in delayed apoptosis and inefficient bacterial clearance, is a characteristic feature of severe pathologies, including sepsis and cystic fibrosis. Human neutrophils detect and respond to bacterial DNA (CpG DNA) through TLR9. We investigated the impact of CpG DNA on phagocytosis, phagocytosis-induced neutrophil apoptosis and clearance of E coli. Culture of human neutrophils with CpG DNA (0.1–3.2 μg/ml) resulted in decreased phagocytosis of opsonized E. coli or yeast. CpG DNA upregulated C3R (CD11b) expression, downregulated C5aR (CD88) expression and induced release of neutrophil elastase. C5aR cleavage was prevented by a specific neutrophil elastase inhibitor and the broad-spectrum serine protease inhibitor PMSF. Consistently, CpG DNA reduced phagocytosis-induced NADPH oxidase-mediated activation of caspase8 and caspase-3. These actions of CpG DNA were blocked by the telomere-derived TLR9 inhibitory oligonucleotide 5′-TTT AGG GTT AGG GTT AGG G-3′. In mice, CpG DNA impaired pulmonary clearance of E coli, suppressed neutrophil apoptosis and delayed resolution of lung injury evoked by intratracheal instillation of live E. coli. Genetic deletion of TLR9 rendered mice unresponsive to CpG DNA. These results identify a novel mechanism, neutrophil elastase-mediated inactivation of C5aR-mediated phagocytosis, by which CpG DNA could contribute to neutrophil dysfunction and prolongation of tissue injury. Our findings also suggest a therapeutic potential for TLR9 antagonists or neutrophil elastase inhibitors for enhancing clearance of bacterial infections in an environment where bacterial DNA is abundantly present.

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Trainor, Diane Amy. "Synthetic inhibitors of human neutrophil elastase." Trends in Pharmacological Sciences 8, no. 8 (August 1987): 303–7. http://dx.doi.org/10.1016/0165-6147(87)90123-4.

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11

Potempa, J., J. K. Wunderlich, and J. Travis. "Comparative properties of three functionally different but structurally related serpin variants from horse plasma." Biochemical Journal 274, no. 2 (March 1, 1991): 465–71. http://dx.doi.org/10.1042/bj2740465.

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Three structurally related but functionally different serpins from horse plasma were isolated and characterized. In spite of their identical N-terminal sequences, which show some similarity to that of human alpha 1-proteinase inhibitor, the reactive-centre loops of each of these proteins show extensive variation. Only inhibitor I, with a P1 methionine residue, resembles human alpha 1-PI with regard to (a) similarity of amino acid sequence in the vicinity of the reactive-site peptide bond, (b) broad inhibitory specificity, (c) sensitivity to oxidative inactivation and (d) high rate of reactivity with neutrophil elastase(s). Inhibitor II, with a P1 arginine residue, is an exclusive trypsin inhibitor, and inhibitor III is an oxidation-resistant slow-reacting elastase inhibitor with a P1 alanine residue. Comparison of association rate constants for the inhibition of horse neutrophil elastases by the three inhibitors indicates that only inhibitor I is likely to be physiologically important in the regulation of these enzymes.

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Wachtfogel, Y. T., C. E. Hack, J. H. Nuijens, C. Kettner, T. M. Reilly, R. M. Knabb, R. Bischoff, et al. "Selective kallikrein inhibitors alter human neutrophil elastase release during extracorporeal circulation." American Journal of Physiology-Heart and Circulatory Physiology 268, no. 3 (March 1, 1995): H1352—H1357. http://dx.doi.org/10.1152/ajpheart.1995.268.3.h1352.

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Cardiopulmonary bypass causes hemorrhagic complications and initiates a biochemical and cellular “whole body inflammatory response.” This study investigates whether a variety of selective inhibitors of the contact pathway of intrinsic coagulation modulate complement and neutrophil activation during simulated extracorporeal circulation. After 60 min of recirculation in the presence of the slow tight-binding boronic acid inhibitor, Bz-Pro-Phe-boroArg-OH (10.7 microM), complete inhibition of kallikrein-C1-inhibitor complex formation and marked inhibition of C1-C1-inhibitor complex formation and the release of human neutrophil elastase were observed. Arg15-aprotinin (3.1 microM), Ala357,Arg358 alpha 1-antitrypsin (2.6 microM), and soybean trypsin inhibitor (48.0 microM) either completely or partially inhibited the generation of kallikrein-C1-inhibitor complexes but were less effective inhibitors of human neutrophil elastase release. The second-order rate constants for the inhibition of kallikrein in purified systems are consistent with the order of effectiveness of the inhibitors in blocking human neutrophil elastase release in heparinized blood. Our results suggest that low-molecular-weight selective inhibitors of kallikrein may be effective agents in the attenuation of the contact-mediated inflammatory response in cardiopulmonary bypass.

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Fitch, P. M., A. Roghanian, S. E. M. Howie, and J. M. Sallenave. "Human neutrophil elastase inhibitors in innate and adaptive immunity." Biochemical Society Transactions 34, no. 2 (March 20, 2006): 279–82. http://dx.doi.org/10.1042/bst0340279.

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Recent evidence shows that human neutrophil elastase inhibitors can be synthesized locally at mucosal sites. In addition to efficiently targeting bacterial and host enzymes, they can be released in the interstitium and in the lumen of mucosa, where they have been shown to have antimicrobial activities, and to activate innate immune responses. This review will address more particularly the pleiotropic functions of low-molecular-mass neutrophil elastase inhibitors [SLPI (secretory leucocyte proteinase inhibitor) and elafin] and, more specifically, their role in the development of the adaptive immune response.

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Jakimiuk, Katarzyna, Jakub Gesek, Atanas G. Atanasov, and Michał Tomczyk. "Flavonoids as inhibitors of human neutrophil elastase." Journal of Enzyme Inhibition and Medicinal Chemistry 36, no. 1 (January 1, 2021): 1016–28. http://dx.doi.org/10.1080/14756366.2021.1927006.

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Giovannoni, Maria Paola, Igor A. Schepetkin, Letizia Crocetti, Giovanna Ciciani, Agostino Cilibrizzi, Gabriella Guerrini, Andrei I. Khlebnikov, Mark T. Quinn, and Claudia Vergelli. "Cinnoline derivatives as human neutrophil elastase inhibitors." Journal of Enzyme Inhibition and Medicinal Chemistry 31, no. 4 (July 21, 2015): 628–39. http://dx.doi.org/10.3109/14756366.2015.1057718.

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Ohbayashi, Hiroyuki. "Current synthetic inhibitors of human neutrophil elastase." Expert Opinion on Therapeutic Patents 12, no. 1 (January 2002): 65–84. http://dx.doi.org/10.1517/13543776.12.1.65.

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Sieńczyk, Marcin, Łukasz Winiarski, Paulina Kasperkiewicz, Mateusz Psurski, Joanna Wietrzyk, and Józef Oleksyszyn. "Simple phosphonic inhibitors of human neutrophil elastase." Bioorganic & Medicinal Chemistry Letters 21, no. 5 (March 2011): 1310–14. http://dx.doi.org/10.1016/j.bmcl.2011.01.083.

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Leahy, Darren, Cameron Grant, Alex Jackson, Alex Duff, Nicholas Tardiota, Jessica Van Haeften, Xingchen Chen, et al. "Discrimination of Methionine Sulfoxide and Sulfone by Human Neutrophil Elastase." Molecules 26, no. 17 (September 2, 2021): 5344. http://dx.doi.org/10.3390/molecules26175344.

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Human neutrophil elastase (HNE) is a uniquely destructive serine protease with the ability to unleash a wave of proteolytic activity by destroying the inhibitors of other proteases. Although this phenomenon forms an important part of the innate immune response to invading pathogens, it is responsible for the collateral host tissue damage observed in chronic conditions such as chronic obstructive pulmonary disease (COPD), and in more acute disorders such as the lung injuries associated with COVID-19 infection. Previously, a combinatorially selected activity-based probe revealed an unexpected substrate preference for oxidised methionine, which suggests a link to oxidative pathogen clearance by neutrophils. Here we use oxidised model substrates and inhibitors to confirm this observation and to show that neutrophil elastase is specifically selective for the di-oxygenated methionine sulfone rather than the mono-oxygenated methionine sulfoxide. We also posit a critical role for ordered solvent in the mechanism of HNE discrimination between the two oxidised forms methionine residue. Preference for the sulfone form of oxidised methionine is especially significant. While both host and pathogens have the ability to reduce methionine sulfoxide back to methionine, a biological pathway to reduce methionine sulfone is not known. Taken together, these data suggest that the oxidative activity of neutrophils may create rapidly cleaved elastase “super substrates” that directly damage tissue, while initiating a cycle of neutrophil oxidation that increases elastase tissue damage and further neutrophil recruitment.

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Wachtfogel, YT, RA Pixley, U. Kucich, W. Abrams, G. Weinbaum, M. Schapira, and RW Colman. "Purified plasma factor XIIa aggregates human neutrophils and causes degranulation." Blood 67, no. 6 (June 1, 1986): 1731–37. http://dx.doi.org/10.1182/blood.v67.6.1731.1731.

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Abstract Plasma kallikrein has been shown to aggregate human neutrophils and release human neutrophil elastase. However, neutrophils resuspended in factor XII-deficient plasma released only 30% of the elastase compared with normal plasma. Isolated human neutrophils were aggregated in a concentration-dependent fashion by 0.06 to 0.6 U/mL factor XIIa (0.022 to 0.22 mumol/L). Factor XIIa (0.1 to 1.0 U/mL) also induced neutrophil degranulation as evidenced by a concentration-dependent release of the specific granule protein, lactoferrin, and azurophilic granule protease, elastase. The release of neutrophil elastase was biphasic, reaching 40% of maximum at 15 seconds with maximal release by 90 minutes. The active site of factor XIIa was required, since the synthetic inhibitor, D-Pro-Phe-Arg-CH2Cl, which reacts with an essential histidine, and the natural plasma inhibitor, Cl-inhibitor, which interacts with the critical serine, both inhibit by more than 90% the release of elastase. The heavy chain is also required, since factor XII fragments failed to aggregate neutrophils or stimulate degranulation. Factor XIIa (0.6 U/mL) can completely correct the defect in elastase release evident in factor XII-deficient plasma. These studies demonstrate that factor XIIa, at concentrations potentially obtainable in plasma in disease states, can activate neutrophils, and thus may participate in the inflammatory response.

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Wachtfogel, YT, RA Pixley, U. Kucich, W. Abrams, G. Weinbaum, M. Schapira, and RW Colman. "Purified plasma factor XIIa aggregates human neutrophils and causes degranulation." Blood 67, no. 6 (June 1, 1986): 1731–37. http://dx.doi.org/10.1182/blood.v67.6.1731.bloodjournal6761731.

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Plasma kallikrein has been shown to aggregate human neutrophils and release human neutrophil elastase. However, neutrophils resuspended in factor XII-deficient plasma released only 30% of the elastase compared with normal plasma. Isolated human neutrophils were aggregated in a concentration-dependent fashion by 0.06 to 0.6 U/mL factor XIIa (0.022 to 0.22 mumol/L). Factor XIIa (0.1 to 1.0 U/mL) also induced neutrophil degranulation as evidenced by a concentration-dependent release of the specific granule protein, lactoferrin, and azurophilic granule protease, elastase. The release of neutrophil elastase was biphasic, reaching 40% of maximum at 15 seconds with maximal release by 90 minutes. The active site of factor XIIa was required, since the synthetic inhibitor, D-Pro-Phe-Arg-CH2Cl, which reacts with an essential histidine, and the natural plasma inhibitor, Cl-inhibitor, which interacts with the critical serine, both inhibit by more than 90% the release of elastase. The heavy chain is also required, since factor XII fragments failed to aggregate neutrophils or stimulate degranulation. Factor XIIa (0.6 U/mL) can completely correct the defect in elastase release evident in factor XII-deficient plasma. These studies demonstrate that factor XIIa, at concentrations potentially obtainable in plasma in disease states, can activate neutrophils, and thus may participate in the inflammatory response.

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Brillard-Bourdet, Michèle, Ahmed Hamdaoui, Eric Hajjar, Christian Boudier, Nathalie Reuter, Laurence Ehret-Sabatier, Joseph G. Bieth, and Francis Gauthier. "A novel locust (Schistocerca gregaria) serine protease inhibitor with a high affinity for neutrophil elastase." Biochemical Journal 400, no. 3 (November 28, 2006): 467–76. http://dx.doi.org/10.1042/bj20060437.

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We have purified to homogeneity two forms of a new serine protease inhibitor specific for elastase/chymotrypsin from the ovary gland of the desert locust Schistocerca gregaria. This protein, greglin, has 83 amino acid residues and bears putative phosphorylation sites. Amino acid sequence alignments revealed no homology with pacifastin insect inhibitors and only a distant relationship with Kazal-type inhibitors. This was confirmed by computer-based structural studies. The most closely related homologue is a putative gene product from Ciona intestinalis with which it shares 38% sequence homology. Greglin is a fast-acting and tight binding inhibitor of human neutrophil elastase (kass=1.2×107 M−1·s−1, Ki=3.6 nM) and subtilisin. It also binds neutrophil cathepsin G, pancreatic elastase and chymotrypsin with a lower affinity (26 nM≤Ki≤153 nM), but does not inhibit neutrophil protease 3 or pancreatic trypsin. The capacity of greglin to inhibit neutrophil elastase was not significantly affected by exposure to acetonitrile, high temperature (90 °C), low or high pH (2.5–11.0), N-chlorosuccinimide-mediated oxidation or the proteolytic enzymes trypsin, papain and pseudolysin from Pseudomonas aeruginosa. Greglin efficiently inhibits the neutrophil elastase activity of sputum supernatants from cystic fibrosis patients. Its biological function in the locust ovary gland is currently unknown, but its physicochemical properties suggest that it can be used as a template to design a new generation of highly resistant elastase inhibitors for treating inflammatory diseases.

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Siedle, Bettina, Andrea Hrenn, and Irmgard Merfort. "Natural Compounds as Inhibitors of Human Neutrophil Elastase." Planta Medica 73, no. 5 (May 2007): 401–20. http://dx.doi.org/10.1055/s-2007-967183.

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Siedle, B., S. Cisielski, R. Murillo, B. Löser, V. Castro, C. A. Klaas, O. Hucke, A. Labahn, M. F. Melzig, and I. Merfort. "Sesquiterpene lactones as inhibitors of human neutrophil elastase." Bioorganic & Medicinal Chemistry 10, no. 9 (September 2002): 2855–61. http://dx.doi.org/10.1016/s0968-0896(02)00149-9.

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António, João P. M., Lídia M. Gonçalves, Rita C. Guedes, Rui Moreira, and Pedro M. P. Gois. "Diazaborines as New Inhibitors of Human Neutrophil Elastase." ACS Omega 3, no. 7 (July 6, 2018): 7418–23. http://dx.doi.org/10.1021/acsomega.8b00702.

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Carden, D., F. Xiao, Candace Moak, Bradley H. Willis, Sherry Robinson-Jackson, and Steve Alexander. "Neutrophil elastase promotes lung microvascular injury and proteolysis of endothelial cadherins." American Journal of Physiology-Heart and Circulatory Physiology 275, no. 2 (August 1, 1998): H385—H392. http://dx.doi.org/10.1152/ajpheart.1998.275.2.h385.

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Intestinal ischemia-reperfusion (I-R) is associated with lung injury and the acute respiratory distress syndrome. The hypothesis of this study was that intestinal I-R activates circulating neutrophils to promote elastase-mediated lung injury. Isolated rat lungs were perfused with blood or plasma obtained after intestinal I-R, and lung neutrophil retention and injury and bronchoalveolar lavage (BAL) elastase were measured. Perfusion with I-R blood caused lung neutrophil accumulation and injury and increased BAL elastase. These effects were attenuated by the elastase inhibitor L-658758. Interference with neutrophil adherence before gut reperfusion blocked BAL elastase accumulation. The role of endothelial junction proteins (cadherins) in I-R-elicited lung damage was also evaluated. Activated human neutrophils proteolyzed cadherins in human umbilical vein endothelial cells. Furthermore, plasma of patients with acute respiratory distress syndrome contained soluble cadherin fragments. The results of this study suggest that the elastase released by systemically activated neutrophils contributes to lung neutrophil accumulation and pulmonary microvascular injury. Elastase-mediated proteolysis of endothelial cell cadherins may represent the mechanism through which lung microvascular integrity is disrupted after intestinal I-R.

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Takeyama, Kiyoshi, Carlos Agustí, Iris Ueki, James Lausier, Lars Olaf Cardell, and Jay A. Nadel. "Neutrophil-dependent goblet cell degranulation: role of membrane-bound elastase and adhesion molecules." American Journal of Physiology-Lung Cellular and Molecular Physiology 275, no. 2 (August 1, 1998): L294—L302. http://dx.doi.org/10.1152/ajplung.1998.275.2.l294.

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We examined the effect of the neutrophil chemoattractants interleukin (IL)-8 and N-formyl-methionyl-leucyl-phenylalanine on goblet cell (GC) degranulation in guinea pigs. Chemoattractants caused time-dependent neutrophil recruitment and GC degranulation in vivo. NPC 15669 (an inhibitor of leukocyte infiltration) prevented both responses, implicating neutrophils. ICI 200,355 (an inhibitor of neutrophil elastase and proteinase-3) or secretory leukocyte protease inhibitor (an inhibitor of elastase but not of proteinase-3) abolished IL-8-induced GC degranulation, implicating elastase. Incubating tracheal segments with IL-8 plus neutrophils caused GC degranulation in vitro, an effect due to activation of the neutrophils themselves (and not an effect present in the supernatant). Chemoattractant increased surface staining of elastase and the cleavage of elastase-specific fluorogenic substrate by neutrophils. Pretreatment with anti-intercellular adhesion molecule-1, anti-CD18, or anti-CD11b antibody inhibited the chemoattractant-induced GC degranulation in vitro, implicating adhesion molecules. These studies suggest that chemoattractants cause neutrophil-dependent GC degranulation involving adhesive interactions between cells, with elastase activity occurring at the cell interface, causing GC secretion. The findings, reproduced in human airways, suggest novel methods of therapeutic intervention.

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Tyagi, Suresh C., and Sanford R. Simon. "Interaction of neutrophil elastase with hydrophobic polyanionic chelators." Biochemistry and Cell Biology 69, no. 9 (September 1, 1991): 624–29. http://dx.doi.org/10.1139/o91-092.

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The polyanionic calcium chelators, ethylenediamine-tetraacetic acid (EDTA), ethylene-bis-(oxyethylenenitrilo)-tetraacetic acid (EGTA), [bis-(O-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid (BAPTA), 1-[2-amino-5-(6-carboxy-indol-2-yl)phenoxyl]-2-(2′-amino-5′-methylphenoxy)ethane- N,N,N′,N′-tetraacetic acid (INDO-1), 1-[2-(5-carboxyoxazol-2yl)-6-phenoxyl]-2-(2′-amino-5′-methylphenoxy)ethane-N,N,N′,N′-tetraacetic acid (FURA-2), and 2-{[2-bis-(carboxymethyl)-amino-5-methylphenoxy]-methyl}-6-methyl-8-bis-(bis-(carboxymethyl)-aminoquinoline (QUIN-2), are all inhibitors of amidolytic activity of human neutrophil elastase (HNE). With MeOSuc-Ala-Ala-Pro-Val-pNA as substrate, these chelators all display mixed partial competitive and partial noncompetitive inhibition, but with the smaller substrate, pGlu-Pro-Val-pNA, only the noncompetitive component persists. The most effective inhibitor is FURA-2, with an apparent Ki of 0.5–0.7 mM. QUIN-2 is somewhat less effective, with a Ki of 2 mM, while EDTA is much less effective, with a Ki of 7 mM. In general, the more hydrophobic chelators are the best inhibitors, although INDO-1, which is about the same size as FURA-2, is surprisingly ineffective as an inhibitor. The chelators no longer function as effective inhibitors if their carboxyl groups are blocked by esterification with acetoxymethyl groups or by complexation with calcium ions, indicating that their binding to HNE is mediated in part through electrostatic interactions with a center of positive charge on the protein. The excitation spectrum of the complex of FURA-2 with HNE differs from that of the chelator with calcium ions, indicating that the structure of the enzyme-inhibitor complex is not like that of the coordination complex of the chelator with the metal ion. The inhibitory capacity of FURA-2 apparently arises from binding to a site that is in the vicinity of the S4 and S5 subsites of the extended substrate binding domain on HNE through a combination of hydrophobic and electrostatic interactions with the enzyme.Key words: elastase, protease inhibitors, chelators, poly anions, calcium.

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Distelhorst, CW, KE Janiga, KJ Howard, SE Strandjord, and EJ Campbell. "Neutrophil elastase produces 52-kD and 30-kD glucocorticoid receptor fragments in the cytosol of human leukemia cells." Blood 70, no. 3 (September 1, 1987): 860–68. http://dx.doi.org/10.1182/blood.v70.3.860.860.

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Abstract Characterization of glucocorticoid receptors in leukemia cells is important to understand mechanisms of glucocorticoid resistance but has been impeded by receptor fragmentation in cytosol extracts. We recently found that formation of 52- and 30-kilodalton (kD) glucocorticoid receptor fragments in cytosol of leukemia cells is due to proteolysis and is blocked by diisopropylfluorophosphate (DFP). In the present study, we identify a 28-kD serine protease in cytosol of leukemia cells that binds [3H]DFP and correlates with the formation of 52- and 30-kD receptor fragments. This protease is immunoprecipitated by antiserum to neutrophil elastase. Limited digestion of [3H]dexamethasone-21-mesylate- labeled receptors by purified neutrophil elastase produces 52- and 30- kD receptor fragments. Receptor fragmentation in the cytosol of leukemia cells in inhibited by methoxysuccinyl-alanyl-alanyl-prolyl- valyl-chloromethylketone, a highly specific inhibitor of neutrophil elastase. The addition of as few as 5% neutrophils to a lymphoid cell suspension provides sufficient elastase to produce receptor fragmentation. Our findings indicate that neutrophil elastase is responsible for receptor fragmentation in the cytosol of leukemia cells. The neutrophil elastase may be endogenous to the leukemia cells or may come from neutrophils that contaminate leukemia cell suspensions.

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Distelhorst, CW, KE Janiga, KJ Howard, SE Strandjord, and EJ Campbell. "Neutrophil elastase produces 52-kD and 30-kD glucocorticoid receptor fragments in the cytosol of human leukemia cells." Blood 70, no. 3 (September 1, 1987): 860–68. http://dx.doi.org/10.1182/blood.v70.3.860.bloodjournal703860.

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Characterization of glucocorticoid receptors in leukemia cells is important to understand mechanisms of glucocorticoid resistance but has been impeded by receptor fragmentation in cytosol extracts. We recently found that formation of 52- and 30-kilodalton (kD) glucocorticoid receptor fragments in cytosol of leukemia cells is due to proteolysis and is blocked by diisopropylfluorophosphate (DFP). In the present study, we identify a 28-kD serine protease in cytosol of leukemia cells that binds [3H]DFP and correlates with the formation of 52- and 30-kD receptor fragments. This protease is immunoprecipitated by antiserum to neutrophil elastase. Limited digestion of [3H]dexamethasone-21-mesylate- labeled receptors by purified neutrophil elastase produces 52- and 30- kD receptor fragments. Receptor fragmentation in the cytosol of leukemia cells in inhibited by methoxysuccinyl-alanyl-alanyl-prolyl- valyl-chloromethylketone, a highly specific inhibitor of neutrophil elastase. The addition of as few as 5% neutrophils to a lymphoid cell suspension provides sufficient elastase to produce receptor fragmentation. Our findings indicate that neutrophil elastase is responsible for receptor fragmentation in the cytosol of leukemia cells. The neutrophil elastase may be endogenous to the leukemia cells or may come from neutrophils that contaminate leukemia cell suspensions.

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30

Woodman, RC, PH Reinhardt, S. Kanwar, FL Johnston, and P. Kubes. "Effects of human neutrophil elastase (HNE) on neutrophil function in vitro and in inflamed microvessels." Blood 82, no. 7 (October 1, 1993): 2188–95. http://dx.doi.org/10.1182/blood.v82.7.2188.2188.

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Abstract The primary objective of this study was to test the hypothesis that human neutrophil elastase (HNE) affects neutrophil infiltration (adhesion and emigration) into inflamed vessels. To determine whether HNE contributes to neutrophil adhesion in vivo, intravital microscopy was used to study neutrophil-endothelial cell interactions in single inflamed postcapillary venules. Superfusion of platelet-activating factor (PAF) (100 nmol/L) onto the mesentery caused an increase in neutrophil-neutrophil interactions, neutrophil adhesion to postcapillary venules, and cellular emigration out of the vasculature. Both L658 758 (an elastase-specific inhibitor), and Eglin C (an elastase and cathepsin G inhibitor) significantly attenuated all of these parameters in vivo. To further characterize the mechanism(s) involved, various in vitro parameters were assessed. HNE, but not trypsin, caused a dose-dependent (0.01 to 1.0 microgram/mL) increase in the expression of the beta subunit (CD18) of the CD11/CD18 adhesive glycoprotein complex on neutrophils. An HNE-dependent increase in CD11b expression was also observed; however, HNE did not affect the expression of other neutrophil adhesion molecules (L-selectin), superoxide production, or degranulation. PAF-enhanced CD18 expression on neutrophils and neutrophil migration were both abolished by L658 758 but PAF-induced neutrophil adhesion to endothelial monolayers was not affected by the antiproteinase. The in vitro data suggest that the antiproteinases do not directly prevent neutrophil adhesion in vivo but may be important in other CD18-dependent events such as neutrophil- neutrophil interaction or neutrophil infiltration (chemotaxis). These results translate into an important, rate-limiting role for elastase in the process of leukocyte infiltration and accumulation in inflamed microvessels.

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Woodman, RC, PH Reinhardt, S. Kanwar, FL Johnston, and P. Kubes. "Effects of human neutrophil elastase (HNE) on neutrophil function in vitro and in inflamed microvessels." Blood 82, no. 7 (October 1, 1993): 2188–95. http://dx.doi.org/10.1182/blood.v82.7.2188.bloodjournal8272188.

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The primary objective of this study was to test the hypothesis that human neutrophil elastase (HNE) affects neutrophil infiltration (adhesion and emigration) into inflamed vessels. To determine whether HNE contributes to neutrophil adhesion in vivo, intravital microscopy was used to study neutrophil-endothelial cell interactions in single inflamed postcapillary venules. Superfusion of platelet-activating factor (PAF) (100 nmol/L) onto the mesentery caused an increase in neutrophil-neutrophil interactions, neutrophil adhesion to postcapillary venules, and cellular emigration out of the vasculature. Both L658 758 (an elastase-specific inhibitor), and Eglin C (an elastase and cathepsin G inhibitor) significantly attenuated all of these parameters in vivo. To further characterize the mechanism(s) involved, various in vitro parameters were assessed. HNE, but not trypsin, caused a dose-dependent (0.01 to 1.0 microgram/mL) increase in the expression of the beta subunit (CD18) of the CD11/CD18 adhesive glycoprotein complex on neutrophils. An HNE-dependent increase in CD11b expression was also observed; however, HNE did not affect the expression of other neutrophil adhesion molecules (L-selectin), superoxide production, or degranulation. PAF-enhanced CD18 expression on neutrophils and neutrophil migration were both abolished by L658 758 but PAF-induced neutrophil adhesion to endothelial monolayers was not affected by the antiproteinase. The in vitro data suggest that the antiproteinases do not directly prevent neutrophil adhesion in vivo but may be important in other CD18-dependent events such as neutrophil- neutrophil interaction or neutrophil infiltration (chemotaxis). These results translate into an important, rate-limiting role for elastase in the process of leukocyte infiltration and accumulation in inflamed microvessels.

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Abbinante-Nissen, J. M., L. G. Simpson, and G. D. Leikauf. "Neutrophil elastase increases secretory leukocyte protease inhibitor transcript levels in airway epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 265, no. 3 (September 1, 1993): L286—L292. http://dx.doi.org/10.1152/ajplung.1993.265.3.l286.

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Airway inflammation is often associated with the infiltration of activated neutrophils and subsequent protease release. Although aiding in the digestion and phagocytosis of foreign proteins and microorganisms, neutrophil proteases can indiscriminately damage healthy lung tissue. In the conducting airway, proteases, particularly neutrophil elastase, are counter-balanced by several antiproteases, including secretory leukocyte protease inhibitor (SLPI). SLPI can be produced locally by a number of cells including the airway epithelial cell. To examine the effects of neutrophil granule components on SLPI transcript levels, airway epithelial cells were treated (up to 96 h) with elastase, other proteases, or enzymes isolated from human sputum. We found that neutrophil elastase increased SLPI transcript levels in primary and transformed human airway epithelial cells in a time- and dose-dependent manner. Other neutrophil products, such as cathepsin G, myeloperoxidase, and lysozyme, had little or no effect on SLPI transcript levels. However, two nonneutrophil proteases, trypsin and pancreatic elastase, also increased SLPI transcript levels at higher doses than that required of neutrophil elastase. Two inflammatory cytokines, tumor necrosis factor-alpha and interleukin-8, produced little or no effect on SLPI transcript levels. This study demonstrates one way in which SLPI is regulated, via a protease that it inhibits, neutrophil elastase.

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Rao, Ravi M., Travis V. Betz, Deanna J. Lamont, Michael B. Kim, Sunil K. Shaw, Richard M. Froio, Françoise Baleux, Fernando Arenzana-Seisdedos, Ronen Alon, and Francis W. Luscinskas. "Elastase Release by Transmigrating Neutrophils Deactivates Endothelial-bound SDF-1α and Attenuates Subsequent T Lymphocyte Transendothelial Migration." Journal of Experimental Medicine 200, no. 6 (September 20, 2004): 713–24. http://dx.doi.org/10.1084/jem.20040499.

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Leukocyte trafficking to sites of inflammation follows a defined temporal pattern, and evidence suggests that initial neutrophil transendothelial migration modifies endothelial cell phenotype. We tested the hypothesis that preconditioning of human umbilical vein endothelial cells (HUVEC) by neutrophils would also modify the subsequent transendothelial migration of T lymphocytes across cytokine-stimulated HUVEC in an in vitro flow assay. Using fluorescence microscopy, preconditioning of HUVEC by neutrophils was observed to significantly reduce the extent of subsequent stromal cell–derived factor-1α (SDF-1α [CXCL12])-mediated T lymphocyte transendothelial migration, without reducing accumulation. In contrast, recruitment of a second wave of neutrophils was unaltered. Conditioned medium harvested after transendothelial migration of neutrophils or supernatants from stimulated neutrophils mediated a similar blocking effect, which was negated using a specific neutrophil elastase inhibitor. Furthermore, T lymphocyte transendothelial migration was inhibited by treatment of HUVEC with purified neutrophil elastase, which selectively cleaved the amino terminus of HUVEC-bound SDF-1α, which is required for its chemotactic activity. The reduction in T lymphocyte transendothelial migration was not observed using a different chemokine, ELC (CCL19), and was not reversed by replenishment of SDF-1α, indicating endothelial retention of the inactivated chemokine. In summary, transmigrating neutrophils secrete localized elastase that is protected from plasma inhibitors, and thereby modulate trafficking of other leukocyte subsets by altering the endothelial-associated chemotactic activities.

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Liu, Hong, Stephen C. Lazarus, George H. Caughey, and John V. Fahy. "Neutrophil elastase and elastase-rich cystic fibrosis sputum degranulate human eosinophils in vitro." American Journal of Physiology-Lung Cellular and Molecular Physiology 276, no. 1 (January 1, 1999): L28—L34. http://dx.doi.org/10.1152/ajplung.1999.276.1.l28.

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Neutrophils, eosinophils, and their proinflammatory constituents are important mediators of airway disease, and high levels of neutrophil proteases and eosinophil cationic protein (ECP) are found in sputum from patients with cystic fibrosis (CF). To investigate whether neutrophil proteases or CF sputum causes eosinophil degranulation, purified eosinophils from atopic asthmatic subjects were incubated for 2 h with neutrophil elastase, cathepsin G, and CF sputum, and the release of ECP was measured. We found that the percent release of ECP was higher after incubation with neutrophil elastase (10−5 M) than with a buffer control [6.1 ± 0.8 (SE) vs. 1.7 ± 0.1%; P < 0.003] and represented >50% of the release caused by positive controls [Ca2+ ionophore A-23187 (5 × 10−6 M) or serum-coated Sephadex beads]. The release of ECP after incubation with cathepsin G (2.3 ± 0.2%) and CF sputum (6.2 ± 2.0%) was also significantly higher than that with a buffer control ( P < 0.05). Neutralization of free elastase activity with α1-proteinase inhibitor reduced the mean percent degranulation of eosinophils by neutrophil elastase by 50% ( P = 0.0004) and by CF sputum by 75% ( P = 0.02). Preincubation of eosinophils with cytochalasin B (10 mg/ml) and depletion of the incubation medium of Ca2+ also significantly attenuated degranulation of eosinophils incubated with purified free neutrophil elastase or CF sputum ( P < 0.05). We conclude that neutrophil proteases, especially neutrophil elastase, and elastase-rich CF sputum cause degranulation of eosinophils in a mechanism partially dependent on Ca2+ and actin filaments.

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Roghanian, A., P. M. Fitch, S. E. M. Howie, and J. M. Sallenave. "Human neutrophil elastase inhibitors in innate and adaptive immunity." Biochemical Society Transactions 34, no. 2 (April 1, 2006): 279. http://dx.doi.org/10.1042/bst20060279.

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Ohbayashi, Hiroyuki. "Current synthetic inhibitors of human neutrophil elastase in 2005." Expert Opinion on Therapeutic Patents 15, no. 7 (July 2005): 759–71. http://dx.doi.org/10.1517/13543776.15.7.759.

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Lucas, S. D., M. P. Carrasco, L. M. Gonçalves, R. Moreira, and R. C. Guedes. "Discovery of C-shaped aurone human neutrophil elastase inhibitors." MedChemComm 6, no. 8 (2015): 1508–12. http://dx.doi.org/10.1039/c5md00164a.

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38

Killackey, John J. F., and Barbara A. Killackey. "Neutrophil-mediated increased permeability of microcarrier-cultured endothelial monolayers: a model for the in vitro study of neutrophil-dependent mediators of vasopermeability." Canadian Journal of Physiology and Pharmacology 68, no. 7 (July 1, 1990): 836–44. http://dx.doi.org/10.1139/y90-127.

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Changes in the permeability of human endothelial monolayers in response to activated human neutrophils were examined in a novel, in vitro model of vasopermeability changes. Microcarrier-cultured human umbilical vein endothelial monolayers were used in a system that responds to histamine. Human neutrophils did not increase Evans Blue staining of the endothelium-covered microcarriers if added alone or if added with the neutrophil-dependent mediator of vasopermeability, formyl-methionyl-leucyl-phenylalanine (FMLP, 0.1 μM). In contrast, neutrophils added to the endothelial cells in a ratio as low as 2.5:1 caused time-dependent increases in microcarrier staining if pretreated with cytochalasin B (5 μg/mL) before addition with FMLP. Neutrophil cell-free releasate and purified human sputum elastase also caused concentration-related increases in Evans Blue staining of the endothelial-covered microcarriers and these effects were inhibited by the elastase inhibitor methoxysuccinyl-alanyl-alanyl-prolyl-valyl chloromethyl ketone. This compound also inhibited neutrophil-mediated endothelial permeability increases. The microcarrier-cultured human endothelial monolayer system rapidly detects permeability alterations of endothelial monolayers in response to activated human neutrophils. This model is a potentially useful screening assay for the development of therapeutic agents, directed at neutrophil degranulation or degranulation products, for the control of inflammatory vasopermeability abnormalities.Key words: neutrophil, endothelium, permeability, elastase, microcarrier.

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39

Zheng, Qinheng, Jordan L. Woehl, Seiya Kitamura, Diogo Santos-Martins, Christopher J. Smedley, Gencheng Li, Stefano Forli, John E. Moses, Dennis W. Wolan, and K. Barry Sharpless. "SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase." Proceedings of the National Academy of Sciences 116, no. 38 (September 4, 2019): 18808–14. http://dx.doi.org/10.1073/pnas.1909972116.

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Sulfur fluoride exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled, agnostic approach for the discovery and optimization of covalent inhibitors of human neutrophil elastase (hNE). Evaluation of our ever-growing collection of SuFExable compounds toward various biological assays unexpectedly revealed a selective and covalent hNE inhibitor: benzene-1,2-disulfonyl fluoride. Synthetic derivatization of the initial hit led to a more potent agent, 2-(fluorosulfonyl)phenyl fluorosulfate with IC50 0.24 μM and greater than 833-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized, yet simple benzenoid probe only modified active hNE and not its denatured form.

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40

Tsai, Yung-Fong, Shun-Chin Yang, Wen-Yi Chang, Jih-Jung Chen, Chun-Yu Chen, Shih-Hsin Chang, and Tsong-Long Hwang. "Garcinia Multiflora Inhibits FPR1-Mediated Neutrophil Activation and Protects Against Acute Lung Injury." Cellular Physiology and Biochemistry 51, no. 6 (2018): 2776–93. http://dx.doi.org/10.1159/000495970.

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Background/Aims: Formyl peptide receptors (FPRs) recognize different endogenous and exogenous molecular stimuli and mediate neutrophil activation. Dysregulation of excessive neutrophil activation and the resulting immune responses can induce acute lung injury (ALI) in the host. Accordingly, one promising approach to the treatment of neutrophil-dominated inflammatory diseases involves therapeutic FPR1 inhibition. Methods: We extracted a potent FPR1 antagonist from Garcinia multiflora Champ. (GMC). The inhibitory effects of GMC on superoxide anion release and elastase degranulation from activated human neutrophils were determined with spectrophotometric analysis. Reactive oxygen species (ROS) production and the FPR1 binding ability of neutrophils were assayed by flow cytometry. Signaling transduction mediated by GMC in response to chemoattractants was assessed with a calcium influx assay and western blotting. A lipopolysaccharide (LPS)-induced ALI mouse model was used to determine the therapeutic effects of GMC in vivo. Results: GMC significantly reduced superoxide anion release, the reactive oxidants derived therefrom, and elastase degranulation mediated through selective, competitive FPR1 blocking in N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF)-stimulated human neutrophils. In cell-free systems, GMC was unable to scavenge superoxide anions or suppress elastase activity. GMC produced a right shift in fMLF-activated concentration-response curves and was confirmed to be a competitive FPR1 antagonist. GMC binds to FPR1 not only in neutrophils, but also FPR1 in neutrophil-like THP-1 and hFPR1-transfected HEK293 cells. Furthermore, the mobilization of calcium and phosphorylation of mitogen-activated protein kinases and Akt, which are involved in FPR1-mediated downstream signaling, was competitively blocked by GMC. In an in vivo study, GMC significantly reduced pulmonary edema, neutrophil infiltration, and alveolar damage in LPS-induced ALI mice. Conclusion: Our findings demonstrate that GMC is a natural competitive FPR1 inhibitor, which makes it a possible anti-inflammatory treatment option for patients critically inflicted with FPR1-mediated neutrophilic lung damage.

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Boudier, C., and J. G. Bieth. "Oxidized mucus proteinase inhibitor: a fairly potent neutrophil elastase inhibitor." Biochemical Journal 303, no. 1 (October 1, 1994): 61–68. http://dx.doi.org/10.1042/bj3030061.

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N-chlorosuccinimide oxidizes one of the methionine residues of mucus proteinase inhibitor with a second-order rate constant of 1.5 M-1.s-1. Cyanogen bromide cleavage and NH2-terminal sequencing show that the modified residue is methionine-73, the P′1 component of the inhibitor's active centre. Oxidation of the inhibitor decreases its neutrophil elastase inhibitory capacity but does not fully abolish it. The kinetic parameters describing the elastase-oxidized inhibitor interaction are: association rate constant kass. = 2.6 x 10(5) M-1.s-1, dissociation rate constant kdiss. = 2.9 x 10(-3) s-1 and equilibrium dissociation constant Ki = 1.1 x 10(-8) M. Comparison with the native inhibitor indicates that oxidation decreases kass. by a factor of 18.8 and increases kdiss. by a factor of 6.4, and therefore leads to a 120-fold increase in Ki. Yet, the oxidized inhibitor may still act as a potent elastase inhibitor in the upper respiratory tract where its concentration is 500-fold higher than Ki, i.e. where the elastase inhibition is pseudo-irreversible. Experiments in vitro with fibrous human lung elastin, the most important natural substrate of elastase, support this view: 1.35 microM elastase is fully inhibited by 5-6 microM oxidized inhibitor whether the enzyme-inhibitor complex is formed in the presence or absence of elastin and whether elastase is pre-adsorbed on elastin or not.

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42

Verbout, Norah, Asako Itakura, Joseph Aslan, Erik Tucker, Andras Gruber, and Owen J. T. McCarty. "Coagulation Factors XIa and XIIa Modulate Neutrophil Elastase Release,." Blood 118, no. 21 (November 18, 2011): 3220. http://dx.doi.org/10.1182/blood.v118.21.3220.3220.

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Abstract Abstract 3220 Neutrophils play a vital role in innate immunity. Activated neutrophils can release proteolytic enzymes capable of neutralizing microbes and contributing importantly to host-defense. In severe sepsis, microbial components and pro-inflammatory cytokines can contribute to excess systemic neutrophil activation, resulting in tissue damage and organ failure. Thus, regulation of neutrophil activation and factor release is critical during pathologic conditions. Recent data indicate that components of the contact system modulate numerous inflammatory mediators during severe sepsis, but the exact role of the contact pathway in host-defense is not well understood. Inhibition of factor XII (FXII) in septic baboons reduces circulating neutrophil elastase (NE), a potent cytolytic enzyme that is increased during sepsis and implicated in organ failure. In vitro studies also indicate that both plasma kallikrein and FXIIa are capable of directly inducing NE release. While it is apparent that factors of the contact system interact with neutrophils, the molecular mechanisms by which these factors modulate neutrophil function have not been established. We therefore examined factor XI (FXI) neutrophil interactions and the cellular signaling pathways regulating FXIIa neutrophil stimulation. Human neutrophils were isolated from peripheral blood and resuspended in HBSS at a concentration of 0.5 ×106/ml. Cells were treated with FXI, FXIa, FXII, or FXIIa with or without fMLP (1 μM) stimulation, and the release of NE was assayed in the cell supernatants via ELISA. FXI, FXIa or FXII had no direct stimulatory effect on NE release compared to vehicle. While neither FXI nor FXII had any inhibitory effect on fMLP induced NE release, FXIa (10 μg/ml) modestly reduced fMLP-induced NE release by 20% (n=3). FXIIa (3, 10, 30 μg/ml) dose-dependently increased NE release in the presence of cytochalasin B (5 μg/ml), consistent with published data. To examine the mechanism by which FXIIa induces NE release, neutrophils were pretreated with signaling inhibitors and subsequently activated with FXIIa (30 μg/ml). Mammalian target of rapamycyin (mTOR) is a downstream serine/threonine kinase of the PI3K/AKT pathway that integrates signals from the microenvironment such as cytokines and growth factors. It is known that inhibition of mTORC2 abrogates neutrophil polarization and directed migration, thus we examined the role of rapamycin complex 1 and 2 (mTORC1/2) in mediating NE release. Pretreatment of cells with RAD001 (20 nM), an mTORC1 inhibitor had no effect on FXIIa-induced NE release, whereas the combined mTORC1/mTORC2 inhibitor, pp242 (100 nM) abrogated FXIIa-induced NE release, suggesting that components of the mTORC2 pathway contribute to NE release. Pretreatment with EHT 1864 (50 uM), a Rac inhibitor, significantly potentiated NE release induced by either fMLP or FXIIa, suggesting that Rac is also capable of modulating FXIIa signaling. Taken together, these results suggest that coagulation factors FXIa and FXIIa differentially modulate neutrophil function, and that the mTOR and Rac signaling pathways participate in FXIIa stimulated neutrophil activation. These data suggest that the contact pathway is involved in neutrophil stimulation through mTOR and Rac signaling, and thus modulating these pathways could be a potential therapeutic strategy for limiting excess neutrophil activation. Disclosures: Gruber: Aronora, LLC: Consultancy, Equity Ownership.

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Areias, L. R. P., E. F. P. Ruivo, L. M. Gonçalves, M. T. Duarte, V. André, R. Moreira, S. D. Lucas, and R. C. Guedes. "A unified approach toward the rational design of selective low nanomolar human neutrophil elastase inhibitors." RSC Advances 5, no. 64 (2015): 51717–21. http://dx.doi.org/10.1039/c5ra07783d.

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Rudolphus, A., R. Heinzel-Wieland, V. A. M. M. Vincent, D. Saunders, G. J. Steffens, J. H. Dijkman, and J. A. Kramps. "Oxidation-resistant variants of recombinant anti-leucoprotease are better inhibitors of human-neutrophil-elastase-induced emphysema in hamsters than natural recombinant antileucoprotease." Clinical Science 81, no. 6 (December 1, 1991): 777–84. http://dx.doi.org/10.1042/cs0810777.

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1. Antileucoprotease, being sensitive to oxidative inactivation, can be produced by recombinant techniques. Via site-directed mutagenesis, two mutants of recombinant antileucoprotease were produced in which one or more of the oxidation-sensitive methionine residues were replaced by leucine: in rALP242, methionine-73 was replaced by leucine, and in rALP231, leucine was substituted for four methionine residues. In vitro, native antileucoprotease and the recombinant antileucoprotease preparations have similar inhibitory characteristics towards human neutrophil elastase. We hypothesized that replacement of methionine residues in the antileucoprotease molecule would result in a reduced oxidation sensitivity of the mutants. 2. After incubation of recombinant antileucoprotease and its mutants with increasing dosages of cis-platinum(II)diammine dichloride, we observed that native antileucoprotease and recombinant antileucoprotease were inactivated by this reagent to the same extent. Compared with this, rALP242 was less inactivated, whereas the inhibitory capacity of rALP231 was not influenced by cis-platinum(II)diammine dichloride at all. 3. After incubation of recombinant antileucoprotease, rALP242 and rALP231 with triggered polymorphonuclear leucocytes, which are thought to produce an excess of oxidants, we measured residual inhibitory activities towards human neutrophil elastase of 10%, 55% and 87%, respectively. 4. In vivo, the inhibitory effects of intratracheally administered rALP242 and rALP231 towards human-neutrophil-elastase-induced emphysema were significantly greater than that of recombinant antileucoprotease. There were no significant differences between the mutants. With respect to secretory cell metaplasia and haemorrhage, rALP231 tended to be a better inhibitor than recombinant antileucoprotease and rALP242. 5. We conclude that the recombinant antileucoprotease mutants are less sensitive to oxidation and consequently inhibit human-neutrophil-elastase-induced emphysema to a greater extent than recombinant antileucoprotease.

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Kang, HanGoo, Jinwon Seo, Eun-Jeong Yang, and In-Hong Choi. "Silver Nanoparticles Induce Neutrophil Extracellular Traps Via Activation of PAD and Neutrophil Elastase." Biomolecules 11, no. 2 (February 19, 2021): 317. http://dx.doi.org/10.3390/biom11020317.

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Silver nanoparticles (AgNPs) are widely used in various fields because of their antimicrobial properties. However, many studies have reported that AgNPs can be harmful to both microorganisms and humans. Reactive oxygen species (ROS) are a key factor of cytotoxicity of AgNPs in mammalian cells and an important factor in the immune reaction of neutrophils. The immune reactions of neutrophils include the expulsion of webs of DNA surrounded by histones and granular proteins. These webs of DNA are termed neutrophil extracellular traps (NETs). NETs allow neutrophils to catch and destroy pathogens in extracellular spaces. In this study, we investigated how AgNPs stimulate neutrophils, specifically focusing on NETs. Freshly isolated human neutrophils were treated with 5 or 100 nm AgNPs. The 5 nm AgNPs induced NET formation, but the 100 nm AgNPs did not. Subsequently, we investigated the mechanism of AgNP-induced NETs using known inhibitors related to NET formation. AgNP-induced NETs were dependent on ROS, peptidyl arginine deiminase, and neutrophil elastase. The result in this study indicates that treatment of 5 nm AgNPs induce NET formation through histone citrullination by peptidyl arginine deiminase and histone cleavage by neutrophil elastase.

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Sugimori, T., J. Cooley, J. R. Hoidal, and E. Remold-O'Donnell. "Inhibitory properties of recombinant human monocyte/neutrophil elastase inhibitor." American Journal of Respiratory Cell and Molecular Biology 13, no. 3 (September 1995): 314–22. http://dx.doi.org/10.1165/ajrcmb.13.3.7654387.

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Kim, Kwan-Chul, Yong-Beom Kwon, Hae-Dong Jang, Jae Wha Kim, Jae Cheol Jeong, Ik-Soo Lee, Byung-Jo Ha, and Ick-Dong Yoo. "Study on the Antioxidant and Human Neutrophil Elastase Inhibitory Activities of Mushroom Ramaria formosa Extracts." Journal of the Society of Cosmetic Scientists of Korea 42, no. 3 (September 30, 2016): 269–78. http://dx.doi.org/10.15230/scsk.2016.42.3.269.

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48

Sallenave, J. M. "Antimicrobial activity of antiproteinases." Biochemical Society Transactions 30, no. 2 (April 1, 2002): 111–15. http://dx.doi.org/10.1042/bst0300111.

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Abstract:

Low-molecular-mass neutrophil elastase inhibitors have been shown to be important in the control of lung inflammation. In addition to inhibiting the enzyme neutrophil elastase, these low-molecular-mass compounds (10 kDa) have been shown to have other activities. For example, secretory leucocyte proteinase inhibitor (SLPI) and elastase-specific inhibitor/SKALP (skin-derived antileucoproteinase)/elafin have also been shown to have ‘defensin’-like antimicrobial activities. Indeed, these inhibitors have antimicrobial properties in vitro against bacteria, fungi and, potentially, HIV. In addition, we have shown, using an adenovirus-mediated gene transfer overexpression strategy, that elafin is also active against Pseudomonas aeruginosa infection in mice in vivo. The mechanism of action is currently under investigation. In addition to these direct or indirect effects on microbes, it has been shown that lipopolysaccharide is able to up-regulate SPLI production in macrophages in vitro, and that the addition of recombinant SLPI to human monocytes or the transfection of macrophages with SPLI can down-regulate pro-inflammatory mediators such as tumour necrosis factor, presumably to limit self-damaging excessive inflammation. Using viral gene transfer vectors, we are currently investigating the potential of these inhibitors in various models of inflammation in vivo.

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Al-Horani, Rami A., and Madhusoodanan Mottamal. "Sulfonated Arylurea Derivatives are Potent Inhibitors of Human Neutrophil Elastase." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.04403.

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Ohmoto, Kazuyuki, Tetsuya Yamamoto, Motohiro Okuma, Toshihide Horiuchi, Hirotoshi Imanishi, Yoshihiko Odagaki, Kazuhito Kawabata, et al. "Development of Orally Active Nonpeptidic Inhibitors of Human Neutrophil Elastase." Journal of Medicinal Chemistry 44, no. 8 (April 2001): 1268–85. http://dx.doi.org/10.1021/jm000410y.

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Journal articles on the topic 'Human neutrophil elastase inhibitors'

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