Inhibition of the chlorinating activity of myeloperoxidase by tempol: revisiting the kinetics and mechanisms

2011 ◽  
Vol 439 (3) ◽  
pp. 423-434 ◽  
Author(s):  
Raphael F. Queiroz ◽  
Sandra M. Vaz ◽  
Ohara Augusto
Keyword(s):  
Hypochlorous Acid ◽  
Tissue Injury ◽  
Kinetic Modelling ◽  
Oxidation Kinetic ◽  
Reversible Inhibitor ◽  
Binding Interaction ◽  
Oxidative Potential ◽  
Oxidant Production ◽  
A Minor ◽  
Kinetics Of

The nitroxide tempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl) reduces tissue injury in animal models of inflammation by mechanisms that are not completely understood. MPO (myeloperoxidase), which plays a fundamental role in oxidant production by neutrophils, is an important target for anti-inflammatory action. By amplifying the oxidative potential of H2O2, MPO produces hypochlorous acid and radicals through the oxidizing intermediates MPO-I [MPO-porphyrin•+-Fe(IV)=O] and MPO-II [MPO-porphyrin-Fe(IV)=O]. Previously, we reported that tempol reacts with MPO-I and MPO-II with second-order rate constants similar to those of tyrosine. However, we noticed that tempol inhibits the chlorinating activity of MPO, in contrast with tyrosine. Thus we studied the inhibition of MPO-mediated taurine chlorination by tempol at pH 7.4 and re-determined the kinetic constants of the reactions of tempol with MPO-I (k=3.5×105 M−1·s−1) and MPO-II, the kinetics of which indicated a binding interaction (K=2.0×10−5 M; k=3.6×10−2 s−1). Also, we showed that tempol reacts extremely slowly with hypochlorous acid (k=0.29 and 0.054 M−1·s−1 at pH 5.4 and 7.4 respectively). The results demonstrated that tempol acts mostly as a reversible inhibitor of MPO by trapping it as MPO-II and the MPO-II–tempol complex, which are not within the chlorinating cycle. After turnover, a minor fraction of MPO is irreversibly inactivated, probably due to its reaction with the oxammonium cation resulting from tempol oxidation. Kinetic modelling indicated that taurine reacts with enzyme-bound hypochlorous acid. Our investigation complements a comprehensive study reported while the present study was underway [Rees, Bottle, Fairfull-Smith, Malle, Whitelock and Davies (2009) Biochem. J. 421, 79–86].

Kinetic modelling of reactions for the synthesis of 2-methyl-5-ethyl pyridine

2021 ◽  
Author(s):  
Emanuele Moioli ◽  
Leo Schmid ◽  
Peter Wasserscheid ◽  
Hannsjoerg Freund
Keyword(s):  
Kinetic Modelling ◽  
Acid Catalyst ◽  
Acid Catalyzed ◽  
Catalyzed Reactions ◽  
Kinetics Of

The kinetics of the acid catalyzed reactions of acetaldehyde ammonia trimer (AAT) and paraldehyde (para) to 2-methyl-5-ethyl pyridine (MEP) in the presence of an acid catalyst were investigated systematically. A...

scholarly journals Rapid systemic surge of IL-33 after severe human trauma: a prospective observational study

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Olav Sundnes ◽  
William Ottestad ◽  
Camilla Schjalm ◽  
Peter Lundbäck ◽  
Lars la Cour Poulsen ◽  
...  
Keyword(s):  
High Resolution ◽  
Prospective Observational Study ◽  
Tissue Injury ◽  
Trauma Patients ◽  
Decoy Receptor ◽  
Interleukin 33 ◽  
Injured Patients ◽  
First Time ◽  
Kinetics Of ◽  
Insight Into

Abstract Background Alarmins are considered proximal mediators of the immune response after tissue injury. Understanding their biology could pave the way for development of new therapeutic targets and biomarkers in human disease, including multiple trauma. In this study we explored high-resolution concentration kinetics of the alarmin interleukin-33 (IL-33) early after human trauma. Methods Plasma samples were serially collected from 136 trauma patients immediately after hospital admission, 2, 4, 6, and 8 h thereafter, and every morning in the ICU. Levels of IL-33 and its decoy receptor sST2 were measured by immunoassays. Results We observed a rapid and transient surge of IL-33 in a subset of critically injured patients. These patients had more widespread tissue injuries and a greater degree of early coagulopathy. IL-33 half-life (t1/2) was 1.4 h (95% CI 1.2–1.6). sST2 displayed a distinctly different pattern with low initial levels but massive increase at later time points. Conclusions We describe for the first time early high-resolution IL-33 concentration kinetics in individual patients after trauma and correlate systemic IL-33 release to clinical data. These findings provide insight into a potentially important axis of danger signaling in humans.

THE ROLE OF MYELOPEROXIDASE AND NEUTROPHIL EXTRACELLULAR TRAPS IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S4-S4
Author(s):  
Belal Chami ◽  
Gulfam Ahmad ◽  
Angie Schroder ◽  
Patrick San Gabriel ◽  
Paul Witting
Keyword(s):  
Disease Severity ◽  
Hypochlorous Acid ◽  
Tissue Injury ◽  
Activity Index ◽  
Critical Role ◽  
Neutrophil Migration ◽  
Sodium Sulphate ◽  
Host Tissue ◽  
Neutrophil Extracellular Trap

Abstract Neutrophils are short-lived immune cells that represent the major cell type recruited to the inflamed bowel releasing their azurophilic granules containing enzymes myeloperoxidase (MPO). Fecal and serum MPO levels has previously been shown to correlate to disease severity in IBD patients. MPO, in the presence of H2O2 and free Cl- undergoes a halogenation cycle, yielding the two-electron oxidant, hypochlorous acid (HOCl) - a potent bactericidal agent. However, chronic intestinal exposure to MPO/HOCl due to perpetual inflammation may cause secondary host-tissue injury and cell death. Neutrophil Extracellular Trap (NET)osis is a specialised form of neutrophil death where MPO is entrapped in a DNA scaffold and continues to elicit HOCl activity and may further contribute to host-tissue injury. We investigated the presence of NETs in surgically excised ileum samples from CD and healthy patients using advanced confocal microscopic techniques and found MPO, Neutrophil Elastase (NE) and Citrullinated Histone h3 (CitH3) - critical components of NET formation, individually positively correlate to the severity of histopathological intestinal injury. Furthermore, multiplex Opal™ IHC performed using LMS880 Airyscan-moduled microscopy with z-stacking revealed colocalization of NE, MPO, CitH3 and DAPI indicating the extensive presence of NETs in severely affected CD tissue. Using two pharmacological inhibitors of MPO in a dextran sodium sulphate (DSS) model of murine colitis, we demonstrated the pathological role of MPO in experimental colitis. MPO inhibitors, TEMPOL and AZD3241 delivered via daily i.p significantly rescued the course of colitis by abrogating clinical indices including body weight loss, disease activity index, inhibiting serum peroxidation, and preserving colon length, while significantly mitigating histoarchitectural damage associated with DSS-induced colitis. We also showed that MPO inhibition decreased neutrophil migration to the gut, suggesting MPO may play a role in perpetuating the inflammatory cell by further recruiting cells to the inflamed gut. Collectively, we have shown for the first time that MPO is not only an important clinical marker of disease severity but may also play a critical role in perpetuating host-tissue damage and inflammation.

scholarly journals Kinetic modelling of NO heterogeneous radiation-catalytic oxidation on the TiO2 surface in humid air under the electron beam irradiation

Nukleonika ◽  
2017 ◽  
Vol 62 (3) ◽  
pp. 235-240 ◽  
Author(s):  
Henrietta Nichipor ◽  
Yongxia Sun ◽  
Andrzej G. Chmielewski
Keyword(s):  
Electron Beam ◽  
Catalytic Oxidation ◽  
Removal Efficiency ◽  
Electron Beam Irradiation ◽  
Kinetic Modelling ◽  
Water Concentration ◽  
Beam Irradiation ◽  
Humid Air ◽  
Kinetics Of ◽  
Influential Parameters

Abstract Theoretical study of NOx removal from humid air by a hybrid system (catalyst combined with electron beam) was carried out. The purpose of this work is to study the possibility to decrease energy consumption for NOx removal. The kinetics of radiation catalytic oxidation of NO on the catalyst TiO2 surface under electron beam irradiation was elaborated. Program Scilab 5.3.0 was used for numerical simulations. Influential parameters such as inlet NO concentration, dose, gas fl ow rate, water concentration and catalyst contents that can affect NOx removal efficiency were studied. The results of calculation show that the removal efficiency of NOx might be increased by 8-16% with the presence of a catalyst in the gas irradiated field.

Oxidation of Olefins Representing Some Structural Units of GR-S

1952 ◽  
Vol 25 (1) ◽  
pp. 21-32 ◽  
Author(s):  
W. C. Warner ◽  
J. Reid Shelton
Keyword(s):  
Phenyl Group ◽  
Kinetic Mechanism ◽  
Oxidation Reactions ◽  
Chain Reaction ◽  
Instantaneous Rate ◽  
Initial Oxygen ◽  
Oxidation Of Olefins ◽  
A Minor ◽  
The Relationship ◽  
Kinetics Of

Abstract Three olefins were oxidized in the liquid phase with molecular oxygen to determine the kinetics of the oxidation reactions and the relationship to oxidation of rubber. The instantaneous rate of oxidation was found to be related to the analytically determined olefin and peroxide concentrations by the equation : Rate=k (unreacted olefin)(peroxide), where rate equals moles of oxygen per mole of original olefin per hour and the parentheses represent molarities. Presence of a phenyl group was found to affect k, but only in a minor way, indicating that the same fundamental kinetic mechanism applies in both aromatic and aliphatic olefins. The data are consistent with the general kinetic mechanism of Bolland involving oxygen attack at the alpha-methylenic group. However, it appears probable that initial oxygen attack can also occur at the double bond, resulting in the formation of a peroxide biradical, which may then react with other olefin molecules, initiating the usual chain reaction mechanism.

Kinetics of reversible DIDS inhibition of chloride self exchange in human erythrocytes

1989 ◽  
Vol 257 (4) ◽  
pp. C601-C606 ◽  
Author(s):  
T. Janas ◽  
P. J. Bjerrum ◽  
J. Brahm ◽  
J. O. Wieth
Keyword(s):  
Transport System ◽  
Time Course ◽  
Order Rate Constant ◽  
Anion Transport ◽  
Disulfonic Acid ◽  
Reversible Inhibitor ◽  
Apparent Dissociation Constant ◽  
Anion Transport System ◽  
Relative Change ◽  
Kinetics Of

The capnophorin (band 3)-mediated chloride self exchange flux in intact erythrocytes and in resealed erythrocyte ghosts was determined at pH 7.3 by measuring the unidirectional efflux of 36Cl-. The time-dependent irreversible inactivation of the anion transport system by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) was measured as the relative change of the unidirectional 36Cl efflux rate. The rate of covalent DIDS binding under conditions of excess DIDS in solution that ensure a complete irreversible inhibition followed an exponential time course with a rate coefficient Kcov (min-1). The Arrhenius activation enthalpy of Kcov was constant, 114 kJ/mol, at 0-38 degrees C. At 38 and 0 degrees C, Kcov was 0.5 min-1 [half time (T1/2) = ln2/Kcov = 1.3 min] and 0.004 min-1 (T1/2 = 178 min), respectively. The slow irreversible DIDS binding to the anion transport system at 0 degrees C allows a determination of the kinetics of the reversible DIDS reaction. The pseudo first-order rate constant for binding, kon, was 3.5 X 10(5) (M.s)-1. The apparent dissociation constant, KD, determined from the steady-state binding to the erythrocyte membrane was 3.1 X 10(-8) M at an equal internal and external Cl- concentration of 165 mM (0 degrees C). The value of KD shows that DIDS is the most efficient reversible inhibitor among the stilbene derivatives so far studied. Maximum reversible inhibition by DIDS was obtained by binding of a minimum of approximately 10(6) molecules/cell membrane. The number is similar to that obtained from studies of irreversible DIDS binding.

scholarly journals Kinetics of the reactions of isoprene-derived hydroxynitrates: gas phase epoxide formation and solution phase hydrolysis

2014 ◽  
Vol 14 (8) ◽  
pp. 12121-12165 ◽  
Author(s):  
M. I. Jacobs ◽  
W. J. Burke ◽  
M. J. Elrod
Keyword(s):  
Gas Phase ◽  
Hydrolysis Rate ◽  
Ionization Mass ◽  
Volatile Organic ◽  
Isoprene Oxidation ◽  
Gas Phase Oxidation ◽  
Acid Catalyzed ◽  
Regional Formation ◽  
A Minor ◽  
Kinetics Of

Abstract. Isoprene, the most abundant non-methane volatile organic compound (VOC) emitted into the atmosphere, is known to undergo gas phase oxidation to form eight different hydroxynitrate isomers in "high NOx" environments. These hydroxynitrates are known to affect the global and regional formation of ozone and secondary organic aerosol (SOA), as well as affect the distribution of nitrogen. In the present study, we have synthesized three of the eight possible hydroxynitrates: 4-hydroxy-3-nitroxy isoprene (4,3-HNI) and E/Z-1-hydroxy-4-nitroxy isoprene (1,4-HNI). Oxidation of the 4,3-HNI isomer by the OH radical was monitored using a flow tube chemical ionization mass spectrometer (FT-CIMS), and its OH rate constant was determined to be (3.64 ± 0.41) × 10−11 cm3 molecule−1 s−1. The products of 4,3-HNI oxidation were monitored, and a mechanism to explain the products was developed. An isoprene epoxide (IEPOX) – a species important in SOA chemistry and thought to originate only from "low NOx" isoprene oxidation – was found as a minor, but significant product. Additionally, hydrolysis kinetics of the three synthesized isomers were monitored with NMR. The bulk, neutral solution hydrolysis rate constants for 4,3-HNI and the 1,4-HNI isomers were (1.59±0.03 × 10−5 s−1 and (6.76 ± 0.09) × 10−3 s−1, respectively. The hydrolysis reactions of each isomer were found to be general acid-catalyzed. The reaction pathways, product yields and atmospheric implications for both the gas phase and aerosol-phase reactions are discussed.

scholarly journals Reactivity of Phenol and Aniline towards Quinolinium Chloro Chromate: A Comparative Oxidation Kinetic Study

2015 ◽  
Vol 59 ◽  
pp. 81-92
Author(s):  
Seplapatty Kalimuthu Periyasamy ◽  
H. Satham Hussain ◽  
R. Manikandan
Keyword(s):  
Oxidation Kinetic ◽  
Activation Parameters ◽  
Dipole Interaction ◽  
Reaction Rates ◽  
Hydrogen Ion ◽  
Aqueous Acetic Acid ◽  
Acetic Acid Medium ◽  
First Order ◽  
Different Temperatures ◽  
Kinetics Of

The kinetics of Oxidation of Phenol and aniline by quinolinium Chlorochromate (QCC) in aqueous acetic acid medium leads to the formation of quinone and azobenzene respectively. The reactions are first order with respect to both Phenol and aniline. The reaction is first order with respect to quinolinium chlorochromate (QCC) and is catalyzed by hydrogen ion. The hydrogen-ion dependence has the form: kobs = a+b [H+]. The rate of oxidation decreases with increasing dielectric constant of solvent, indicating the presence of an ion-dipole interaction. The reaction does not induced the polymerization of acrylonitrile. The retardation of the rate by the addition of Mn2+ ions confirms that a two electron transfer process is involved in the reaction. The reaction rates have been determined at different temperatures and the activation parameters have been calculated. From the above observations kinetic results a probable mechanism have been proposed.

Reduction in hepatic endothelin-1 clearance in cirrhosis

2003 ◽  
Vol 105 (2) ◽  
pp. 227-234 ◽  
Author(s):  
Anh Thu TRAN DUC ◽  
Andreas J. SCHWAB ◽  
André SIMARD ◽  
Louis VILLENEUVE ◽  
Jocelyn DUPUIS
Keyword(s):  
Binding Site ◽  
Kinetic Modelling ◽  
Hepatic Clearance ◽  
Reversible Binding ◽  
Endothelin 1 ◽  
Multiple Indicator Dilution ◽  
Etb Receptor ◽  
Multiple Indicator ◽  
A Minor ◽  
Receptor Antibodies

Circulating endothelin-1 (ET-1) levels are increased in cirrhosis. The liver is an important site for circulating ET-1 clearance through the ETB receptor. We evaluated ET-1 kinetics in cirrhosis to determine if a reduced liver clearance contributes to this process. Cirrhosis was induced by carbon tetrachloride in rats. Hepatic ET-1 clearance was measured in isolated perfused livers using the single bolus multiple indicator-dilution technique. Plasma ET-1 levels doubled in cirrhosis from 0.49±0.04 fmol/ml (mean±S.E.M.) to 1.0±0.18 fmol/ml (P<0.01). Liver ET-1 extraction was reduced from 81±1% (mean±S.E.M.) in controls to 50±6% in cirrhosis (P<0.01). Kinetic modelling revealed a major irreversible binding site for ET-1 that is blocked by the selective ETB receptor antagonist BQ788 and a minor non-specific reversible binding site that cannot be blocked with BQ788 or the selective ETA antagonist BQ123. Reduced hepatic clearance correlated with the biochemical markers of cirrhosis, portal vein perfusion pressure (r=-0.457; P<0.001) and the increase in ET-1 levels (r=-0.462; P=0.002). Immunohistofluorescence with specific anti-(ETB receptor) antibodies revealed a preponderant distribution of ETB receptors on hepatic stellate cells, which was increased in cirrhosis. We conclude that cirrhosis reduces ET-1 clearance probably by capillarization of hepatic sinusoids and reduced access to ETB receptors. This relates to the severity of cirrhosis and may contribute to the increase in circulating ET-1 levels.

scholarly journals Kinetic Modelling of [68Ga]Ga-DOTA-Siglec-9 in Porcine Osteomyelitis and Soft Tissue Infections

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4094 ◽  
Author(s):  
Lars Jødal ◽  
Anne Roivainen ◽  
Vesa Oikonen ◽  
Sirpa Jalkanen ◽  
Søren B. Hansen ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Hind Limb ◽  
Kinetic Modelling ◽  
Compartment Model ◽  
Cell Surface Expression ◽  
Soft Tissue Infections ◽  
Tissue Samples ◽  
Tissue Compartment ◽  
Arterial Blood ◽  
Kinetics Of

Background: [68Ga]Ga-DOTA-Siglec-9 is a positron emission tomography (PET) radioligand for vascular adhesion protein 1 (VAP-1), a protein involved in leukocyte trafficking. The tracer facilitates the imaging of inflammation and infection. Here, we studied the pharmacokinetic modelling of [68Ga]Ga-DOTA-Siglec-9 in osteomyelitis and soft tissue infections in pigs. Methods: Eight pigs with osteomyelitis and soft tissue infections in the right hind limb were dynamically PET scanned for 60 min along with arterial blood sampling. The fraction of radioactivity in the blood accounted for by the parent tracer was evaluated with radio-high-performance liquid chromatography. One- and two-tissue compartment models were used for pharmacokinetic evaluation. Post-mortem soft tissue samples from one pig were analysed with anti-VAP-1 immunofluorescence. In each analysis, the animal’s non-infected left hind limb was used as a control. Results: Tracer uptake was elevated in soft tissue infections but remained low in osteomyelitis. The kinetics of [68Ga]Ga-DOTA-Siglec-9 followed a reversible 2-tissue compartment model. The tracer metabolized quickly; however, taking this into account, produced more ambiguous results. Infected soft tissue samples showed endothelial cell surface expression of the Siglec-9 receptor VAP-1. Conclusion: The kinetics of [68Ga]Ga-DOTA-Siglec-9 uptake in porcine soft tissue infections are best described by the 2-tissue compartment model.

Sign in / Sign up

Export Citation Format

Share Document