scholarly journals Macrophage oxygen-dependent antimicrobial activity. III. Enhanced oxidative metabolism as an expression of macrophage activation.

1980 ◽  
Vol 152 (6) ◽  
pp. 1596-1609 ◽  
Author(s):  
H W Murray ◽  
Z A Cohn
Keyword(s):  
Antimicrobial Activity ◽  
Oxidative Metabolism ◽  
Macrophage Activation ◽  
Systemic Infection ◽  
Peritoneal Macrophages ◽  
H2o2 Production ◽  
Oxygen Intermediates ◽  
Cultivation In Vitro

The capacity of 15 separate populations of mouse peritoneal macrophages to generate and release H2O2 (an index of oxidative metabolism) was compared with their ability to inhibit the intracellular replication of virulent Toxoplasma gondii. Resident macrophages and those elicited by inflammatory agents readily supported toxoplasma multiplication and released 4-20X less H2O2 than macrophages activated in vivo by systemic infection with Bacille Calmette-Guérin or T. gondii, or by immunization with Corynebacterium parvum. Immunologically activated cells consistently displayed both enhanced H2O2 production and antitoxoplasma activity. Exposure to lymphokines generated from cultures of spleen cells from T. gondii immune mice and toxoplasma antigen preserved both the antitoxoplasma activity and the heightened H2O2 release of toxoplasma immune and immune-boosted macrophages, which otherwise were lost after 48-72 h of cultivation. In vitro activation of resident and chemically-elicited cells by 72 h of exposure to mitogen- and antigen-prepared lymphokines, conditions that induce trypanocidal (5) and leishmanicidal activity (14), stimulated O2- and H2O2 release, and enhanced nitroblue tetrazolium reduction in response to toxoplasma ingestion. Such treatment, however, failed to confer any antitoxoplasma activity, indicating that intracellular pathogens may vary in their susceptibility to macrophage microbicidal mechanisms, including specific oxygen intermediates. In contrast, cocultivating normal macrophages with lymphokine plus heart infusion broth for 18H rendered these cells toxoplasmastatic. This in vitro-acquired activity was inhibited by scavengers of O2-, H2O2, OH., and 1O2, demonstrating a role for oxidative metabolites in lymphokine-induced enhancement of macrophage antimicrobial activity. These findings indicate that augmented oxidative metabolism is an consistent marker of macrophage activation, and that oxygen intermediates participate in the resistance of both in vivo- and vitro-activated macrophages toward the intracellular parasite, T. gondii.

scholarly journals Macrophage oxygen-dependent antimicrobial activity. I. Susceptibility of Toxoplasma gondii to oxygen intermediates.

1979 ◽  
Vol 150 (4) ◽  
pp. 938-949 ◽  
Author(s):  
H W Murray ◽  
Z A Cohn
Keyword(s):  
Antimicrobial Activity ◽  
Toxoplasma Gondii ◽  
Xanthine Oxidase ◽  
Peritoneal Macrophages ◽  
Fluorescent Staining ◽  
Oxygen Intermediates ◽  
In Vitro Susceptibility ◽  
Parasite Viability ◽  
Sensitive Method

A sensitive method for evaluating extracellular parasite viability was used to determine the in vitro susceptibility of virulent Toxoplasma gondii to selected oxygen intermediates. By acridine orange fluorescent staining criteria, toxoplasmas were resistant to up to either 10(-3) M reagent H2O2 or H2O2 generated by glucose-glucose oxidase. In keeping with a lack of sensitivity to H2O2, toxoplasmas contained endogenous catalase (5.7 x 10(-4) Baudhuin units/10(6) organisms). The addition of a peroxidase and halide, however, markedly accelerated killing and lowered the H2O2 requirement by 1,000-fold. In contrast, toxoplasmas were promptly killed after exposure to products generated by xanthine (1.5 x 10(-4) M) and xanthine oxidase (50 micrograms). The inhibition of this system's microbicidal activity by scavengers of O2- (superoxide dismutase) and H2O2 (catalase) indicated that although neither O2- nor H2O2 were toxoplasmacidal, their interaction was required for parasite killing. Quenching OH. and 1O2, presumed products of O2--H2O2 interaction, by mannitol, benzoate, diazabicyclooctane, and histidine, also inhibited toxoplasma killing by xanthine-xanthine oxidase. These findings suggested that O2- and H2O2 functioned in precursor roles and that OH. and 1O2 were toxoplasmacidal. The capacity of normal peritoneal macrophages to pinocytose an oxygen intermediate scavenger, soluble catalase, was also demonstrated. Appreciable extraphagosomal concentrations of catalase were achieved by exposing macrophages to 1 mg/ml of the enzyme for 3 h. Maintenance of high intracellular levels required constant exposure because interiorized catalase was rapidly degraded.

Nanocarriers with Gentamicin to Treat Intracellular Pathogens

2006 ◽  
Vol 6 (9) ◽  
pp. 3296-3302 ◽  
Author(s):  
C. Lecaroz ◽  
C. Gamazo ◽  
M. J. Blanco-Prieto
Keyword(s):  
Macrophage Activation ◽  
Polymeric Nanoparticles ◽  
Current Treatment ◽  
Delivery Systems ◽  
Oxygen Intermediates ◽  
Water Solvent ◽  
Biodistribution Studies ◽  
Target Organs

Brucellosis is a worldwide zoonosis caused by different species of the genus Brucella. The intracellular localisation of this pathogen, particularly in macrophages, renders treatment difficult since most antibiotics known to be efficient in vitro do not actively pass through cellular membranes. As alternative to current treatment, polymeric drug delivery systems containing gentamicin have been developed. These particulate carriers target the drug into the mononuclear-phagocytic system, where the pathogen resides that will allow intracellular accumulation of the antibiotic after particle degradation. Besides, particle uptake may induce macrophage activation, increasing the production of reactive oxygen intermediates, involved in host defense against the intracellular pathogen. The aim of the present work was to study the suitability of polymeric nanoparticles for gentamicin entrapment in view to treat brucellosis. Different poly(lactide-co-glycolide) PLGA polymers were used to formulate the nanoparticles containing gentamicin by a water-oil-water solvent evaporation method. Furthermore, in vitro macrophage activation upon nanoparticles phagocytosis and in vivo distribution of the nanocarriers in the target organs for Brucella (liver and spleen) were also studied. The nanoparticle sizes were below 350 nm, the gentamicin encapsulation efficiency depended on the polymer type used for their preparation and the in vitro release of the antibiotic exhibited a continuos pattern (PLGA 502H). PLGA 502H nanoparticles were the most suitable due to the highest entrapment and the most sustained release. The nanoparticles were successfully phagocyted by a J774 murine monocytes cell line and biodistribution studies in mice after intravenous administration of the delivery systems revealed that the particles reached the target organs of Brucella (liver and spleen). All together, these results indicate that the nanocarriers described in this work may be suitable as gentamicin delivery system to control brucellosis.

scholarly journals Macrophage oxygen-dependent antimicrobial activity. IV. Role of endogenous scavengers of oxygen intermediates.

1980 ◽  
Vol 152 (6) ◽  
pp. 1610-1624 ◽  
Author(s):  
H W Murray ◽  
C F Nathan ◽  
Z A Cohn
Keyword(s):  
Antimicrobial Activity ◽  
Oxidative Capacity ◽  
Oxygen Intermediates ◽  
Protective Mechanisms ◽  
Extracellular Release ◽  
Macrophage Populations ◽  
Scavenging Enzymes

The activities of the endogenous O2- and H2O2 scavenging enzymes, superoxide dismutase (SOD), glutathionine peroxidase (GP), and catalase, were measured in lysates of the intracellular parasite, Toxoplasma gondii, and in various macrophage populations. During 72 h of cultivation in standard medium alone, the catalase activity of in vivo-activated toxoplasma-immune macrophages (IM) and immune-boosted macrophages (IB) progressively increased by eight- to ninefold, and correlated with the previously observed parallel decline in these cells' antitoxoplasma activity and capacity to release H2O2. SOD and GP activities either remained constant or decreased during this 3-d period. Lymphokine exposure, which preserved the antitoxoplasma activity and oxidative capacity of 48- and 72-h cultures of IB and IM cells, blunted the rise in catalase levels and had no effect on SOD or GP. Inhibition of IB and IM macrophage catalase by aminotriazole maintained toxoplasmastatic activity otherwise lost after 48 h of cultivation. In addition, IB and IM cells from acatalasemic mice contained 20- to 30-fold less catalase, and showed comparatively little decline in either H2O2 release or antitoxoplasma activity during 72 h in culture. In vitro-(lymphokine) activated resident macrophages from normal mice had the highest levels of SOD, GP, and catalase, and these cells failed to kill or inhibit T. gondii despite enhanced extracellular release of O2- and H2O2. Toxoplasmas were also found to contain all three enzymatic scavengers. Aminotriazole inhibition of lymphokine-activated cells' catalase or of toxoplasma catalase was effective in inducing these macrophages to display antitoxoplasma activity. Moreover, and in contrast to normocatalasemic resident cells, those from acatalesemic mice were readily induced by lymphokine to inhibit the replication of untreated virulent toxoplasmas. These results suggest that endogenous O2- and H2O2 scavenging enzymes, which function within both T. gondii and activated macrophages as host cell antioxidant protective mechanisms, may reduce the effectiveness of phagocyte antimicrobial activity. Thus, the presence of SOD, GP, and especially catalase within both target and effector cell may be important determinants of macrophage oxygen-dependent processes.

scholarly journals Interleukin-2 therapy enhances salicylate oxidation by blood granulocytes

Blood ◽  
1991 ◽  
Vol 78 (11) ◽  
pp. 2931-2936 ◽  
Author(s):  
AL Jr Sagone ◽  
RM Husney ◽  
PL Triozzi ◽  
J Rinehart
Keyword(s):  
Oxidative Metabolism ◽  
Interleukin 2 ◽  
H2o2 Production ◽  
Oxidant Injury ◽  
Myristate Acetate ◽  
Metastatic Renal Cancer ◽  
Comparable Activity ◽  
Blood Granulocyte

Abstract These studies determined the effect of interleukin-2 (IL-2) immunotherapy on the oxidative metabolism of the blood granulocytes of eight patients with metastatic renal cancer. We quantitated the rate of the hexose monophosphate shunt activity (HMPS), hydrogen peroxide (H2O2) production, and salicylate oxidation of the unstimulated and phorbol myristate acetate (PMA)-stimulated granulocyte cultures before, during, and after a 5-day continuous infusion of IL-2. There was no change in the rate of HMPS activity. However, the rate of salicylate oxidation of the unstimulated and PMA-stimulated cultures of these patients was significantly increased after the therapy was complete. Overall, there was no increase in the rate of H2O2 production, although the PMA-stimulated cultures of three of eight patients had a twofold higher production of H2O2 after treatment compared with the pretreatment values. The enhanced rate of salicylate oxidation by the granulocytes after treatment indicates that these cells were “stimulated” in vivo to produce a potent oxidant, which is most likely hydroxyl radical or an oxidant of comparable activity. Further, the granulocytes were primed (“activated”), since they had an augmented response to PMA. IL-2 did not stimulate the oxidative metabolism of granulocyte cultures in vitro, suggesting that the IL-2 effect in vivo is not a direct one. Our results indicate that IL-2 immunotherapy is associated with the activation of blood granulocyte oxidative metabolism and that these activated granulocytes may be related to some of the toxic side effects of IL-2 therapy such as the capillary leak syndrome. Further oxidant injury to the granulocytes may explain the reported defect in chemotaxis.

scholarly journals Regulation of arachidonic acid metabolism by macrophage activation.

1982 ◽  
Vol 155 (4) ◽  
pp. 1148-1160 ◽  
Author(s):  
W A Scott ◽  
N A Pawlowski ◽  
H W Murray ◽  
M Andreach ◽  
J Zrike ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Macrophage Activation ◽  
Peritoneal Macrophages ◽  
Arachidonic Acid Metabolism ◽  
Prostaglandin Synthesis ◽  
Activated Macrophages ◽  
Synthetic Enzymes ◽  
Oxygenated Products

Levels of zymosan-induced arachidonic acid (20:4) metabolism by peritoneal macrophages elicited with inflammatory agents and resident macrophages were similar. Thyioglycollate (THIO)-elicited macrophages represented the exception; however, the diminished metabolism by these cells was reproduced by exposing resident cells to 5 mg/ml THIO broth in vitro. In contrast, reduced prostaglandin synthesis by macrophages from mice variously treated with the immunologic agents, Corynebacterium parvum or Bacille Calmette Guérin (BCG), closely correlated with enhanced antitoxoplasma activity, one measure of macrophage activation. This relationship, although not causative, suggested that the capacity for 20:4 metabolism is a function of the macrophage activation state. Modulation of macrophage 20:4 metabolism in vivo apparently required factors in addition to lymphocyte-derived products. Treatment of resident macrophages in vitro with BCG lymphokine was without effect on 20:4 release or prostaglandin synthesis. Activated macrophages from animals inoculated i.p. with C. parvum exhibited reduced 20:4 release and also failed to metabolize 70% of the 20:4 released in response to a zymosan stimulus. Consequently, the quantities of 20:4 metabolites formed were significantly less than expected from 20:4 release. These activated macrophages displayed greatly reduced synthesis of prostacylcin and leukotriene C compared with other 20:4 metabolites. It appeared that factors that regulate macrophage 20:4 metabolism influence the level of the inducible phospholipase and synthetic enzymes for specific 20:4 oxygenated products.

scholarly journals Interleukin-2 therapy enhances salicylate oxidation by blood granulocytes

Blood ◽  
1991 ◽  
Vol 78 (11) ◽  
pp. 2931-2936
Author(s):  
AL Jr Sagone ◽  
RM Husney ◽  
PL Triozzi ◽  
J Rinehart
Keyword(s):  
Oxidative Metabolism ◽  
Interleukin 2 ◽  
H2o2 Production ◽  
Oxidant Injury ◽  
Myristate Acetate ◽  
Metastatic Renal Cancer ◽  
Comparable Activity ◽  
Blood Granulocyte

These studies determined the effect of interleukin-2 (IL-2) immunotherapy on the oxidative metabolism of the blood granulocytes of eight patients with metastatic renal cancer. We quantitated the rate of the hexose monophosphate shunt activity (HMPS), hydrogen peroxide (H2O2) production, and salicylate oxidation of the unstimulated and phorbol myristate acetate (PMA)-stimulated granulocyte cultures before, during, and after a 5-day continuous infusion of IL-2. There was no change in the rate of HMPS activity. However, the rate of salicylate oxidation of the unstimulated and PMA-stimulated cultures of these patients was significantly increased after the therapy was complete. Overall, there was no increase in the rate of H2O2 production, although the PMA-stimulated cultures of three of eight patients had a twofold higher production of H2O2 after treatment compared with the pretreatment values. The enhanced rate of salicylate oxidation by the granulocytes after treatment indicates that these cells were “stimulated” in vivo to produce a potent oxidant, which is most likely hydroxyl radical or an oxidant of comparable activity. Further, the granulocytes were primed (“activated”), since they had an augmented response to PMA. IL-2 did not stimulate the oxidative metabolism of granulocyte cultures in vitro, suggesting that the IL-2 effect in vivo is not a direct one. Our results indicate that IL-2 immunotherapy is associated with the activation of blood granulocyte oxidative metabolism and that these activated granulocytes may be related to some of the toxic side effects of IL-2 therapy such as the capillary leak syndrome. Further oxidant injury to the granulocytes may explain the reported defect in chemotaxis.

scholarly journals Macrophage activation: increased ingestion of IgG-coated erythrocytes after administration of interferon inducers to mice.

1978 ◽  
Vol 147 (2) ◽  
pp. 593-598 ◽  
Author(s):  
S I Hamburg ◽  
R E Manejias ◽  
M Rabinovitch
Keyword(s):  
Macrophage Activation ◽  
Peritoneal Macrophages ◽  
Response Curves ◽  
Polycytidylic Acid ◽  
Vesicular Stomatitis ◽  
Macrophage Populations ◽  
And Control ◽  
Mouse Peritoneal Macrophages

In vitro phagocytosis of IgG-opsonized sheep erythrocytes (EA) was used to measure the in vivo activation of mouse peritoneal macrophages. Uptake of EA as enhanced by the extraperitoneal administration of Newcastle disease virus, vesicular stomatitis virus, tilorone or polyinosinic-polycytidylic acid. Ingestion of EA was similarly stimulated by lipopolysaccharide or killed Corynebacterium parvum. Dose-response curves relating concentrations of IgG to phagocytosis were parallel for both treated and control animals. This indicates that the heterogeneity of the macrophage populations did not change and that the overall populations were activated with respect to phagocytic ability. Numbers of macrophages were not increased (except in C. parvum-treated mice), suggesting that resident, rather than newly recruited macrophages, were activated by the different agents.

Synthesis of Novel 3(N,N-dialkylamino)alkyl/phenyl Substituted Thieno [2,3-d]pyrimidinones as H1-Anti-Histaminic and Antimicrobial Agents

2019 ◽  
Vol 15 (1) ◽  
pp. 63-70
Author(s):  
Shiv Dev Singh ◽  
Arvind Kumar ◽  
Firoz Babar ◽  
Neetu Sachan ◽  
Arun Kumar Sharma
Keyword(s):  
Antimicrobial Activity ◽  
Potassium Hydroxide ◽  
Antimicrobial Agents ◽  
Pyrimidine Ring ◽  
Antimicrobial Activities ◽  
Screening Methods ◽  
Chlorpheniramine Maleate ◽  
In Vivo Screening

Background: Thienopyrimidines are the bioisoster of quinazoline and unlike quinazoline exist in three isomeric forms corresponding to the three possible types annulation of thiophene to the pyrimidine ring viz thieno[2,3-d] pyrimidine, thieno[3,2-d] pyrimidine and thieno[3,4-d]pyrimidine. Heterocyclic containing the thienopyrimidinone moiety exhibits various pronounced activities such as anti-hypertensive, analgesic and anti-inflammatory, antiviral, platelet aggregation inhibitory, antiprotozoal bronchodilatory, phosphodiesterase inhibitory, antihistaminic, antipsychotic and antimicrobial activity. Objective: Synthesis of novel 3(N,N-dialkylamino)alkyl/phenyl substituted thieno[2,3-d]pyrimidinones as H1-anti-histaminic and antimicrobial agents. Methods: A series of 3-[(N,N-dialkylamino)alkyl/phenyl]-2-(1H)thioxo-5,6,7,8-tetrahydrobenzo(b) thieno(2,3-d)pyrimidine-4(3H)-ones[4a-d], their oxo analogous [5a-d] and 3-[(N,N-dialkylamino)alkyl]- 2-chlorophenyl-5,6,7,8-tetrahydrobenzo(b)thieno(2,3-d)pyrimidine- 4 (3H)-ones[6a-d]derivative were synthesized from 2-amino-4,5,6,7-tetrahydrobenzo(b)thiophene-3-carboxylic acid by nucleophilic substitution of different N,N-dialkyl alkylene/phenylene diamines on activated 3-acylchloride moiety followed by cyclocondensation with carbon disulfide and ethanolic potassium hydroxide to get [4a-d] and in second reaction by condensation with 4-chlorobenzoyl chloride to get [6a-d] by single pot novel innovative route. The oxo analogous [5a-d] were prepared by treating derivatives [4a-d] with potassium permagnate in ethanolic KOH. The synthesized compound were evaluated for H1-antihistaminic and antimicrobial activities. Results: All synthesized compounds exhibited significant H1-antihistaminic activity by in vitro and in vivo screening methods and data were verified analytically and statistically. The compound 4a, 4b, 5a and 5b showed significant H1-antihistaminiic activity than the reference standard chlorpheniramine maleate. The compound 6d, 6c, 5c and 4c exhibited significant antimicrobial activity.

scholarly journals High-throughput screening and rational design of biofunctionalized surfaces with optimized biocompatibility and antimicrobial activity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhou Fang ◽  
Junjian Chen ◽  
Ye Zhu ◽  
Guansong Hu ◽  
Haoqian Xin ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
High Throughput ◽  
High Throughput Screening ◽  
Rational Design ◽  
Click Reaction ◽  
Reaction Times ◽  
Great Promise ◽  
Biomaterial Surfaces

AbstractPeptides are widely used for surface modification to develop improved implants, such as cell adhesion RGD peptide and antimicrobial peptide (AMP). However, it is a daunting challenge to identify an optimized condition with the two peptides showing their intended activities and the parameters for reaching such a condition. Herein, we develop a high-throughput strategy, preparing titanium (Ti) surfaces with a gradient in peptide density by click reaction as a platform, to screen the positions with desired functions. Such positions are corresponding to optimized molecular parameters (peptide densities/ratios) and associated preparation parameters (reaction times/reactant concentrations). These parameters are then extracted to prepare nongradient mono- and dual-peptide functionalized Ti surfaces with desired biocompatibility or/and antimicrobial activity in vitro and in vivo. We also demonstrate this strategy could be extended to other materials. Here, we show that the high-throughput versatile strategy holds great promise for rational design and preparation of functional biomaterial surfaces.

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