mocetinostat has been researched along with Aspergillosis* in 16 studies
2 review(s) available for mocetinostat and Aspergillosis
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[Contribution of neutrophils to Aspergillus infection].
Neutrophil disfunction, caused by a decreased production of effective radical oxygen species by myeloperoxidase (MPO) and NADPH oxidase within the neutrophil, may result in susceptibility to opportunistic fungal infections. In vitro, MPO produces OCl, which kills bacteria and viruses. In the case of MPO deficiency, susceptibility to Candida albicans infection was observed. Furthermore, it was demonstrated that MPO knockout mice were primarily susceptible to C. albicans infection. With regards to NADPH oxidase deficiency, such a patient was found to have severe chronic granulomatous disease (CGD) due to Aspergillus infection. This deficiency may have resulted from a gene mutation and/or abnormality of the NADH oxidase components, particularly cytochrome b558 (gp91phox and p22phox) in membrane and cytosol factors p47phox, p67phox, p40phox and others in neutrophil. Thus,irregular regulation of transcription factors for gene expression of phox molecules and MPO permits susceptibility to Aspergillus and Candida infections. Topics: Animals; Aspergillosis; Humans; Immunity, Innate; Mice; Mice, Knockout; NADPH Oxidases; Neutrophil Activation; Neutrophils; Peroxidase; Reactive Oxygen Species | 2002 |
Disseminated fungal infection associated with myeloperoxidase deficiency in a premature neonate.
Topics: Adult; Aspergillosis; Aspergillus flavus; Candida; Candidiasis; Child; Child, Preschool; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Middle Aged; Peroxidase | 2000 |
14 other study(ies) available for mocetinostat and Aspergillosis
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Therapeutic effect of Atractylenolide I on Aspergillus fumigatus keratitis by affecting MyD88/ NF-κB pathway and IL-1β, IL-10 expression.
Atractylenolide I (AT-I) is a natural sesquiterpene with anti-inflammatory effects. The purpose of this study was to research the anti-inflammatory effect of AT-I on Aspergillus fumigatus(A. fumigatus) keratitis in mice.. Cytotoxicity test and cell scratch test were used to determine the therapeutic concentrations of corneal infections. In vivo and in vitro studies, mouse cornea and human corneal epithelial cells (HCECs) infected with A. fumigatus were treated with AT-I or dimethyl sulfoxide (DMSO). Then, to analyze the effect of AT-I on inflammatory response, namely neutrophil or macrophage recruitment and the expression of cytokines involving MyD88, NF-κB, interleukin 1β (IL-1β) and interleukin 10 (IL-10). To study the effects of the drug, the techniques used include slit-lamp photography, immunofluorescence, myeloperoxidase (MPO) detection, quantitative real-time polymerase chain reaction (QRT-PCR), and western blot. At the same time, in order to explore the combined effect of the drug and natamycin, slit-lamp photographs and clinical scores were used to visually display the disease process.. No cytotoxicity was observed under the action of AT-I at a concentration of 800 μM. In mouse models, AT-I significantly suppressed inflammatory responses, reduced neutrophil and macrophage recruitment, and decreased myeloperoxidase levels early in infection. Studies have shown that AT-I may reduce the levels of IL-1β and IL-10 by inhibiting the MyD88/ NF-κB pathway. The drug combined with natamycin can increase corneal transparency in infected mice.. AT-I may inhibit MyD88 / NF-κB pathway and the secretion of inflammatory factors IL-1 β and IL-10 to achieve the therapeutic effect of fungal keratitis. Topics: Adaptor Proteins, Signal Transducing; Animals; Anti-Inflammatory Agents; Aspergillosis; Aspergillus fumigatus; Humans; Interleukin-10; Interleukin-1beta; Keratitis; Mice; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; Natamycin; NF-kappa B; Peroxidase; Sesquiterpenes | 2023 |
0.01% Hypochlorous Acid Treats Aspergillus fumigatus Keratitis in Rats by Reducing Fungal Load and Inhibiting the Inflammatory Response.
To investigate the antifungal and anti-inflammatory effects of 0.01% hypochlorous acid (HCLO) on rats with Aspergillus fumigatus keratitis.. The time-kill assay and broth microdilution procedures were used in vitro to demonstrate that 0.01% HCLO was fungicidal and fungistatic. The severity of the disease was evaluated in vivo using a clinical score and slit-lamp photographs. Fungal load, polymorphonuclear neutrophil infiltration, and the production of related proteins were determined using colony plate counting, in vivo confocal microscopy, periodic acid-Schiff staining, fungal fluorescence staining, immunofluorescence staining, myeloperoxidase assay, and Western blotting.. In vitro, 0.01% HCLO can destroy A. fumigatus spores in 1 minute. The optical density of the 0.01% HCLO group was significantly lower than that of the phosphate-buffered saline control group (P < 0.01), and no visible mycelium was observed using a fluorescence microscope. 0.01% HCLO reduced the severity of A. fumigatus keratitis in rats by decreasing the clinical score, fungal loading (periodic acid-Schiff, plate count, and fungal fluorescence staining), and inhibiting neutrophil infiltration and activity (immunofluorescence staining and myeloperoxidase). Furthermore, the Western blot analysis revealed that 0.01% HCO decreased protein expression levels of tumor necrosis factor-α and IL-1β.. According to our findings, 0.01% HCLO can kill A. fumigatus spores in vitro. It has antifungal and anti-inflammatory effects on A. fumigatus keratitis in rats. It also inhibited A. fumigatus growth; decreased neutrophil infiltration, tumor necrosis factor-α, and IL-1β expression; and provided a potential treatment for fungal keratitis.. This study provides a potential treatment for fungal keratitis in the clinic. Topics: Animals; Anti-Inflammatory Agents; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Eye Infections, Fungal; Hypochlorous Acid; Keratitis; Periodic Acid; Peroxidase; Rats; Tumor Necrosis Factor-alpha | 2023 |
CLEC-1 Acts as a Negative Regulator of Dectin-1 Induced Host Inflammatory Response Signature in Aspergillus fumigatus Keratitis.
C-type lectin-like receptor-1 (CLEC-1) is a member of the Dectin-1 cluster of pattern recognition receptors (PRRs). It is involved in host immunity, has immunoregulatory function, and supports allograft tolerance. Our study aimed to describe the role of CLEC-1 in response to fungal keratitis, in situ, in vivo, and in vitro.. Quantitative polymerase chain reaction (qRT-PCR) and immunofluorescence were used to detect the expression of CLEC-1 in corneas of patients with Aspergillus fumigatus (A. fumigatus) keratitis. In vitro and in vivo experiments were designed in THP-1 macrophages and C57BL/6 mouse models, respectively. The expression of CLEC-1 in corneas of mice model was determined by qRT-PCR, Western blot, and immunofluorescence. CLEC-1 overexpression in mouse corneas was achieved by intrastromal injection of adeno-associated virus (AAV) vectors. Disease response was evaluated by slit-lamp photography, clinical score, and colony forming unit (CFU). Bioluminescence imaging system image acquisition, myeloperoxidase (MPO) assays, immunofluorescence staining, qRT-PCR, and Western blot were used to investigate the role of CLEC-1. To further define the role of CLEC-1, we used lentivirus vectors to overexpress CLEC-1 or/and Dectin-1 in THP-1 macrophages.. The expression of CLEC-1 was increased in corneas of patients with A. fumigatus keratitis. In corneas of mice from the A. fumigatus keratitis model, the expression of CLEC-1 was decreased in the acute inflammatory stage and increased during convalescence. Following Natamycin treatment, CLEC-1 was upregulated in A. fumigatus keratitis mice. Compared with normal C57BL/6 mice, overexpression of CLEC-1 converted the characteristic susceptible response to resistance, as demonstrated by slit-lamp photography and clinical score. In vivo studies revealed decreased MPO levels and neutrophils recruitment and higher fungal load after the upregulation of CLEC-1. Compared with control corneas, CLEC-1 overexpression impaired corneal pro-inflammatory cytokine IL-1β production.. These findings demonstrate that CLEC-1 may act as a negative regulator of Dectin-1 induced host inflammatory response via suppressing neutrophils recruitment and production of pro-inflammatory cytokine IL-1β production in response to A. fumigatus keratitis. Topics: Animals; Aspergillosis; Aspergillus fumigatus; Blotting, Western; Cytokines; Dependovirus; Disease Models, Animal; Eye Infections, Fungal; Female; Gene Expression Regulation; Genetic Vectors; Humans; Keratitis; Lectins, C-Type; Macrophages; Membrane Proteins; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Neutrophil Infiltration; Peroxidase; Real-Time Polymerase Chain Reaction; Receptors, Mitogen; Slit Lamp Microscopy | 2021 |
Different roles of intracellular and extracellular reactive oxygen species of neutrophils in type 2 diabetic mice with invasive aspergillosis.
Diabetic patients have an increased risk of invasive aspergillosis (IA), but the mechanism is still unclear. Reactive oxygen species (ROS) produced by neutrophils play a key role in defense against Aspergillus infection. Since diabetes mellitus affects the production of ROS from neutrophils, the purpose of this study is to investigate whether this effect is related to the susceptibility of diabetic mice to IA. C57BL/6 mice were used to establish type 2 diabetes mellitus (T2DM) model, and IA was induced by airway infection with Aspergillus fumigatus. After infection, the fungal load, neutrophil count and ROS content in the lung tissues of T2DM mice were higher than those in the control mice, and the inflammation of the lung tissue was more serious. After being exposed to hyphae in vitro, compared with the control group, neutrophils in T2DM mice had higher apoptosis rate and intracellular ROS content, as well as lower viability, extracellular ROS content and fungicidal ability. In summary, after T2DM mice are infected with A. fumigatus, the reduction of extracellular ROS produced by neutrophils may lead to a decrease in fungicidal ability, while the increase of intracellular ROS is related to neutrophil and lung tissue damage. Topics: Animals; Apoptosis; Aspergillosis; Aspergillus fumigatus; Bronchoalveolar Lavage Fluid; Cell Survival; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Interleukin-1beta; Leukocyte Count; Lung; Lung Diseases; Male; Mice, Inbred C57BL; NADPH Oxidase 2; Neutrophils; Peroxidase; Reactive Oxygen Species; Tumor Necrosis Factor-alpha | 2020 |
Wedelolactone suppresses IL-1β maturation and neutrophil infiltration in Aspergillus fumigatus keratitis.
Wedelolactone, a chemical compound extracted from Wedelia calendulacea or Eclipta alba, has been reported to regulate key steps in inflammation. However, the effects of wedelolactone on fungal keratitis are not known. Hence, we aimed to characterize the impact of wedelolactone in Aspergillus fumigatus keratitis.. Aspergillus fumigatus was used to establish an in vivo mouse model of fungal keratitis and an in vitro model of THP-1 macrophages. Mice and THP-1 macrophages were pre-treated with wedelolactone. Clinical evaluation, myeloperoxidase (MPO) assay, neutrophil staining, western blot and quantitative polymerase chain reaction (qRT-PCR) were used to assess the effect of wedelolactone on A. fumigatus infection. Therapeutic effect of natamycin treatment with or without wedelolactone was measured via slit lamp microscopy.. We confirmed that wedelolactone attenuated the infiltration of neutrophils and decreased MPO level at earlier time points in mice with A. fumigatus keratitis. Pre-treatment with wedelolactone decreased pro-inflammatory cytokine interleukin 1 beta (IL-1β) maturation by inhibiting caspase-1 activity. Combined with natamycin, wedelolactone protected corneal transparency in mouse with fungal keratitis.. Present findings indicated that wedelolactone reduced host immune responses by attenuating neutrophil recruitment and IL-1β maturation in Aspergillus fumigatus keratitis. Wedelolactone combined with an antifungal medicine could be a potential therapy for reducing lesion severity in fungal keratitis. Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Cornea; Coumarins; Disease Models, Animal; Eye Infections, Fungal; Female; Humans; Interleukin-1beta; Keratitis; Mice, Inbred C57BL; Natamycin; Neutrophil Infiltration; Peroxidase; THP-1 Cells | 2019 |
Neutrophils differentially attenuate immune response to Aspergillus infection through complement receptor 3 and induction of myeloperoxidase.
Invasive aspergillosis (IA) remains a major cause of morbidity in immunocompromised hosts. This is due to the inability of the host immunity to respond appropriately to Aspergillus. An established risk factor for IA is neutropenia that is encountered by patients undergoing chemotherapy. Herein, we investigate the role of neutrophils in modulating host response to Aspergillus. We found that neutrophils had the propensity to suppress proinflammatory cytokine production but through different mechanisms for specific cytokines. Cellular contact was requisite for the modulation of interleukin-1 beta production by Aspergillus with the involvement of complement receptor 3. On the other hand, inhibition of tumour necrosis factor-alpha production (TNF-α) was cell contact-independent and mediated by secreted myeloperoxidase. Specifically, the inhibition of TNF-α by myeloperoxidase was through the TLR4 pathway and involved interference with the mRNA transcription of TNF receptor-associated factor 6/interferon regulatory factor 5. Our study illustrates the extended immune modulatory role of neutrophils beyond its primary phagocytic function. The absence of neutrophils and loss of its inhibitory effect on cytokine production explains the hypercytokinemia seen in neutropenic patients when infected with Aspergillus. Topics: Aspergillosis; Cell Adhesion Molecules; Cells, Cultured; Humans; Immunomodulation; Interleukin-1beta; Microscopy, Confocal; Neutropenia; Neutrophils; Peroxidase; Tumor Necrosis Factor-alpha | 2018 |
The Crystal Structure of Peroxiredoxin Asp f3 Provides Mechanistic Insight into Oxidative Stress Resistance and Virulence of Aspergillus fumigatus.
Invasive aspergillosis and other fungal infections occur in immunocompromised individuals, including patients who received blood-building stem cell transplants, patients with chronic granulomatous disease (CGD), and others. Production of reactive oxygen species (ROS) by immune cells, which incidentally is defective in CGD patients, is considered to be a fundamental process in inflammation and antifungal immune response. Here we show that the peroxiredoxin Asp f3 of Aspergillus fumigatus inactivates ROS. We report the crystal structure and the catalytic mechanism of Asp f3, a two-cysteine type peroxiredoxin. The latter exhibits a thioredoxin fold and a homodimeric structure with two intermolecular disulfide bonds in its oxidized state. Replacement of the Asp f3 cysteines with serine residues retained its dimeric structure, but diminished Asp f3's peroxidase activity, and extended the alpha-helix with the former peroxidatic cysteine residue C61 by six residues. The asp f3 deletion mutant was sensitive to ROS, and this phenotype was rescued by ectopic expression of Asp f3. Furthermore, we showed that deletion of asp f3 rendered A. fumigatus avirulent in a mouse model of pulmonary aspergillosis. The conserved expression of Asp f3 homologs in medically relevant molds and yeasts prompts future evaluation of Asp f3 as a potential therapeutic target. Topics: Animals; Aspergillosis; Aspergillus fumigatus; Crystallography, X-Ray; Female; Fungal Proteins; Gene Deletion; Kinetics; Mice; Models, Molecular; Mutant Proteins; Oxidation-Reduction; Oxidative Stress; Peroxidase; Peroxiredoxins; Protein Multimerization; Protein Structure, Secondary; Superoxides; Virulence | 2016 |
Fungal antioxidant pathways promote survival against neutrophils during infection.
Filamentous fungi are a common cause of blindness and visual impairment worldwide. Using both murine model systems and in vitro human neutrophils, we found that NADPH oxidase produced by neutrophils was essential to control the growth of Aspergillus and Fusarium fungi in the cornea. We demonstrated that neutrophil oxidant production and antifungal activity are dependent on CD18, but not on the β-glucan receptor dectin-1. We used mutant A. fumigatus strains to show that the reactive oxygen species-sensing transcription factor Yap1, superoxide dismutases, and the Yap1-regulated thioredoxin antioxidant pathway are each required for protection against neutrophil-mediated oxidation of hyphae as well as optimal survival of fungal hyphae in vivo. We also demonstrated that thioredoxin inhibition using the anticancer drug PX-12 increased the sensitivity of fungal hyphae to both H2O2- and neutrophil-mediated killing in vitro. Additionally, topical application of PX-12 significantly enhanced neutrophil-mediated fungal killing in infected mouse corneas. Cumulatively, our data reveal critical host oxidative and fungal anti-oxidative mediators that regulate hyphal survival during infection. Further, these findings also indicate that targeting fungal anti-oxidative defenses via PX-12 may represent an efficacious strategy for treating fungal infections. Topics: Animals; Antioxidants; Aspergillosis; Aspergillus flavus; Aspergillus fumigatus; CD18 Antigens; Cells, Cultured; Cornea; Enzyme Activation; Fungal Proteins; Fusariosis; Fusarium; Host-Pathogen Interactions; Humans; Keratitis; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbial Viability; NADPH Oxidases; Neutrophil Infiltration; Neutrophils; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Reactive Oxygen Species; Superoxide Dismutase; Thioredoxins; Transcription Factors | 2012 |
[An autopsy case of microscopic polyangiitis complicated with pulmonary aspergilloma and cytomegalovirus pneumonia].
A 71-year-old man was admitted to our hospital because of fever and rapidly progressive renal insufficiency over a month. He had depression and Alzheimer's disease as complications. On admission, his serum creatinine was 5.4 mg/dL, and the serum CRP and MPO-ANCA were 18.2 mg/dL and 285 EU, respectively. A computed tomographic chest scan showed pericardiac effusion and fibrosis in both lower lung fields. Although microscopic polyangiitis(MPA)was inferred from a positive MPO-ANCA, renal biopsy could not be carried out. The initial therapy was started with pulse methylprednisolone therapy, followed by oral administration of prednisolone at the dose of 1 mg/kg(60 mg/day). As a result, his fever and inflammatory findings disappeared, and renal insufficiency was ameliorated with a smooth recovery and the pericardial effusion was markedly diminished. However, on the 18th hospital day, chest radiography revealed a nodular shadow in the right lung. Fungus infection was suspected because his serum beta-D-glucan level was extremely high (above 999 pg/mL). Mikafungin, therefore, was started at a dose of 75 mg/day and then, the dose was increased up to 300 mg/day. Nevertheless, he finally died of respiratory failure on the 26th hospital day. The autopsy findings revealed a cavity of 4.0 x 3.0 x 3.0 centimeters in size in the upper lobe of the right lung. There was a great number of fungal threads with a septal wall branched in a Y-shaped figure around the cavity, thus indicating pulmonary aspergilloma. Intranuclear inclusion bodies staining positive for cytomegalovirus were observed in all the lung fields, suggestive of a cytomegalovirus infection. In the kidney, a cellular crescent formation was noted in the majority of glomeruli showing crescentic glomeluronephritis, compatible with MPA. Topics: Aged; Alzheimer Disease; Antibodies, Antineutrophil Cytoplasmic; Aspergillosis; Cytomegalovirus Infections; Glomerulonephritis; Humans; Lung Diseases, Fungal; Male; Methylprednisolone; Peroxidase; Pneumonia, Viral; Prednisolone; Pulse Therapy, Drug; Vasculitis | 2007 |
Effects of Aspergillus fumigatus gliotoxin and methylprednisolone on human neutrophils: implications for the pathogenesis of invasive aspergillosis.
Aspergillus fumigatus (AF) is a ubiquitous mold and the most common cause of invasive aspergillosis (IA) in immunocompromised patients. In stem cell transplant recipients, IA now occurs most frequently in the setting of therapy with corticosteroids, including methylprednisolone (MP). We showed previously that gliotoxin (GT), an AF-derived mycotoxin, induces apoptosis in monocytes and dendritic cells, resulting in the suppression of AF-specific T cell responses. We examined the ability of GT to induce apoptosis in polymorphonuclear leukocytes (PMN) and assessed GT effects on important neutrophil functions, including phagocytic function, degranulation, myeloperoxidase activity, and the production of reactive oxygen species (ROS). In contrast to its effects on monocytes, PMN remained resistant to GT-mediated apoptosis. Although many essential neutrophil functions were unaffected, GT inhibited phagocytosis and also induced a decrease in ROS generation by PMN. In contrast, MP therapy potentiated ROS production, suggesting a mechanism that may facilitate tissue injury in IA. Distinct from its effects on untreated PMN, GT augmented ROS production in MP-treated PMN. Our results suggest that although GT may suppress the adaptive immune response, GT may also serve to increase PMN-mediated inflammation, which is likely to play an important role in tissue destruction in the setting of IA. Topics: Anti-Inflammatory Agents; Apoptosis; Aspergillosis; Aspergillus fumigatus; Cell Degranulation; Cells, Cultured; Dendritic Cells; Gliotoxin; Humans; Immunocompromised Host; Inflammation; Methylprednisolone; Monocytes; Neutrophils; Peroxidase; Phagocytosis; Reactive Oxygen Species; Stem Cell Transplantation | 2007 |
Relative contributions of myeloperoxidase and NADPH-oxidase to the early host defense against pulmonary infections with Candida albicans and Aspergillus fumigatus.
Generation of oxidative products by phagocytic cells is known to be an important host defense mechanism directed toward killing of invading microorganisms. The importance of two major oxidant-producing enzymes, myeloperoxidase (MPO) and NADPH-oxidase, in in vivo fungicidal action was directly compared in genetically engineered mice. Both MPO-deficient (MPO-/-) and NADPH-oxidase-deficient (X-linked chronic granulomatous disease [X-CGD]) mice showed increased susceptibility to pulmonary infections with Candida albicans and Aspergillus fumigatus compared with normal mice, and the X-CGD mice exhibited shorter survivals than MPO-/- mice. This increased mortality of X-CGD mice was associated with a 10- to 100-fold increased outgrowth of the fungi in their organs during the first 6 days. These results suggest that superoxide (O2-) produced by NADPH-oxidase is more important than hypochlorous acid (HOCl) produced by MPO, although both oxidative products obviously contribute to the host defense against pulmonary infection with those fungi. We also observed that MPO-/-/X-CGD double knockout mice showed comparable levels of susceptibility to the X-CGD mice against C. albicans and A. funigatus, indicating that MPO is unable to play a role in host defense in the absence of NADPH-oxidase. This strongly suggests that hydrogen peroxide, the precursor of HOCl, is solely derived from O2- produced by NADPH-oxidase. Topics: Animals; Aspergillosis; Aspergillus fumigatus; Candida albicans; Candidiasis; Female; Granulomatous Disease, Chronic; Hypochlorous Acid; Lung Diseases, Fungal; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidases; Neutrophils; Peroxidase | 2002 |
Differential host susceptibility to pulmonary infections with bacteria and fungi in mice deficient in myeloperoxidase.
Myeloperoxidase (MPO), which is located within neutrophils capable of producing hypochlorous acid, is active in vitro against bacteria and fungi. However, MPO-deficient persons are usually healthy. To define the in vivo contribution of MPO to early host defense against pulmonary infections, MPO-deficient and control mice were intranasally infected with various fungi and bacteria, and the number of residual microorganisms in lungs was compared 48 h later. MPO-deficient mice showed severely reduced cytotoxicity to Candida albicans, Candida tropicalis, Trichosporon asahii, and Pseudomonas aeruginosa. However, the mutant mice showed a slight but significantly delayed clearance of Aspergillus fumigatus and Klebsiella pneumoniae and had comparable levels of resistance to the wild type against Candida glabrata, Cryptococcus neoformans, Staphylococcus aureus, and Streptococcus pneumoniae. These results suggest that the MPO-dependent oxidative system is important for host defense against fungi and bacteria, although the effect varies by pathogen species. Topics: Animals; Aspergillosis; Aspergillus fumigatus; Bacterial Infections; Candidiasis; Cryptococcosis; Female; Genetic Predisposition to Disease; Homozygote; Klebsiella Infections; Klebsiella pneumoniae; Lung Diseases; Lung Diseases, Fungal; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; Pneumonia, Pneumococcal; Pseudomonas Infections; Staphylococcal Infections; Trichosporon | 2000 |
Variant chronic granulomatous disease: modulation of the neutrophil defect by severe infection.
The present studies document the cellular and biochemical processes involved in granulocyte O2- production in three patients from two kindreds with variant chronic granulomatous disease (CGD). Rates of O2- production were 9% to 30% of normal, depending on the individual tested and the stimulus; the two brothers from one family responded to each stimulus with rates very similar to each other. Kinetic analysis of NADPH-dependent O2- production in subcellular fractions revealed all three to have NADPH oxidases with both diminished substrate affinity for NADPH (high Kmapp) and decreased maximal velocities of O2- production. Their granulocytes had normal lag times for activation of the respiratory burst but abnormal rates of stimulus-induced membrane depolarization. Cytochrome b was not found in granulocytes or subcellular fractions despite the use of a spectrophotometric assay sensitive enough to detect the cytochrome if its content were proportional to the residual rate of O2- generation. A striking finding in one patient from each kindred was a threefold to tenfold decrease in the rate of O2- production accompanying serious infection. The residual O2(-)-generating activity of CGD variants helps to explain their relative freedom from the recurrent infections of the classic disease. However, the marked decrease described in the present study indicates the potential for a vicious cycle in which an infection, once established, leads to increasing impairment of host defense. Topics: Abscess; Aspergillosis; Cell Compartmentation; Cytochrome b Group; Flavoproteins; Granulomatous Disease, Chronic; Humans; Hydrogen Peroxide; Membrane Potentials; NADH, NADPH Oxidoreductases; NADPH Oxidases; Neutrophils; Oxygen Consumption; Pedigree; Peroxidase; Superoxides; Vitamin B 12 | 1986 |
Mechanisms of destruction of Aspergillus fumigatus hyphae mediated by human monocytes.
Normal monocytes attached to and destroyed Aspergillus hyphae by morphologic and metabolic criteria. Inhibition by anaerobiosis, azide, cyanide, halide-free conditions, catalase, histidine, and tryptophan suggested mediation of hyphal damage primarily through the myeloperoxidase system. However, myeloperoxidase-independent oxidative or nonoxidative mechanisms appeared active in hyphal damage by monocytes from patients with myeloperoxidase deficiency or chronic granulomatous disease (CGD). Moreover, hyphae were damaged by lysates and granule-enriched fractions of monocytes from patients with CGD, whereas comparable fractions of normal monocytes were active only with added halide and H2O2. Hyphal damage by both whole monocytes and granule-enriched fractions from patients with CGD was inhibited by polyanions, a result suggesting that cationic proteins may be involved. Hyphal damage by normal monocytes or monocytes from patients with CGD was inhibited by cells that lacked antihyphal activity (chlorpromazine-treated normal neutrophils or neutrophils from patients with CGD, respectively). This effect may predispose patients with CGD to chronic, invasive aspergillosis. Topics: Aspergillosis; Aspergillus fumigatus; Cytotoxicity, Immunologic; Female; Granulomatous Disease, Chronic; Humans; Male; Monocytes; Neutrophils; Peroxidase | 1983 |