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Biomedical subjects

N Borregaard

Publications and source records attributed to N Borregaard.

At least 145 records · Page 8Linked to original sources
PubMed1983

Chronic granulomatous disease: a syndrome of phagocyte oxidase deficiencies.

Chronic granulomatous disease (CGD) is an inherited disorder of host defense due to the inability of the phagocyte to generate toxic oxygen metabolites upon appropriate stimulation. The disorder is heterogeneous even within the confines of a defective respiratory burst oxidase function, and may arise from a biochemical lesion at either the receptor, the activating pathways or the enzyme level. The identification of defects in plasma membrane depolarization, missing cytochrome and abnormal enzymatic function has yielded new insights into the pathophysiologic basis of CGD. A classification of this syndrome based on more precise biochemical criteria is proposed, which defines the disease as distinct from other associated enzymopathies with similar pathology and emphasizes the metabolic basis of the pathophysiologic defect in phagocyte function. Review of the clinical manifestations, pathogenic organisms and natural course of the disease, emphasizes the critical role of the oxidative metabolism of the normal neutrophil and offers a perspective on oxygen free radical biochemistry in the inflammatory response.

Adolescent↗
PubMed1982

On the mechanism of enhanced monocyte and neutrophil cytotoxicity in severe psoriasis.

Monocyte and neutrophil function assessed as antibody-dependent cell-mediated cytotoxicity (ADCC) using IgG-sensitizing human erythrocytes as target cells was enhanced in patients with severe psoriasis when compared to healthy controls. We found significant correlation between increased monocyte ADCC and increased neutrophil ADCC, No differences in basal cAMP levels and cAMP responses during initiation of the ADCC reaction was observed between psoriatics and normals. Also degranulation determined as lysozyme release during ADCC was normal. In contrast, the increase in ADCC was significantly correlated to an enhanced hexose monophosphate shunt activation in the effector cells during the cytotoxic reaction. Activity of enzymes responsible for the respiratory burst was not altered in psoriasis since superoxide production after stimulation with phorbol myristate acetate was normal. Likewise, oxygen consumption and degranulation following phagocytosis of opsonized zymosan particles in neutrophils was found normal in psoriasis. Since monocytes showed increased binding of IgG-sensitized erythrocytes these data indicate that the enhanced monocyte and neutrophil ADCC is caused by an enhancement of the respiratory burst possibly induced by increased Fc receptor activity.

Adult↗
PubMed1982

Involvement of cytochrome b-245 in the respiratory burst of human neutrophils.

The cytochrome b 245 of human neutrophils was reduced when the neutrophils under anaerobic conditions were stimulated by serum-treated zymosan, immune complexes, or phorbol myristate acetate. Reintroduction of oxygen rapidly reoxidized the cytochrome; azide was without effect on any of these reactions. This indicates that cytochrome b 245 participates in the respiratory burst of neutrophils.

Adult↗
PubMed1982

Energy metabolism of human neutrophils during phagocytosis.

Detailed quantitative studies were performed on the generation and utilization of energy by resting and phagocytosing human neutrophils. The ATP content was 1.9 fmol/cell, was constant during rest, and was not influenced by the presence or absence of glucose in the medium. The intracellular content of phosphocreatine was less than 0.2 fmol/cell. In the presence of glucose, ATP was generated almost exclusively from lactate produced from glucose taken up from the surrounding medium. The amount of lactate produced could account for 85% of the glucose taken up by the cells, and the intracellular glycosyl store, glycogen, was not drawn upon. The rate of ATP generation as calculated from the rate of lactate production was 1.3 fmol/cell/min. During phagocytosis, there was no measurable increase in glucose consumption or lactate production, and the ATP content fell rapidly to 0.8 fmol/cell. This disappearance of ATP was apparently irreversible since no corresponding increase in ADP or AMP was observed. It therefore appears that this phagocytosis-induced fall in ATP concentration represents all the extra energy utilized in human neutrophils in the presence of glucose. In the absence of glucose, the rate of ATP generation in the resting cell was considerably smaller, 0.75 fmol/cell per min, as calculated from the rate of glycolysis, which is sustained exclusively by glycogenolysis. Under this condition, however, phagocytosis induces significant enhancement of glycogenolysis and the rate of lactate production is increased by 60%, raising the rate of ATP generation to 1.2 fmol/cell per min. Nonetheless, the ATP content drops significantly from 1.9 to 1.0 fmol/cell. Neutrophils from patients with chronic granulomatous disease have the same rate of glycolysis and the same ATP content as normal cells, thus confirming that the defective respiration of these cells does not affect their energy metabolism.

Adenine Nucleotides↗
PubMed1981

Effect of glycogenolytic agents on glycogen synthase activity in polymorphonuclear leukocytes. Evidence for a Ca2+-mediated regulation of glycogen synthase activity.

Human polymorphonuclear leukocytes were found to respond to the beta-receptor activators, adrenalin and isoproterenol, with a rapid transient increase in cyclic AMP, activation of cyclic AMP-dependent protein kinase, phosphorylase kinase, deactivation of glycogen synthase and glycogen breakdown. This response was unaffected by the presence of 10 mM EGTA. Incubation of leukocytes with phorbol myristate acetate, which stimulates the hexose monophosphate shunt by a Ca2+ mediated mechanism, resulted in activation of phosphorylase without affecting cyclic AMP-dependent protein kinase or phosphorylase kinase activity, thus indicating a Ca2+-mediated activation of phosphorylase. This was, however, unaffected by EGTA. Prolonged incubation with phorbol myristate acetate was found to result in a parallel activation of phosphorylase and glycogen synthase secondary to a pronounced depletion of cellular glycogen. Addition of glucose to polymorphonuclear leukocytes resulted in total conversion of phosphorylase a to the b form and activation of glycogen synthase, however, when EGTA was included, the response to glucose was greatly amplified, thus indicating the synthase conversion is regulated by Ca2+ sensitive mechanisms which do not involve phosphorylase kinase. Addition of adrenalin to cells previously activated by glucose resulted in an increase in the concentration of cyclic AMP and activation of cyclic AMP-dependent protein kinase but deactivation of synthase was not effectuated under these conditions.

Adrenergic beta-Agonists↗
PubMed1981

Activation of the glycogenolytic cascade in human polymorphonuclear leucocytes by different phagocytic stimuli.

Human polymorphonuclear leucocytes were found to respond to activation by immunoglobulin opsonized latex particles and to complement opsonized zymosan particles with a rapid transient increase in cAMP concentration, dissociation of the cAMP dependent protein kinase, activation of glycogen phosphorylase and glycogen break down. However, since phosphorylase kinase was not activated, the activation of phosphorylase is believed to be secondary to non-covalent activation of phosphorylase kinase by Ca2+. Activation by the soluble stimulator phorbol myristate acetate resulted in activation of phosphorylase and glycogen break down, whereas no changes in cAMP concentration, protein kinase activity, or phosphorylase kinase activity were observed. The activation of phosphorylase is ascribed to an increase in cytosolic Ca2+ concentration. The response to stimulation by zymosan was strongly inhibited by ethylene glycol-bis-(beta-aminoethyl ether)-N,N1-tetraacetic acid, which did not affect stimulation by either latex particles or phorbol myristate acetate. The same differential effect of ethylene glycol-bis(beta-aminoethyl ether)-N,N1-tetraacetic acid was observed when the response of the cells was measured as increase in oxygen consumption and activation of the hexose monophosphate shunt.

Calcium↗
PubMed1981

Mechanisms of decreased antibody-dependent cytotoxicity mediated by monocytes and neutrophils in atopic dermatitis.

By using IgG-sensitized erythrocytes as target cells, we found the antibody-dependent cytotoxicity mediated by monocytes and neutrophils to be depressed in atopic dermatitis. This change was accompanied by a reduction of phagocytosis of target cells by the effector cells, and also by a decreased lysozyme liberation from, and hexose monophosphate shunt activation in, the effector cells during the cytotoxic reaction. However, the binding of target cells to effector cells remained normal. In individual patients, cytotoxicity and phagocytosis were equally depressed. No relation was found between cytotoxicity and lysozyme liberation in atopic dermatitis, but a relation between cytotoxicity and hexose monophosphate shunt activity was highly significant. These results suggest that the decreased cytotoxicity mediated by monocytes and neutrophils in atopic dermatitis is caused by a diminished production of oxygen radicals during the respiratory burst. This reduced respiratory burst was not due to any defect in the enzymes responsible for this process, since the superoxide production of monocytes and neutrophils stimulated with phorbol myristate acetate was found normal in atopic dermatitis. It therefore seems that although binding of target cells to effector cells was normal, the signals created by the binding process were defective in activating monocytes and neutrophils in atopic dermatitis.

Adolescent↗
PubMed1981

Relation of monocyte and neutrophil oxidative metabolism to skin and oral lesions in carriers of chronic granulomatous disease.

Out of fifteen carriers of X-linked chronic granulomatous disease five had discoid lupus erythematosus-like skin lesions together with recurrent aphthous-like stomatitis, another five had only recurrent aphthous-like stomatitis, and the remainder were symptom-free. In individual carriers monocytes and neutrophils were equally reduced in their capacity for superoxide production, [1-14C]glucose oxidation and antibody-dependent cytotoxicity; but within he group of carriers a broad spectrum of depression was found. The degree of depression was closely related to the manifestations of clinical disease. It is suggested that the defective oxygen-dependent metabolism might play an aetiological role in the development of inflammatory diseases in carriers of chronic granulomatous disease. Two out of 10 unselected females with discoid lupus erythematosus were shown to be carriers of X-linked chronic granulomatous disease. Screening for this carrier state might therefore be of importance in these patients.

Adult↗
PubMed1980

Role of oxygen in antibody-dependent cytotoxicity mediated by monocytes and neutrophils.

The antibody-dependent cell-mediated cytoxicity (ADCC) by human monocytes and neutrophils was investigated by measuring the release of 51chromate from prelabeled erythrocytes coated with immunoglobulin G. ADCC was found to be positively correlated to phagocytosis of 51Cr-labeled erythrocytes and to the postphagocytic events of the effector cells, activation of the hexose monophosphate shunt, and degranulation. Exclusion of oxygen from the incubation media halved the ADCC by both cell types without affectijg phagocytosis or degranulation. Likewise, ADCC by cells from patients suffering from chronic granulomatous disease (CGD) was only half the intensity of ADCC by cells from normals. Inhibitors of mitochondrial respiration were without depressing effect of ADCC. Azide, which in addition to its blocking action on oxydative phosphorylation also inhibits catalase and myeloperoxidase, resulted in a approximately equal to 40% stimulation of ADCC by cells from normals but was without effect of ADCC by cells from CGD patients. The hydroxyl radical scavenger, mannitol, significantly depressed ADCC by cells from normals (P < 0.01) but was without effect on cells from CGD patients. Azide and mannitol also were without effect on ADCC by normal cells when oxygen was excluded. In a xanthine-xanthine oxidase system, erythrocytes were effectively lysed. This lysis was inhibited by catalase, superoxide dismutase, and mannitol. When comparable concentrations of glucose oxidase were used no lysis was observed. H2O2 either alone or in combination with azide did not lyse erythrocytes. It is suggested that ADCC by both monocytes and neutrophils is partly dependent on the generation of hydroxyl radicals by the effector cells.

Anaerobiosis↗