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Biomedical subjects

A F LoBuglio

Publications and source records attributed to A F LoBuglio.

At least 109 records · Page 6Linked to original sources
PubMed1982

Phagocyte-generated oxygen metabolites and cellular injury.

Phagocytic leukocytes are motile cells capable of inducing damage and lysis of a wide variety of biologic targets. Recent insights into the mechanisms of phagocyte-mediated destruction have derived from the observation that these cells can consume and metabolize oxygen to generate an impressive array of reactive oxygen intermediates. The role of oxygen metabolites in antimicrobial defense mechanisms has been the subject of intensive study, but only recently has attention focused on the potential importance of oxygen in phagocyte-mammalian cell interactions. In this review we will examine evidence obtained in a variety of in vitro model systems demonstrating the ability of intact phagocytes to generate oxygen metabolites capable of destroying normal or neoplastic cells. A basic understanding of the biochemistry of phagocyte-mediated oxygen-dependent events should allow us to elucidate and potentially modulate immunologic defenses against neoplastic invasion, the destruction of normal tissue in pathogenic states, and the course of the inflammatory response. The role of phagocyte-derived oxygen metabolites in microbicidal activity will not be the subject of this report, and the reader is referred to recent comprehensive reviews.

Animals↗
PubMed1982

Effect of mouse anti-I region antiserum and complement on human mononuclear cell response to concanavalin A.

Pretreatment of human peripheral blood mononuclear cells with mouse anti-Ia serum and complement was found to inhibit the subsequent T cell proliferative response to Con A. The cells from each individual tested were inhibited, regardless of DR allospecificity. Inhibition of Con A response by mouse anti-Ia antibodies and C was found to be due to elimination of adherent accessory cells (monocytes) rather than T cells. Anti-Ia serum appeared to recognize an essential subpopulation of human monocytes bearing cross-reactive antigens, since not all monocytes treated with anti-Ia serum and C were lysed. The use of highly restricted mouse anti-Ia serum demonstrated that the required monocyte population expressed antigens recognized by antibodies with activity to I-Ek products (Ia specificities Ia.7 and Ia.22). The required monocyte subpopulation was also recognized by a monoclonal antibody specific for Ia.7. Mouse anti-I-Ek alloantiserum or monoclonal anti-Ia.7 antibodies may be important tools with which to study human monocytes, and for further characterization of DR determinant requirements for monocyte-antigen presentation and monocyte-T cell interactions.

Animals↗
PubMed1981

Role of hydrogen peroxide in neutrophil-mediated destruction of cultured endothelial cells.

Human neutrophils stimulated with phorbol myristate acetate were able to destroy suspensions or monolayers of cultured human endothelial cells. Neutrophil-mediated cytotoxicity was related to phorbol myristate acetate concentration, time of incubation and neutrophil number. Cytolysis was prevented by the addition of catalase, while superoxide dismutase had no effect on cytotoxicity. The addition of the heme-enzyme inhibitors, azide or cyanide, markedly stimulated neutrophil-mediated damage while exogenous myeloperoxidase failed to stimulate cytolysis. Neutrophils isolated from patients with chronic granulomatous disease did not destroy the endothelial cell targets while myeloperoxidase-deficient neutrophils successfully mediated cytotoxicity. Endothelial cell damage mediated by the myeloperoxidase deficient cells was also inhibited by catalase but not superoxide dismutase. The addition of purified myeloperoxidase to the deficient cells did not stimulate cytotoxicity. Glucose-glucose oxidase, an enzyme system capable of generating hydrogen peroxide, could replace the neutrophil as the cytotoxic mediator. The addition of myeloperoxidase at low concentrations of glucose oxidase did not increase cytolysis, but at the higher concentrations of glucose oxidase it stimulated cytotoxicity. The destruction of endothelial cells by the glucose oxidase-myeloperoxidase system was inhibited by the addition of hypochlorous acid scavengers. In contrast, neutrophil-mediated cytolysis was not effectively inhibited by the hypochlorous acid scavengers. Based on these observations, we propose that human neutrophils can destroy cultured human endothelial cells by generating cytotoxic quantities of hydrogen peroxide.

Cell Survival↗
PubMed1981

Monocyte-mediated antibody-dependent cell-mediated cytotoxicity: the role of the metabolic burst.

Human monocytes respond to opsonized microorganisms with a "metabolic burst" composed of an increase in oxygen consumption, an increase in hexose monophosphate shunt (HMPS) activity, and the generation of reactive oxygen species (ROS). We investigated the role of the metabolic burst in antibody-dependent cell-mediated cytotoxicity (ADCC) by human monocytes toward anti-D coated erythrocyte target cells because recent studies suggested a role for oxygen-dependent bactericidal mechanisms in ADCC. In normal monocytes, we found that ADCC was nearly halved under hypoxic conditions. Several agents known to impair activation of the burst, such as vincristine, cation chelators, and a sulfhydryl reagent, all decreased cytotoxicity if added before initiation of contact between target and effector cells. Cytotoxicity was inhibited by 2-deoxyglucose but not fluoride, suggesting a nonglycolytic role for glucose in ADCC, perhaps in the HMPS pathway. Although these data suggested a role for the metabolic burst in ADCC, scavengers of ROS did not impair cytotoxicity, and monocytes from chronic granulomatous disease (CGD) patients who had a defective metabolic burst had normal levels of ADCC. We conclude that ADCC toward anti-D coated erythrocyte target cells was the result of at least two independent but closely related cytotoxic pathways. Although one of these pathways appeared to involve the metabolic burst, the potentially cytotoxic reactive oxygen species did not appear to play a role in this system.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1980

Immune Hemolytic anemia.

Immune hemolytic anemia is an acquired anemia resulting from the premature destruction of red cells caused by the presence of antibody and/or complement on the red cell surface. The Coombs test, modified and improved, remains the mainstay of diagnosis.

Adrenal Cortex Hormones↗
PubMed1980

Oxidative mechanisms of monocyte-mediated cytotoxicity.

Human monocytes stimulated with phorbol myristate acetate were able to rapidly destroy autologous erythrocyte targets. Monocyte-mediated cytotoxicity was related to phorbol myristate acetate concentration and monocyte number. Purified preparations of lymphocytes were incapable of mediating erythrocyte lysis in this system. The ability of phorbol myristate acetate-stimulated monocytes to lyse erythrocyte targets was markedly impaired by catalase or superoxide dismutase but not by heat-inactivated enzymes or albumin. Despite a simultaneous requirement for superoxide anion and hydrogen peroxide in the cytotoxic event, a variety of hydroxyl radical and singlet oxygen scavengers did not effect cytolysis. However, tryptophan significantly inhibited cytotoxicity. The myeloperoxidase inhibitor cyanide enhanced erythrocyte destruction, whereas azide reduced it modestly. The inability of cyanide to reduce cytotoxicity coupled with the protective effect of superoxide dismutase suggests that cytotoxicity is independent of the classic myeloperoxidase system. We conclude that monocytes, stimulated with phorbol myristate acetate, generate superoxide anion and hydrogen peroxide, which together play an integral role in this cytotoxic mechanism.

Catalase↗
PubMed1980

An oxygen-dependent mechanism of neutrophil-mediated cytotoxicity.

Human neutophils stimulated with phorbol myristate acetate were able to rapidly destroy autologous red blood cell targets. Neutrophil-mediated cytotoxicity was related to phorbol myristate acetate concentration and neutrophil number. The ability of stimulated neutrophils to lyse red blood cell targets was markedly impaired by catalase or superoxide dismutase but not by heat-inactivated enzymes or albumin. Despite a simultaneous requirement for O2.- and H2O2 in the cytotoxic event, a variety of OH. and 1O2 did not effect cytolysis. The myeloperoxidase inhibitor cyanide did not reduce red blood destruction, while azide consistently impaired cytolysis. The inability of cyanide to reduce cytotoxicity coupled with the protective effect of superoxide dismutase suggests that cytotoxicity is independent of the classic myeloperoxidase-H2O2-halide system. We propose that neutrophils, stimulated with phorbol myristate acetate, generate O2.- and H2O2, which play an integral role in a novel cytotoxic mechanism.

Azides↗
PubMed1979

Human monocyte killing of Staphylococcus aureus: modulation by agonists of cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3',5'-monophosphate.

This study was designed to test whether cyclic nucleotides play a role in the regulation of bacterial killing by human monocytes. Agents were tested for their ability to activate monocyte adenylate or guanylate cyclase in cell-free preparations, to increase cyclic adenosine 3',5'-monophosphate (cAMP) or cyclic guanosine 3',5'-monophosphate (cGMP) in intact human monocytes, and to modulate monocyte-induced killing of Staphylococcus aureus in vitro. Prostaglandin E1 and cholera toxin activated monocyte adenylate cyclase and inhibited monocyte killing of S. aureus. An adenylate cyclase inhibitor, RMI 12330A, reversed the prostaglandin E1-mediated inhibition of bacterial killing, thus implicating cAMP as the intracellular mediator of this inhibition. In contrast, monocyte cGMP levels were increased 5- and 17-fold by 5-hydroxytryptamine and N-methyl-N' -nitro-N-nitrosoguanidine, respectively, but neither agent was effective in modulating monocyte bactericidal activity. Thus, modulation of bactericidal activity in human monocytes did not conform to the yin/yang theory of opposing actions by cAMP and cGMP, for although monocyte-mediated killing of S. aureus was inhibited by cAMP agonists, it was not enhanced by cGMP agonists.

Adenylyl Cyclases↗
PubMed1979

Neoantigen response in patients successfully treated for lymphoma. A Southwest Oncology Group study.

To ascertain the cellular immune function of patients successfully treated for lymphoma, we measured skin-test reactivity to a battery of recall antigens, phytohemmagglutinin (PHA), and the neoantigens keyhole limpet hemocyanin (KLH) and dinitrochlorobenzene (DNCB). Seventy-four patients with Hodgkin's disease and 31 patients with non-Hodgkin's lymphoma were studied from 3 to 186 months after cessation of therapy for lymphoma. Although reactivity to recall antigens and PHA was normal, the number of patients responding to the neoantigens was significantly (P less than 0.01) lower than normal (KLH, 35%; and DNCB, 34%). This impairment in reactivity to neoantigens could not be correlated with specific diagnosis, stage of disease, or type of treatment. Reactivity to DNCB was significantly (P less than 0.01) improved in those patients studied more than 3 years after treatment, but the number who reacted was still markedly abnormal (17 of 33). Thus, successfully treated patients with lymphoma seem to have difficulty in responding to new foreign antigens.

Adolescent↗
PubMed1978

Human granulocyte generation of hydroxyl radical.

Human granulocytes were capable of oxidizing 2-keto-4 thiomethylbutyric acid to ethylene during phagocytosis or membrane perturbation. The reaction required hydrogen peroxide and superoxide and in addition was inhibited by various hydroxyl radical (OH) scavengers. These observations represent direct evidence for the generation of OH by human granulocytes. Further, inhibition of ethylene generation by azide and cyanide suggests that OH generation in granulocytes may be linked to myeloperoxidase.

Blood Bactericidal Activity↗
PubMed1978

Superoxide generation by human monocytes and macrophages.

Intracellular and extracellular superoxide (O2.-) generation by human monocytes and macrophages was quantitated by the nitroblue tetrazolium (NBT) reduction method. Human monocytes reduced 4.4 +/- 0.9 nmoles/10(6) cells/15 minutes with an increase to 12.4 +/- 1.3 during phagocytosis of zymosan. Based on inhibition by superoxide dismutase, superoxide generation of these cells was 1.8 +/- 0.9 nmoles in the resting state and 16.8 +/- 2.8 nmoles with zymosan phagocytosis. Human macrophages obtained by thoracentesis had comparable levels of NBT reduction and O2.-generation. Monocytes from a patient with chronic granulomatous disease demonstrated no increment in O2.-production during phagocytosis. Thus, human monocytes and macrophages appear capable of generating substantial amounts of O2.-during phagocytosis which may play an important role in bactericidal and other cell functions.

Humans↗
PubMed1978

Phagocytosis of technetium-99m sulfur colloid by human polymorphonuclear leukocytes.

This study characterizes a new phagocytic assay system utilizing technetium-99m sulfur colloid as the phagocytic particle. Uptake of sulfur colloid by human polymorphonuclear leukocytes is a time and temperature dependent process that requires glucose for optimal uptake. In contrast to many other systems, sulfur colloid phagocytosis appears to be serum and divalent cation independent. An attractive feature of this system is the 10-fold increase in particle uptake with phagocytosis as compared to that at zero time.

Colloids↗