Search PubMed⌕ Search

Biomedical subjects

I M Goldstein

Publications and source records attributed to I M Goldstein.

At least 91 records · Page 5Linked to original sources
PubMed1979

Infection in patients with systemic lupus erythematosus. Association with a serum inhibitor of complement-derived chemotactic activity.

We have found subnormal amounts of chemotactic activity in zymosan-treated sera from 13 of 29 patients with systemic lupus erythematosus (SLE). As an explanation for this abnormality, the presence of a uniquely specific, heat-stable inhibitor of complement (C5)-derived chemotactic activity has been documented in sera from 11 of these patients. Sera from 2 other patients contained elevated levels of nonspecific, heat-labile chemotactic factor inactivator (CFI) activity. The serum from 1 patient contained the heat-stable inhibitor as well as elevated levels of CFI. Patients with SLE whose sera contained the heat-stable inhibitor had more active disease clinically, but otherwise they were indistinguishable from patients without the inhibitor. When patients with the heat-stable inhibitor improved clinically, this usually was accompanied by a decrease in serum inhibitory activity. Only one episode of bacterial infection was observed among 16 patients with SLE whose sera yielded normal amounts of chemotactic activity after treatment with zymosan. In contrast, 7 of 11 patients with SLE whose sera contained the heat-stable inhibitor suffered serious bacterial infections. The presence of this heat-stable inhibitor in sera from some patients with SLE may contribute, in part, to their increased susceptibility to infection.

Adolescent↗
PubMed1979

A new function for ceruloplasmin as an acute-phase reactant in inflammation: a scavenger of superoxide anion radicals.

In summary, purified human ceruloplasmin inhibits several reactions mediated by superoxide anion in a fashion consistent with an ability to scavenge this free radical. It must be pointed out, however, that on a weight basis, the superoxide-scavenging activity of ceruloplasmin is substantially less than that of purified human erythrocyte superoxide dismutase. Nevertheless, since superoxide dismutase is almost exclusively an intracellular enzyme, ceruloplasmin probably represents the major circulating scavenger of superoxide anion radicals. The level of superoxide dismutase in human plasma has been reported to be 0.7 microgram/ml. It is not clear, however, how this was measured. We have found that concentrations of plasma exceeding 10% (v/v) interfere significantly with the assays routinely employed for detecting superoxide-scavenging activity. Consequently, we have not yet been able to quantify the superoxide-scavenging activity of either ceruloplasmin or superoxide dismutase in whole human plasma. Thus, we can only speculate that under conditions where levels of ceruloplasmin are markedly elevated, as during pregnancy, during acute infections, or in association with inflammatory diseases (such as rheumatoid arthritis), this acute-phase reactant may play a major role as a circulating scavenger of oxygen-derived free radicals.

Ceruloplasmin↗
PubMed1978

Thromboxane generation by human peripheral blood polymorphonuclear leukocytes.

Human peripheral blood polymorphonuclear leukocytes were stimulated to generate thromboxane B2 in a time- and concentration-dependent fashion upon exposure to serum-treated zymosan particles. Conversion by stimulated PMN of [14C] arachidonic acid to [14C]thromboxane B2 was confirmed by thin-layer radiochromatography, radio-gas chromatography, and mass spectrometry. Generation of thromboxane B2 was independent of platelet contamination and could be inhibited by the cyclooxygenase inhibitor, indomethacin. Cells rendered incapable of ingesting particles by treatment with cytochalasin B generated comparable amounts of thromboxane B2. These results suggest that human peripheral blood polymorphonuclear leukocytes synthesize thromboxanes in response to surface stimulation independently of phagocytosis.

Humans↗
PubMed1978

A specific inhibitor of complement (C5)-derived chemotactic activity in serum from patients with systemic lupus erythematosus.

In the course of examining polymorphonuclear leukocyte (PMN) chemotaxis in patients with systemic lupus erythematosus (SLE), we have found a previously undescribed serum inhibitor of complement (C5)-derived chemotactic activity. Serum from a 25-yr-old Black female with untreated SLE, when activated with zymosan, failed completely to attract either her own or normal PMN. Incubation of normal PMN with the patient's serum did not affect their subsequent random motility or chemotactic response toward normal zymosan-treated serum (ZTS). The patient's serum, however, did inhibit the chemotactic activity of normal ZTS and of column-purified C5-derived peptide(s), but had no effect on the chemotactic activity of either the synthetic peptide, N-formylmethionyl leucyl-phenylalanine or a filtrate prepared from a culture of Escherichia coli (bacterial chemotactic factor). The inhibitory activity in the patient's serum resisted heating at 56 degrees C for 30 min and could be separated from C5-derived chemotactic activity in the patient's ZTS (or normal ZTS that had been incubated with the patient's serum) by chromatography on Sephadex G-75. Despite its effect on C5-derived chemotactic activity, the patient's serum did not influence two other C5-derived biologic activities: PMN lysosomal enzyme-releasing activity and PMN-aggregating activity. Chromatography of the patient's serum (65% ammonium sulfate pellet) on Sephadex G-200 yielded three distinct peaks of inhibitory activity. Two were heat labile and exhibited other properties of the previously described chemotactic factor inactivators of normal human serum. The third and most active peak, however, resisted heating at 56 degrees C for 30 min, eluted with an apparent mol wt of 50,000-60,000, and acted specifically on C5-derived chemotactic activity. This uniquely specific, heat-stable inhibitor of C5-derived chemotactic activity has been found thus far in serum from 4 of 11 patients with active SLE and may account, in part, for altered host defenses against infections caused by pyogenic microorganisms.

Adult↗
PubMed1977

Influence of local anesthetics upon human polymorphonuclear leukocyte function in vitro. Reduction of lysosomal enzyme release and superoxide anion production.

Cationic local anesthetics have been reported to influence cellular responses to surface stimuli by interfering with the function of microtubules and microfilaments. Since unimpaired microtubule and microfilament functions are required by human polymorphonuclear leukocytes in order to respond normally to surface stimulation, we have studied effects of the local anesthetic, tetracaine on the function and morphology of these cells in vitro. Tetracaine (0.25--1.0 mM) significantly reduced extracellular release of the lysosomal enzymes, beta-glucuronidase and lysozyme from polymorphonuclear leukocytes exposed to serum-treated zymosan (a particulate stimulus), zymosan-treated serum (a soluble stimulus), and to the surface-active lectin, concanavalin A. Tetracaine also significantly reduced superoixde anion production (superoxide dismutase-inhibitable cytochrome c reduction) by these cells. Tetrancaine was not cytotoxic and its effects could be reversed completely by washing cells once with buffer. Electron microscope examination of tetracaine-treated cells revealed marked alterations of surface membranes. Microtubules and microfilaments appeared normal in "resting" polymorphonuclear leukocytes, but the increase in microtubules normally observed in stimulated cells was not seen after tetracaine treatment. These results suggest that tetracaine interferes with those interactions between immune reactants and the polymorphonuclear leukocyte cell surface which provoke exocytosis and increased oxidative metabolism.

Anesthetics, Local↗
PubMed1977

Prostaglandins, thromboxanes, and polymorphonuclear leukocytes: mediation and modulation of inflammation.

When appropriately stimulated (even in the absence of phagocytosis), human polymorphonuclear leukocytes release and/or generate proinflammatory materials and substances capable of provoking tissue injury. These include hydrolases and nonenzymatic substances ordinarily contained within lysosomes, as well as oxygen-derived free radicals. It is now possible to add prostaglandins and thromboxanes to this list. Whereas prostaglandins are capable of eliciting many phenomena associated with inflammation, their effects on cyclic nucleotide metabolism may render these compounds antiinflammatory. Thus, the very cells that release mediators of inflammation provide a mechanism for modulating the inflammatory response.

Animals↗
PubMed1977

Role of microtubule assembly in lysosomal enzyme secretion from human polymorphonuclear leukocytes. A reevaluation.

The dose-related inhibition by colchicine of both lysosomal enzyme release and microtubule assembly was studied in human polymorphonuclear leukocytes (PMN) exposed to the nonphagocytic stimulus, zymosan-treated serum (ZTS). Cells were pretreated with colchicine (60 min, 37 degrees C) with or without cytochalasin B (5 microng/ml, 10 min) and then stimulated with ZTS (10%). Microtubule numbers in both cytochalasin B-treated and untreated PMN were increased by stimulation and depressed below resting levels in a dose-response fashion by colchicine concentrations above 10(-7) M. These concentrations also inhibited enzyme release in a dose-response fashion although the inhibition of microtubule assembly was proportionately greater than the inhibition of enzyme release. Other aspects of PMN morphology were affected by colchicine. Cytochalasin B-treated PMN were rounded, and in thin sections the retracted plasma membrane appeared as invaginations oriented toward centrally located centrioles. Membrane invaginations were restricted to the cell periphery in cells treated with inhibitory concentrations of colchicine, and the centrioles and Golgi apparatus were displaced from their usual position. After stimulation and subsequent degranulation, the size and number of membrane invaginations greatly increased. They remained peripheral in cells pretreated with greater than 10(-7) M colchicine but were numerous in the pericentriolar region in cells treated with less than 10(-7) M. Similarly, untreated PMN that were permitted to phagocytose immune precipitates had many phagosomes adjacent to the centriole. After colchicine treatment, phagosomes were distributed randomly, without any preferential association with the centrioles. These data suggest that microtubules are involved in maintaining the internal organization of cells and the topologic relationships between organelles and the plasma membrane.

Cell Membrane↗
PubMed1977

Evidence that the superoxide-generating system of human leukocytes is associated with the cell surface.

Superoxide anion (O-2-) generation by human peripheral blood polymorphonuclear leukocytes is enhanced when these cells encounter appropriate soluble or particulate stimuli. O-2- generation requires intact, viable cells and proceeds independently of phagocytosis. To investigate the possibility that the O-2--generating system is associated with the outer surface of the polymorphonuclear leukocyte plasma membrane, we have examined the effects upon O-2- production of p-diazobenzenesulfonic acid, a reagent which can react predominantly with proteins of the external cell membrane. When normal human polymorphonuclear leukocytes were preincubated with cytochalasin B (to minimize endocytosis) and then exposed to the surface-active lectin, concanavalin A, the cells were stimulated to generate O-2- in a concentration- and time-dependent fashion and selectively to discharge the granule-associated enzyme, lysozyme, into the surrounding medium. These responses, as well as cellular binding of [H] concanavalin A, could be blocked by alpha-methyl-D-mannoside. Brief treatment (less than 5 min at 4 degrees C) of the cells with p-diazobenzenesulfonic acid (1.0-5.0 mM) significantly interfered with concanavalin A-mediated O-2- generation but had no influence upon lysozyme release or upon binding of [3H] concanavalin A. The diazonium salt did not alter cell viability or the specific activity of the cytoplasmic enzyme, lactate dehydrogenase (inhibitable under conditions which allowed entry of this reagent into the cytosol). p-Diazobenzenesulfonic acid, therefore, very likely exerted its effects at the cell surface of the intact polymorphonuclear leukocyte, selectively inhibiting O-2- production (either directly or indirectly) without influencing another response to lectin-cell contact: release of lysozyme. These results support the possibility that a polymorphonuclear leukocyte ectoenzyme is responsible for O-2- production.

Azo Compounds↗
PubMed1976

Dissociation of phagocytosis, metabolic stimulation and lysosomal enzyme release in human leukocytes.

In this paper studies are reported concerning the relationship between particle binding to the plasma membrane of human polymorphonuclear leukocytes (PMN's), phagocytosis, generation of oxidative metabolites, and the release of lysosomal enzymes by these cells. Superoxide (O2-) generation by, and lysosomal enzyme release from, normal PMN's and cytochalasin B-treated cells were measured. We have found that neither phagocytosis nor lysosomal degranulation are prerequisites for enhanced O2- generation. Cytochalasin B-treated PMN's, incapable of ingesting particles but still able to bind particles to membrane receptors, generated enhanced amounts of O2- when treated with serum-treated zymosan (STZ), a C3b receptor stimulus, or with aggregated IgG (agg IgG), an Fc receptor stimulus. Moreover, the soluble stimulators complement component C5a, phorbol myristate acetate (PMA), and calcium ions in the presence of the ionophore A23187, also increased the O2- production of these cells. In all cases a time and dose-dependent stimulation was found of both the O2- generation and the lysosomal enzyme release, but there was no correlation between ability of any stimulus to provoke enzyme release and its ability to stimulate O2- generation. When PMN's were preincubated with 5 X 10(-4) M hydrocortisone-Na-succinate, lysosomal enzyme exocytosis with the immune reactants was inhibited 16-35%. Hydrocortisone also inhibited O2- generation, except when STZ was used as the stimulus. Thus, in the case of stimulation of functional processes of PMN's via the C3b receptor, hydrocortisone inhibits membrane fusion without interfering with one of the early biochemical events (O2-production).

Cell Membrane↗
PubMed1976

Independent effects of IgG and complement upon human polymorphonuclear leukocyte function.

Particle ingestion by polymorphonuclear leukocytes (PMN) is promoted by cell surface recognition and binding of fragments of the third component of complement (C3) and Fc regions of certain immunoglobulin (IgG) molecules. In order to determine the influence of these specific ligandsurface membrane interactions upon other PMN functions, we have employed nonphagocytosable particles (serum-treated Sepharose beads) coated with fragments of C3 and/or IgG, and have investigated whether these provide a sufficient stimulus for the metabolic changes and degranulation that ordinarly accompany phagocytosis by PMN. Sepharose 4B activates complement in fresh normal serum and consequently is coated with fragments of C3 (confirmed by immunoelectrophoretic evidence of factor B and C3 conversion and by immunofluorescence). Adsorbed IgG could be removed from serum-treated Sepharose by boiling in 2 M NaCl without significantly influencing bound complement. We have found that normal human PMN recognize and adhere to Sepharose beads coated with fragments of C3 and consequently are stimulated to increase their oxidative metabolism (measured as superoxide anion generation). This PMN response occurred in the absence of IgG but could be amplified if this immunoglobulin was also present on the bead surfaces. Both adherence and metabolic stimulation could be blocked by treatment of the beads with F(ab)2 anti-C3. In contrast to metabolic stimulation, degranulation (selective extracellular release of lysosomal constituents) was observed only when PMN encountered both C3 fragments and IgG on the beads. This response could be blocked by treating beads with either F(ab)2 anti-C3 or F(ab)2 anti-IgG. These results indicate that cell surface stimulation of PMN is not an "all or none" phenomenon and that certain vital functions of these cells may be mediated or modulated independently by immunoglobulins and complement.

Cell Adhesion↗