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N Hanna

Publications and source records attributed to N Hanna.

At least 91 records · Page 5Linked to original sources
PubMed1988

Methotrexate inhibits macrophage activation as well as vascular and cellular inflammatory events in rat adjuvant induced arthritis.

We demonstrated previously that variables of macrophage activation are associated with the development and progression of the arthritic lesion in the model of adjuvant induced arthritis. This association was investigated further by assessing the ability of antiarthritic agents to modulate variables of macrophage activation in direct comparison to effects on the arthritic lesion. Whereas indomethacin effectively reduced hindpaw edema, it had no significant effect on Ia expression or on any measurement of activation. Prednisolone inhibited hindpaw edema and the production of interleukin-1 (IL-1) by splenic macrophages. Only methotrexate inhibited hindpaw edema and all variables of macrophage activation (PGE2 and IL-1 production, cyanine dye accumulation) as well as the influx of Ia positive macrophages into synovial tissue.

Animals↗
PubMed1987

Effect of auranofin treatment on aberrant splenic interleukin production in adjuvant arthritic rats.

Adjuvant-induced arthritis (AA) in rats is associated with a number of immunologic abnormalities which include a marked decrease in spleen cell mitogenic responses. In this study we investigated the altered production of interleukins in arthritic rats and evaluated the effects of auranofin treatment on disease progression and aberrant interleukin production. The capacity of the AA rat spleen cells to produce interleukin (IL) 2 and IL-3 was found to decrease during the development of the arthritic lesion, with maximum suppression occurring 16 to 17 days after adjuvant injection. In contrast, the production of IL-1 by splenic adherent cells from arthritic rats was markedly increased. Prophylactic treatment of AA rats with auranofin resulted in a slight reduction in paw edema, a complete normalization of the depressed IL-2 production, and a reduction of the elevated IL-1 production, but had no effect on the depressed IL-3 production. In contrast, auranofin administered to normal rats, in the same dosing regimen, did not affect interleukin production. Therapeutic administration of auranofin to AA rats with established disease resulted in normalization of IL-1 production without affecting the suppressed IL-2 and IL-3 levels. In contrast, while indomethacin treatment effectively decreased paw edema, it did not appreciably affect the systemic aberrant interleukin production. Taken together, these results suggest that disease-associated abnormalities in interleukin production may be mediated by different mechanisms with differential sensitivity to the effects of the disease-modifying drug auranofin. Furthermore, defining the relationship between drug-mediated normalization of aberrant immune parameters and clinical improvement will provide a basis for the elucidation of the mechanism of action of disease-modifying antiarthritic drugs as well as for assessment of clinical efficacy of drug treatment.

Animals↗
PubMed1987

SK&F 86002: a structurally novel anti-inflammatory agent that inhibits lipoxygenase- and cyclooxygenase-mediated metabolism of arachidonic acid.

The effects of SK&F 86002 [5-(4-pyridyl)-6 (4-fluorophenyl)-2,3-dihydroimidazo (2,1-b) thiazole] on the generation of eicosanoids in vitro and on inflammatory responses in vivo are described and compared to other non-steroidal anti-inflammatory drugs. SK&F 86002 inhibited prostaglandin H2 (PGH2) synthase activity (IC50 120 microM) as well as prostanoid production by rat basophilic leukemia (RBL-1) cells (IC50 70 microM) and its sonicate (IC50 100 microM) and human monocytes (IC50 1 microM). In addition, SK&F 86002 inhibited the generation of dihydroxyeicosatetraenoic acid (diHETE) and 5-hydroxyeicosatetraenoic acid (5-HETE) by a high speed supernatant fraction of RBL-1 cells (IC50 10 microM). Cellular production of 5-lipoxygenase products was inhibited by SK&F 86002 as measured by leukotriene B4 (LTB4) generation from human neutrophils (IC50 20 microM), leukotriene C4 (LTC4) generation by human monocytes (IC50 20 microM), and 5-HETE production by RBL-1 cells (IC50 40 microM). The in vivo profile of anti-inflammatory activity of SK&F 86002 supports the dual inhibition of arachidonate metabolism as indicated by its activity in inflammation models that are insensitive to selective cyclooxygenase inhibitors. The responses of arachidonic-acid-induced edema in the mouse ear and rat paw, as well as the cell infiltration induced by carrageenan in the mouse peritoneum and by arachidonic acid in the rat air pouch, were inhibited by SK&F 86002 and phenidone but not by the selective cyclooxygenase inhibitors naproxen and indomethacin.

Animals↗
PubMed1987

Arachidonic acid-induced inflammation: inhibition by dual inhibitor of arachidonic acid metabolism, SK&F 86002.

The antiinflammatory activity of the structurally novel dual inhibitor of arachidonic acid metabolism, SK&F 86002 was evaluated using arachidonic acid-induced edema and inflammatory cell infiltration. Histological examination demonstrated extensive subcutaneous edema and neutrophil (PMN) accumulation in perivascular and interstitial locations one hour after application of arachidonic acid to the ear. SK&F 86002 and, to a lesser extent, phenidone demonstrated potent inhibition of this inflammatory response following oral and topical administration. Nordihydroguaiaretic acid (NDGA) displayed only topical activity. The selective cyclooxygenase inhibitors ibuprofen and naproxen were either inactive or stimulated ear swelling. Histological evaluation of the lesion in drug-treated animals revealed that SK&F 86002 impaired edema formation and caused a significant reduction in numbers of infiltrating neutrophils. Using arachidonic acid-induced peritoneal exudation, a reduction in the cellular infiltrate was observed after oral treatment with SK&F 86002 or phenidone, but not with naproxen. Taken together, these data illustrate the potent antiinflammatory effects of SK&F 86002 and support the suggestion that 5-lipoxygenase products play a significant role in both the edematous and cellular phases of arachidonic acid-induced inflammation.

Animals↗
PubMed1987

Pharmacologic characterization of the antiinflammatory properties of a new dual inhibitor of lipoxygenase and cyclooxygenase.

SK&F 86002 [6-(4-fluorophenyl)2,3-dihydro-5-(4-pyridinyl)imidazo (2,1-b)thiazole], a dual inhibitor of arachidonic acid metabolism, administered orally to rats prevented the development of carrageenan-induced edema, immune- and nonimmune-mediated inflammation of adjuvant-induced arthritis (AA) and reduced established inflammation in AA and collagen type II-induced arthritis. A similar profile of activity was observed following treatment with the cyclooxygenase inhibitor, indomethacin. However, unlike other nonsteroidal antiinflammatory drugs, SK&F 86002 exhibited antiinflammatory activity in inflammation models that are insensitive to cyclooxygenase inhibitors such as the established inflammation in carrageenan-induced edema and the edema induced by arachidonic acid and platelet activating factor. Moreover, SK&F 86002, but not indomethacin, inhibited the immune-mediated inflammatory responses evoked in sensitized animals by challenge with purified protein derivative. In addition, SK&F 86002 produced dose-related analgesia in mice, which was not reversed by the narcotic antagonist, naltexone. SK&F 86002 thus represents an orally active antiarthritic and analgesic compound with novel antiinflammatory properties.

Administration, Oral↗
PubMed1987

The pharmacology of arachidonic acid-induced rat paw edema.

Arachidonic acid (AA) injected into hindpaws of Lewis rats produces a severe edematous response. Treatment with corticosteroids (dexamethasone, prednisolone), dual inhibitors of arachidonate metabolism (phenidone, SK & F 86002), anti-histamine/serotonin agents (chlorpheniramine, cyproheptadine) and a gold compound (auranofin) inhibited AA-induced edema. In contrast, administration of high doses of cyclooxygenase inhibitors (indomethacin, piroxicam, naproxen, ibuprofen, meclofenamic acid and tiflamizole) did not affect AA-induced hind paw edema. The involvement of lipoxygenase products and mast cell mediators in the edematous response to arachidonic acid render this model potentially useful for studying antiinflammatory agents with a mechanism of action different from that of cyclooxygenase inhibitors.

Adrenal Cortex Hormones↗
PubMed1987

Effect of antiarthritic drugs on the enhanced interleukin-1 (IL-1) production by macrophages from adjuvant-induced arthritic (AA) rats.

The effect of antiarthritic drugs on hindpaw edema and enhanced IL-1 production by macrophages from adjuvant arthritic (AA) rats was determined. Hindpaw edema was inhibited by indomethacin (INDO), methotrexate (MTX) or prednisolone (PRED) but not by D-penicillamine (D-PEN) or chloroquine (CQ). IL-1 production by splenic adherent cells was decreased by MTX and PRED; whereas, IL-1 production by peritoneal exudate cells was decreased by PRED, INDO and D-PEN. This normalization in IL-1 production is not caused by a direct inhibition of IL-1 production by the drugs but most likely reflects clinical improvement in the disease. Whether reduction in IL-1 levels provides a more meaningful parameter than paw edema for assessing clinical efficacy of disease-modifying drugs remains to be determined.

Animals↗
PubMed1987

Augmentation of human natural killer cell activity by influenza virus antigens produced in Escherichia coli.

A series of Escherichia coli cloned influenza viral gene products were assayed for their ability to augment human natural cytotoxicity in overnight cultures (18 h) at 37 degrees C. Nylon wool nonadherent peripheral blood mononuclear cells (PBMC) proved responsive to stimulation by a number of cloned viral proteins, the most effective being the nonstructural (NS1) protein (but not NS2 protein) and haemagglutinin and matrix antigen components fused to the N-terminal 81 amino acid sequence of NS1. Furthermore, interferon (IFN) was generated in cultures in which enhanced cytotoxicity was detected and was identified as mostly IFN alpha (greater than 90%) with less than 10% IFN gamma contamination. The cell type responding to antigen stimulation was present in Percoll fractions enriched for large granular lymphocytes (LGLs); furthermore PBMC activated by NS1 protein fractionated in the low density Percoll fractions (LGL enriched). Using specific anti-IFN antisera, it was shown that IFN alpha but not IFN gamma was responsible for the enhancement of cytotoxicity. Interferon induction and activation of cytotoxicity could not be ascribed to the presence of contaminating bacterial products. These results suggest that a particular NS1 protein configuration is capable of activating human natural killer cells via the induction of IFN alpha.

Antigens, Viral↗
PubMed1986

Differential sensitivity of T suppressor cell expression to inhibition by histamine type 2 receptor antagonists.

The ability of the histamine type 2 (H2) receptor antagonists cimetidine and oxmetidine to inhibit the immune suppression mediated by different types of murine T suppressor cells has been evaluated. Both compounds at doses as low as 1 mg/kg administered as a per os (p.o.) twice a day (b.i.d.) regimen abrogated the expression of dinitrobenzene sulfonic acid-induced, Lyt-2+, T suppressor cells and stimulated contact sensitivity to dinitrofluorobenzene in adoptive transfer experiments. Comparable inhibition of Lyt-1+, T suppressor cell activity induced by UV irradiation required higher doses of cimetidine and oxmetidine (200 and 25 mg/kg; p.o., b.i.d., respectively). In contrast, the T suppressor cell-mediated unresponsiveness induced by inoculation with a high dose of sheep red blood cells was refractory to treatment in vivo with either cimetidine or oxmetidine regardless of the dose. These results indicate that T suppressor cell populations differ markedly in their susceptibility to modulation by H2 antagonists. The histamine type 1 (H1) receptor antagonist diphenhydramine, had no effect on suppressor cell activity in any of these systems, indicating that modulation of suppressor cell activity is mediated through an H2 receptor interaction.

Animals↗
PubMed1986

Quantitative Western blot assay for measurement of the murine acute phase reactant, serum amyloid P component.

Quantitation of the murine acute-phase reactant, serum amyloid P component (SAP), by Western blot is described. The assay is sensitive, reliable and inexpensive. Electrophoresis in standard SDS-polyacrylamide gels (SDS-PAGE) effectively separates SAP from other serum proteins. Electrophoretic blotting of SAP from the SDS-PAGE onto nitrocellulose (NC) paper is followed by a bovine serum albumin 'blocking' wash and exposure to anti-SAP antibody. Subsequent incubation with radioiodinated protein A was followed by autoradiography, and SAP bands were cut from the NC paper and counted in a gamma counter. The utility of this method for quantitation of SAP in biological fluids was verified using sera from normal mice and mice undergoing an acute inflammatory response. The results confirm the elevation of SAP associated with acute inflammation. The sensitivity of this technique coupled with the minute volumes of biological sample required renders it of potential utility for SAP quantitation in a variety of inflammatory disease states.

Amyloid↗
PubMed1986

Identification and characterization of a human T cell line-derived lymphokine with MAF-like activity distinct from interferon-gamma.

Culture supernatants of several human T cell leukemia cell lines were screened for macrophage-activating activity (MAF) as defined by induction of tumoricidal activity against human melanoma cells in a 72-hr assay. Two cell lines, MT-2 and C10/MJ2, were found to produce high levels of MAF activity constitutively, but the MT-2 cell line, unlike C10/MJ2, produced little IFN-gamma. This observation was confirmed by Northern blot analysis performed with specific IFN-gamma cDNA probe. The MT-2 cell line thus provides a useful system to evaluate the existence of lymphokines with MAF activity that are distinct from IFN-gamma. The MAF activity produced by MT-2 cells was distinguished from IFN-gamma by the following criteria. MAF activity was not removed by immunoaffinity chromatography with the use of immobilized specific polyclonal antibodies to IFN-gamma and was not neutralized by a monoclonal antibody to IFN-gamma. Heat or acid treatments of IFN-gamma resulted in loss of its antiviral activity, but these treatments had no effect on MAF activity. MAF activity was not abolished by polymyxin B sulfate, suggesting that this activity is not mediated by or dependent on LPS. Initial characterization studies performed by using membrane filtration, gel filtration chromatography, and isoelectric focusing indicate that the non-IFN-gamma MAF activity produced by MT-2 cells has an apparent m.w. of 55,000 and an isoelectric point of 5.5. Collectively, these data suggest that the MT-2 human T cell line constitutively produces high levels of MAF and low levels of IFN-gamma and offers a useful source for the further purification of a unique human lymphokine with macrophage-activating activity that is distinct from IFN-gamma.

Cell Line↗
PubMed1986

Macrophage activation in rat models of inflammation and arthritis. Systemic activation precedes arthritis induction and progression.

The association between the induction and progression of adjuvant-induced arthritis (AA) and the development of synovial and systemic macrophage activation was assessed by studying the temporal development of these parameters in a rat model. Rats with AA developed significant edema of the uninjected hind leg beginning 10 days post-adjuvant injection, with progressive increases in edema continuing through day 17. Several parameters of macrophage activation, including the enhanced ability to secrete interleukin-1 and prostaglandin E2, kill tumor cells, accumulate fluorescent cyanine dyes, emigrate into the peritoneal cavity and synovium, and express Ia antigen, as well as the decreased ability to secrete superoxide anion, were associated temporally with the development of the arthritic lesion. In addition to the temporal association between macrophage activation and development of arthritis, a positive correlation between macrophage activation and arthritis induction was seen with the use of synthetic adjuvants at arthritogenic and nonarthritogenic doses. These data taken together suggest that induction and progression of AA in rats is associated with both systemic (blood, spleen, and peritoneal cavity) and local (synovium) macrophage activation.

Animals↗
PubMed1986

Macrophage activation in rat models of inflammation and arthritis: determination of markers of stages of activation.

Disease-associated alterations in macrophage functions were assessed by investigating the stages of activation of peritoneal macrophages obtained from adjuvant-induced arthritic rats. The stages of activation were established by defining several functional parameters in macrophages obtained from normal, sterile-irritant injected and Propionibacterium acnes injected animals. Peritoneal macrophages taken from arthritic rats 17 days post adjuvant injection displayed parameters characteristic of activated, but not elicited or resident macrophages. Specifically, an increased number of macrophages was recovered from arthritic rats which spread readily in culture, exhibited enhanced Fc receptor-mediated phagocytosis, increased leucine aminopeptidase ectoenzyme activity, enhanced secretion of prostaglandin E2 and interleukin 1, and ability to lyse tumor cells spontaneously. In addition, these macrophages were impaired in their ability to secrete superoxide anion. These data demonstrate distinct differences in parameters of peritoneal macrophage activation in rats compared to mice and that macrophage activation is associated with disease progression in adjuvant-induced arthritic rats.

Animals↗
PubMed1986

Antiarthritic and immunoregulatory activity of spirogermanium.

Spirogermanium is a novel metal containing azaspirane compound with reported antitumor activity. The results of the present investigation demonstrate that spirogermanium also exhibits antiarthritic and immunoregulatory activities after p.o. administration to rats. Spirogermanium decreased hindleg inflammatory lesions of adjuvant arthritic rats when administered p.o. before or after the development of the arthritic lesions. After termination of spirogermanium administration, the adjuvant-injected hindleg lesions remained significantly suppressed for at least 2 weeks postdrug treatment; whereas, the uninjected, immune-mediated hindleg inflammation tended to increase postdrug treatment. In multiparameter ex vivo studies, untreated arthritic rats exhibited enhanced cyanine dye fluorescence in peripheral blood monocytes, enhanced interleukin (IL)-1 production by adherent spleen cells and depressed IL-2 and IL-3 production by splenic lymphocytes. Spirogermanium normalized these changes to various degrees, with the exception of the depressed IL-2 and IL-3 production. Spirogermanium administered to normal nonarthritic rats decreased mitogenic responses of spleen cells to Concanavalin A which was found to be caused, at least in part, by enhanced suppressor cell activity. The antiarthritic and immunoregulatory profile of spirogermanium appeared to be different from the profiles of the antiarthritic agents, auranofin and indomethacin.

Animals↗
PubMed1986

Induction of tumor immunity and natural killer cell cytotoxicity in mice by 5-halo-6-phenyl pyrimidinone.

We have investigated the effect of pyrimidinone molecule 2-amino-5-iodo-6-phenyl-4 pyrimidinone (AIPP) on natural killer (NK) cell lytic potential and on the growth of ascitic mammary adenocarcinoma, ACA-755, in B6D2F1 mice. Our studies demonstrated that AIPP was effective in both the prophylaxis and the therapy of this tumor and that the antitumor effect was mediated via induction of NK cell lytic activity. In vitro characterization studies showed that the AIPP-induced cytotoxic cells were not macrophages and exhibited characteristics of NK cells such as morphology of the large granular lymphocytes and sensitivity to asialo GM-1 antibody. Analysis of the mechanism of potentiation of NK cell cytotoxic function by AIPP indicated that the enhancement of cytotoxicity was accomplished by recruitment of NK cell tumor-binding potential (primarily those with large granular lymphocytic morphology) as well as by increased frequency of lytic NK cells. These studies implicate NK cells in the defense against malignant tumors and suggest that regional therapy with AIPP may represent a new therapeutic modality for treatment of cancer.

Animals↗
PubMed1985

Structure and biological activity of polysomes stained with Coomassie blue.

Polysomes prestained with Coomassie blue were fractionated on sucrose density gradients giving rise to visible bands corresponding to different size classes of aggregates. Coomassie blue staining enhanced the capacities of brain and liver polysomes to synthesize proteins in vitro, including the synthesis of neuron-specific enolase. This positive action of the dye was restricted to polysomes and was not manifested when mRNAs isolated from prestained polysomes were tested in in vitro translation or reverse transcription, indicating that the action of the dye consists in stabilization of polysomal structure.

Animals↗
PubMed1985

Induction of suppressor cells, interleukin-2 production and mitogenesis with monomeric concanavalin A: different actions of tetrameric and monomeric concanavalin A.

The ability of a photoalkylated monomeric concanavalin A (Con A) derivative to induce mitogenesis, interleukin-2 (IL-2) production and suppressor cells in murine spleen cell cultures has been compared with the activity of native, tetrameric Con A. The monomeric derivative was prepared by photochemically induced alkylation of tryptophan residues of tetravalent Con A in the presence of chloroacetamide followed by sizing chromatography [Tanaka et al. (1981) J. Biochem. 89, 1643-1646]. The monomeric derivative appeared to display less mitogenic activity than the tetramer and was also less effective in inducing IL-2 production. No difference was detected between the monomeric and tetrameric forms of Con A in inducing suppressor cells. The data suggest that cross-linking and bridging via sugar-binding sites, while potentiating mitogenesis and IL-2 production, had little effect on suppressor cell induction.

Animals↗