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Biomedical subjects

R B Bressler

Publications and source records attributed to R B Bressler.

14 recordsLinked to original sources
PubMed1998

Resident cardiac mast cells degranulate and release preformed TNF-alpha, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion.

BACKGROUND: Neutrophil-induced cardiomyocyte injury requires the expression of myocyte intercellular adhesion molecule (ICAM)-1 and ICAM-1-CD11b/CD18 adhesion. We have previously demonstrated interleukin (IL)-6 activity in postischemic cardiac lymph; IL-6 is the primary stimulus for myocyte ICAM- 1 induction. Furthermore, we found that induction of IL-6 mRNA occurred very early on reperfusion of the infarcted myocardium. We hypothesized that the release of a preformed upstream cytokine induced IL-6 in leukocytes infiltrating on reperfusion. METHODS AND RESULTS: Constitutive expression of TNF-alpha and not IL-1beta was demonstrated in the normal canine myocardium and was localized predominantly in cardiac mast cells. Mast cell degranulation in the ischemic myocardium was documented by demonstration of a rapid release of histamine and TNF-alpha in the cardiac lymph after myocardial ischemia. Histochemical studies with FITC-labeled avidin demonstrated degranulating mast cells only in ischemic samples of canine myocardium. Immunohistochemistry suggested that degranulating mast cells were the primary source of TNF-alpha in the ischemic myocardium. In situ hybridization studies of reperfused myocardium localized IL-6 mRNA in infiltrating mononuclear cells and in mononuclear cells appearing in the postischemic cardiac lymph within the first 15 minutes of reperfusion. Furthermore, isolated canine mononuclear cells incubated with postischemic cardiac lymph demonstrated significant induction of IL-6 mRNA, which was partially blocked with a neutralizing antibody to TNF-alpha. CONCLUSIONS: Cardiac mast cells degranulate after myocardial ischemia, releasing preformed mediators, such as histamine and TNF-alpha. We suggest that mast cell-derived TNF-alpha may be a crucial factor in upregulating IL-6 in infiltrating leukocytes and initiating the cytokine cascade responsible for myocyte ICAM-1 induction and subsequent neutrophil-induced injury.

Animals↗
PubMed1997

Production of IL-5 and granulocyte-macrophage colony-stimulating factor by naive human mast cells activated by high-affinity IgE receptor ligation.

BACKGROUND: The late-phase allergic reaction is an eosinophilic inflammatory response that begins several hours after allergen exposure, may persist for 24 hours, and is an important pathogenic mechanism in allergic disease. OBJECTIVE: Cultured naive human mast cells were used to investigate whether mast cells are a direct source of the eosinophil-promoting cytokines IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: Naive human mast cells were derived from bone marrow mononuclear cells cultured in the presence of stem-cell factor. Cytokine message and protein production in response to high-affinity IgE receptor ligation of cultured mast cells were measured by semiquantitative polymerase chain reaction and ELISA, respectively. RESULTS: IL-5, IL-3, and GM-CSF messenger RNA increased within 2 hours of mast cell activation, with IL-5 and GM-CSF message remaining elevated for 24 hours, whereas IL-3 mRNA rapidly declined. IL-5 and GM-CSF protein were measurable 4 to 6 hours after stimulation and peaked by 24 and 12 hours, respectively. IL-3 protein was not detectable. CONCLUSION: These findings demonstrate that naive mast cells do not constitutively produce IL-5 or GM-CSF protein but are a major source of these eosinophilotropic cytokines on high-affinity IgE receptor ligation.

Base Sequence↗
PubMed1997

Behçet's-like syndrome associated with idiopathic CD4+ T-lymphocytopenia, opportunistic infections, and a large population of TCR alpha beta+ CD4- CD8- T cells.

Herein we report a patient with Behçet's like syndrome, idiopathic CD4+ T-lymphocytopenia, opportunistic infections, and a large polyclonal population of TCR alpha beta + CD4- CD8- T cells. Microfluorimetric analysis of peripheral blood mononuclear cells revealed CD4+ T-cell counts of 10 +/- 5/mm3. The CD3+ T cells were 99% TCR alpha beta +, of which 74 +/- 5% were CD4- CD8-. No clonal populations were detected by southern analysis for T-cell receptor V beta gene rearrangements. No evidence of human immunodeficiency virus infection was present, although nocardia, candida, pneumocystis, cytomegalovirus, and herpes infections were documented. The concomitant presence of opportunistic infections and a large population of TCR alpha beta + CD4- CD8- T cells suggests a pathogenic association and an intense immune response to microbial lipid or lipoglycan antigens presented in the context of CD1 molecules. This case demonstrates the potential for idiopathic CD4+ T-lymphocytopenia to occur in Behçet's-like syndrome with lethal consequences.

Behcet Syndrome↗
PubMed1992

Urticaria and angioedema.

Urticaria and angioedema are usually the clinical consequence of vasoactive mediators derived from mast cells in the skin or mucosal tissues. Efforts to classify mast cell-mediated causes of urticaria and angioedema have generally been frustrated by their diverse pathogenesis and clinical course. The term acute is typically used to describe fleeting lesions whose recurrence does not extend beyond 6 weeks. Chronic is the term used to describe lesions that persist for more than a few hours but usually less than a day, and recurrences extend for more than 6 weeks. These definitions do not take histology into account. Skin biopsies of fleeting lesions demonstrate a paucity of inflammatory cells, whereas more persistent lesions display a spectrum of perivascular cuffing by predominantly T cells and monocytes. The presence of leukocytoclastic vasculitis in persistent lesions indicates an underlying immune complex disease. Many of the physical urticarias have fleeting lesions that can be induced with the appropriate stimulus for years. This review article has emphasized the clinical course and histology of urticaria and angioedema lesions in an effort to provide a more complete understanding of the pathogenesis and appropriate treatment. Clearly, avoidance of an identifiable inciting stimulus is optimum management, although most patients have no etiology defined or the cause is not realistically avoidable. At present, treatment options for these patients rely on antihistamines to control the immediate consequence of mast cell degranulation. Corticosteroids are reserved for the treatment of patients whose urticaria or angioedema lesions persist, reflecting the increasing involvement of mononuclear cells in the disease process. For leukocytoclastic vasculitis, corticosteroids are indicated, and cytotoxic drugs may be required for adequate treatment. Future treatments of urticaria and angioedema will evolve based on elucidation of the relevant cells and soluble mediators and will include counterregulatory or antagonistic peptides and drugs. C1 esterase inhibitor deficiency is a relatively uncommon cause of angioedema but is important to understand because of its ability to clinically mimic mast cell-mediated angioedemas and its unique pathogenesis and treatment. HAE can be divided into two serologic subtypes that simply reflect the location of the defect in one of the codominantly expressed C1-INH genes on chromosome 11. AAE can be divided into two serologic subtypes. AAE type I is due to massive consumption of C1-INH, presumably by tumor-related immune complexes. AAE type II is due to an anti-C1-INH autoantibody.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗
PubMed1990

Sequential appearance of basophils and mast cells from human bone marrow in long-term suspension culture.

Human bone marrow cells grown in liquid culture in the presence of conditioned medium from concanavalin A stimulated peripheral blood mononuclear cells, from mixed lymphocyte reactions, or from an osteogenic sarcoma tumor line gave rise to basophils which were maximal in number at 1-3 weeks. Basophils had a multilobed nucleus, contained large cytoplasmic granules of variable size which stained metachromatically with acid, but not neutral toluidine blue, were negative for chloroacetate esterase, and did not contain human mast cell tryptase. In long-term cultures, mast cells were detected after 5-6 weeks. Mast cells had cytoplasmic granules that stained with acid and neutral toluidine blue, were positive for chloroacetate esterase, and contained human mast cell tryptase. It, therefore, appears that in liquid cultures even in the absence of feeder layers, human bone marrow cell cultures can give rise initially to basophils, and then to mast cells.

Animals↗
PubMed1989

Inhibition of the growth of IL-3-dependent mast cells from murine bone marrow by recombinant granulocyte macrophage-colony-stimulating factor.

The mouse mast cell line PT-18 demonstrates [3H] thymidine uptake in the presence of either mouse IL-3 or mouse recombinant granulocyte-macrophage CSF (rGM-CSF). Experiments were thus undertaken to determine whether rGM-CSF would affect IL-3-dependent growth of mast cells from mouse bone marrow cells (BMC). BMC placed in liquid culture containing 50 U/ml of IL-3 gave rise to cultures containing up to 95% mast cells by 2 to 3 wk. The rise in percentage of mast cells was accompanied by an increase in total cell-associated histamine. In contrast, BMC grown in the presence of 50 U/ml of rGM-CSF gave rise to cultures containing primarily macrophages and granulocytes with less than 1% mast cells. The addition of increasing amounts of rGM-CSF to BMC cultures grown in the presence of IL-3 resulted in a decrease in the number of mast cells present in culture at 2 to 3 wk. Cells other than mast cells in these cultures consisted principally of granulocytes and macrophages. The rGM-CSF-related inhibition of mast cell growth was not abrogated by the addition of indomethacin to cultures. Granulocyte-macrophage cell populations added to IL-3-containing cultures did not inhibit mast cell growth. The suppressive effect of rGM-CSF on IL-3-dependent mast cell growth may indicate an important role for GM-CSF in the down-regulation of mast cell proliferation in tissues.

Animals↗
PubMed1989

Therapy of chronic idiopathic urticaria with nifedipine: demonstration of beneficial effect in a double-blinded, placebo-controlled, crossover trial.

The efficacy of nifedipine, a calcium channel antagonist, in the treatment of chronic idiopathic urticaria, was evaluated in a double-blinded, placebo-controlled, crossover trial. Ten patients with chronic urticaria refractory to maximally tolerated doses of H1 and H2 antihistamines and in whom extensive evaluation failed to identify a cause for their urticaria were entered into the study. Patients continued with their prestudy antihistamine regimens. A study drug dosage was titrated in each patient and maintained throughout the trial. Patients were treated with placebo or nifedipine for 4 weeks and then crossed over to the other medication for 4 weeks. One patient withdrew because of unrelated medical illness, two patients withdrew after crossover to placebo because of intolerable urticaria, and seven patients completed the study. A beneficial effect of nifedipine was clearly demonstrated. Hive count, hive index, and itch index were all significantly improved at the end of 4 weeks of nifedipine treatment (p = 0.023, 0.003, and 0.003, respectively) but not placebo treatment (p = 0.194, 0.664, and 0.944, respectively). Additionally, end point hive index and itch index scores with nifedipine compared to corresponding placebo scores were significantly improved (p = 0.010 and 0.008, respectively). Nifedipine was well tolerated. Thus, when nifedipine is used as an adjunct to antihistamines, it appears to be a safe, efficacious drug for the treatment of chronic idiopathic urticaria.

Adult↗
PubMed1989

Analysis of the wheal-and-flare reactions that follow the intradermal injection of histamine and morphine in adults with recurrent, unexplained anaphylaxis and systemic mastocytosis.

It has been suggested that patients with recurrent, unexplained anaphylaxis may be more responsive, and patients with systemic mastocytosis, less responsive, to mast cell-derived mediators, including histamine, compared to normal subjects. This would help explain why patients with recurrent, unexplained anaphylaxis have an anaphylactic response and, conversely, why patients with systemic mastocytosis can tolerate high levels of plasma histamine. To test this hypothesis, intradermal titrations (0.02 ml of solution from 1 ng/ml to 2 micrograms/ml) of histamine and morphine sulfate (MS) (10 ng/ml to 10 micrograms/ml) were administered to normal volunteers (N = 15), patients with recurrent, unexplained anaphylaxis (N = 10), and patients with systemic mastocytosis (N = 18). Antihistamines were stopped at least 72 hours before the study. Resultant areas of wheal and flare were determined with a computerized morphometric system. Comparison of any two given means at each dose of histamine or morphine with the two-sample Student's t test with Bonferroni inequality demonstrated no significant differences (p greater than 0.05) among the three groups. The median amount of MS or histamine required to produce a half-maximal response was compared for equality. None of the differences observed reached statistical significance, in agreement with the similarity of the dose-response curves. An analysis of the correlation between response to MS and to histamine in individual subjects revealed the responses to be significantly correlated in all cases, with the exception of wheal in patients with recurrent, unexplained anaphylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Controlled pilot trial of monthly intravenous cyclophosphamide in multiple sclerosis.

Monthly intravenous cyclophosphamide treatment was compared with placebo treatment for one year in a controlled trial of 14 patients with relapsing/remitting multiple sclerosis. Eight patients received placebo and six patients received cyclophosphamide. The cyclophosphamide group showed a definite trend to have less frequent and less prolonged episodes than the placebo group. When each group served as their own controls, the cyclophosphamide group had a significant decrease in episodes while the placebo group did not. When the placebo group was then given cyclophosphamide, they also had a significant decrease in episodes. When all patients who were receiving cyclophosphamide were combined for analysis, the decrease in episodes was even more evident. Complications were minimal. These results suggest that monthly intravenous doses of cyclophosphamide may influence the frequency and duration of episodes of relapsing/remitting multiple sclerosis.

Adult↗
PubMed1988

Characterization of basophil-like cells derived from nonhuman primate bone marrow.

In order to determine whether mast cells or basophils could be derived from nonhuman primate bone marrow, cells from bone marrow aspirates were cultured in the presence of concanavalin A-stimulated nonhuman primate spleen cell supernatants (CAS). Culture conditions were identical to those used for culturing mucosal-like mast cells from mouse bone marrow. In this situation, basophil-like cells (BLC) could be identified in liquid cultures and averaged 14-19 microM in size, were round or oval in appearance, had lobulated nuclei, and contained less than 100 metachromatically staining granules per cell. By electron microscopy, granules had dense oval or semilunar cores with surrounding fibrous whorls. BLC were peroxidase positive, chloroacetate esterase negative, stained positively with acid toluidine blue, and contained 0.1-0.3 pg histamine per cell. BLC expressed IgE receptors and were Leu 5b and Leu 16 negative. IgE-sensitized BLC released histamine after stimulation with antihuman IgE or the calcium ionophore A23187. [35S]-labeled proteoglycans were degraded with chondroitinase ABC but not with heparinase, indicating the absence of heparin in BLC. Thus, culture conditions that include the use of CAS and lead to the growth of mast cells from rodent bone marrow result in the growth of BLC from nonhuman primate bone marrow. These observations suggest that fundamental differences exist in the type of histamine containing cells that arise from rodent and primate bone marrow when such bone marrow cells are cultured under identical conditions.

Animals↗
PubMed1986

Piperacillin-induced anemia and leukopenia.

Piperacillin is being used with increasing frequency as an important antibiotic for the treatment of severe and life-threatening infections. Many of these patients may have multiple possible causes of leukopenia and/or anemia. An awareness of the potential for piperacillin to cause the rapid onset of leukopenia and/or anemia may have important therapeutic implications, especially in severely ill patients.

Adult↗
PubMed1986

Prevention of mast-cell degranulation by ketotifen in patients with physical urticarias.

The capacity for ketotifen to prevent mast-cell degranulation in vivo was studied in patients with physical urticarias. Patients were exposed to the appropriate stimulus to elicit their physical urticaria before and during ketotifen therapy. Histamine concentrations in plasma samples, obtained before and serially after the physical provocation, were determined by radioenzymatic thin-layer chromatography. Ketotifen therapy was associated with marked reductions in plasma histamine levels after stimulation and in clinical evidence of urticaria in each patient. A direct correlation of ketotifen therapy and a reduction in histamine release was confirmed in a patient with a cold-induced urticaria who was studied again after discontinuation and again after reinstitution of therapy. Although the mechanism of action is unknown, this report shows that ketotifen is capable of inhibiting cutaneous mast-cell degranulation and its accompanying symptoms. These findings suggest important therapeutic alternatives for patients with mast-cell-mediated diseases.

Adult↗
PubMed1985

Water intoxication following moderate-dose intravenous cyclophosphamide.

Moderate-dose (15 to 20 mg/kg) bolus intravenous (IV) cyclophosphamide is increasingly being employed for the treatment of autoimmune diseases. High-dose (30 to 50 mg/kg) IV cyclophosphamide, which is used in transplantation and oncology, may cause water intolerance and water intoxication. Described herein is the first patient, to our knowledge, to develop water intoxication following administration of moderate-dose IV cyclophosphamide. A water challenge test demonstrated the absence of an underlying syndrome of inappropriate antidiuretic hormone secretion. Water intolerance was demonstrated in five additional patients receiving moderate-dose IV cyclophosphamide and hydration with hypotonic fluids. Thus, contrary to previous reports, water intoxication can occur following administration of moderate-dose IV cyclophosphamide. Patients with renal insufficiency who are receiving hypotonic fluids following moderate-dose IV cyclophosphamide administration may be at greatest risk for development of symptomatic water intoxication.

Cyclophosphamide↗