[Acquisition of myocardial ischemic tolerance and its clinical significance].
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Angina Pectoris↗
Biomedical subjects
H Fuji
Publications and source records attributed to H Fuji.
Transcardiac alteration of neutrophil function before and after coronary thrombolysis in human myocardial infarction.
We examined function of isolated neutrophils taken from aorta and coronary sinus before and after thrombolytic reperfusion in 17 patients whose infarct-related coronary arteries were totally occluded. Before reperfusion in left coronary artery disease, free radical generation by activated neutrophils in coronary sinus, assessed by ferricytochrome c reduction (phorbol myristate acetate, 10 ng/ml) and luminol-enhanced chemiluminescence (A23187, 2 microM), was reduced by 20% (P less than 0.05) and 30% (P less than 0.05), respectively, compared with those in aorta. Neutrophil aggregation (A23187, 10 microM) and chemotactic activity (formyl-methionyl-leucyl-phenylalanine, 5 microM) were also reduced in coronary sinus by 21% and 20%. After reperfusion the extent of such neutrophil function in coronary sinus recovered and was similar to that in aorta. There were no significant differences between neutrophil counts in aorta and coronary sinus before and after reperfusion. In right coronary artery disease, no significant changes were seen in these functions of neutrophils of aorta and coronary sinus before and after reperfusion. These results indicate that function of neutrophils passing through coronary circulation fluctuated significantly in association with reperfusion, suggesting (1) factor(s) that depress neutrophil function are produced in coronary circulation during myocardial ischemia and their effects are overcome after reperfusion or (2) activated neutrophils, trapped in the ischemic coronary bed, are washed out to coronary sinus after reperfusion.
Chemotaxis, Leukocyte↗
Neutrophil-induced myocardial cell damage and active oxygen metabolites.
Free radicals derived from polymorphonuclear leukocytes (PMN) have been suggested to play an important role in myocardial ischemia-reperfusion injury. To define the mechanism by which activated PMN exacerbate ischemic myocardial damage, we investigated the extent of cell injury, free radical generation and lipid peroxidation in embryo mouse myocardial cells co-incubated with activated PMN. The generation of free radicals derived from PMN correlated with the extent of myocardial cell injury. Among the cell sheets preconditioned with hypoxic and glucose free medium, PMN-adhered myocardial cells were initially injured after adding PMN activator, extending to adjacent cells. Chemiluminescence emission and thiobarbituric acid reactive substance in the co-incubated cells were markedly increased and sustained compared with those in each cell monoincubation. The augmented lipid peroxidation was related to the progression of myocardial cell injury. These results indicate that PMN-derived free radicals cause membrane disruption, contributing to the progression of myocardial injury.
Animals↗
Detection of oxygen-derived free radical generation in the canine postischemic heart during late phase of reperfusion.
To define the relation between oxygen-derived free radical (oxy-radical) generation in the reperfused ischemic myocardium and the progression of myocardial damage, we measured oxy-radical generation in the ischemic myocardium and the propagating infarct size in a model of canine coronary occlusion (90 minutes) and reperfusion. We used electron paramagnetic resonance spin-trapping techniques (5,5-dimethyl-1-pyrroline N-oxide [DMPO]) to detect oxy-radicals in the rapidly frozen myocardial samples taken by needle biopsy. There was no detectable generation of DMPO adducts in the normal myocardium before or after reperfusion. In the reperfused ischemic myocardium, electron paramagnetic resonance signals of DMPO-OOH (superoxide anion) and DMPO-OH (hydroxyl radical) were detected, with peak concentrations at 1 hour after reperfusion for DMPO-OOH and at 3 hours after reperfusion for DMPO-OH, respectively. These DMPO adducts were also detected during the early phase (15 seconds) of reperfusion, but the concentrations of these signals were much less than those during the late phase of reperfusion. Treatment with human recombinant superoxide dismutase (2.5 mg/kg/hr) and catalase (2.5 mg/kg/hr) during the course of experiments abolished DMPO-OOH formation but had little effect on DMPO-OH formation. Infarct size (percent of risk area infarcted), quantified by a dual staining method with Evans blue dye and triphenyltetrazolium chloride, was 18.3 +/- 4.8% (mean +/- SEM) at 90 minutes of occlusion. After 5 hours of reperfusion, infarct size increased to 43.6 +/- 7.2%. These results indicate that a greater magnitude of oxy-radical generation was sustained in the ischemic myocardial tissue during the late phase (1-3 hours) of reperfusion, associated with the progression of myocardial infarction. The concurrent appearance of oxy-radicals and progressive infarction may support the view that a chain reaction of oxy-radicals contributes to the propagation of myocardial cell damage in the postischemic heart.
Animals↗
[Role of oxy-radicals in myocardial oxygen paradox].
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Animals↗
Recombinational sites observed in naturally occurring intra-RT1 recombinant strains.
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Animals↗
Role of free radicals and neutrophils in canine myocardial reperfusion injury: myocardial salvage by a novel free radical scavenger, 2-octadecylascorbic acid.
To define the role of oxygen free radicals and neutrophil involvement in evolving myocardial reperfusion injury, we evaluated the effect of 2-octadecylascorbic acid (CV-3611), a novel free radical scavenger, on neutrophil function and the extent of myocardial damage resulting from 90 min of ischaemia followed by 5 h of reperfusion in an experimental model of myocardial infarction. Dogs were randomly assigned to receive CV-3611 (5 mg.kg-1.[5 min]-1, intravenously) just before the onset of reperfusion. Infarct size, as a percent of area at risk, was reduced by 60% in CV-3611 treated group as compared with control, at 16.7(SEM 3.1)% v 41.5(4.5)%, p less than 0.01. Administration of CV-3611 markedly reduced function of neutrophils isolated from peripheral circulation during reperfusion ex vivo as estimated by free radical generation (ferricytochrome c reduction and luminol enhanced chemiluminescence), chemotactic activity, and aggregation induced by A23187. Under these conditions, the enhancement in neutrophil infiltration and free radical generation (luminol enhanced chemiluminescence) in myocardium within area at risk, especially in the border zone between viable and irreversible injured myocardium, was markedly reduced. Haemodynamic profiles were similar between control and CV-3611 treated group. These results suggest that activated neutrophils, especially their generation of oxygen free radicals, contribute to reperfusion induced myocardial injury.
Animals↗
[An autopsy case of primary cutaneous plasmacytoma].
An autopsy case of primary cutaneous plasmacytoma with very unusual extensive skin involvement resulting in death 9 months later, was reported. A 75-year-old female was admitted to our hospital in November, 1985 because of an enlarging skin nodule on the right neck of 5 month's duration. The nodule was a 5 x 7 x 4-cm, firm and mobile mass. Light- and electron-microscopic studies of its biopsy specimen revealed a cutaneous plasmacytoma which was composed of dense aggregates of plasma cells. Cytogenic study on the biopsy specimen revealed hypotetraploid and structural abnormalities such as 7q+, 11q+ and 20q+. After radiotherapy, the right neck nodule became smaller, but subcutaneous indurations with erosions extended to the surrounding skin. The biopsy specimen of these skin lesions microscopically revealed massive infiltrations of plasma cells in the dermis. The PAP method revealed a definite evidence of monoclonal kappa light chain production by these cells. 3H-thymidine were incorporated in 5.6% of the plasma cells. The skin lesions were refractory to chemotherapy and gradually extended. The clinical course showed a progressive one leading to persistent deterioration and she died in August, 1986. Repeated examinations including immunoelectrophoresis of serum and concentrated urine, bone marrow aspirations and skeletal x-ray films, excluded the diagnosis of myeloma. At autopsy, massive infiltrations of plasma cells in the skin of chest wall and neck, small metastatic tumors in the liver and bilateral axillary lymph nodes were found, but there was no evidence of bone marrow involvement.
Aged↗
Identification of an alternatively spliced Kd and the Qa-6d mRNAs by using amplified cDNA.
We have employed the primer chain reaction method for direct sequencing of H-2 mRNAs. This approach is highly sensitive and permits quantitation and sequencing of the canonical as well as alternatively spliced mRNAs that may be expressed at 5-10% level in comparison to the major H-2 species. Using this technique, we have identified a novel species of alternatively spliced Kd mRNA expressed in L1210 lymphoma and in the spleen and liver of DBA/2 mice. Similarly, we found a previously described alternatively spliced species of H-2Dd mRNA to be expressed in L1210 lymphoma and have determined the sequence of the cytoplasmic domain of Ld mRNA. In addition, we have identified a Class I MHC transcript presumably encoded by a gene allelic to Q6 gene of BALB/c mice.
Animals↗
Tumor-specific idiotype vaccines. II. Analysis of the tumor-related network response induced by the tumor and by internal image antigens (Ab2 beta).
In this study the tumor-specific immuneresponse induced by irradiated tumor cells (L1210/GZL) and by anti-idiotype antibodies was analyzed. The anti-idiotype antibodies (Ab2) were made against the paratope of a monoclonal antitumor antibody (11C1) that recognizes a tumor-associated antigen which cross-reacts with the mouse mammary tumor virus-encoded envelope glycoprotein 52. Two Ab2, 2F10 and 3A4, induced idiotypes expressed by the monoclonal antitumor antibodies 11C1 and 2B2. Cytotoxic T cells, generated by immunization with irradiated tumor cells, lyse 2F10 and 3A4 hybridoma cells. Furthermore, immunization with Ab2 induces tumor-specific cytotoxic T lymphocytes. The frequency of tumor-reactive cytotoxic T lymphocyte was found to be similar in mice immunized with Ab2 or irradiated tumor cells when examined at the precursor level. However, only 2F10 induces protective immunity against the growth of L1210/GZL tumor cells. The depletion of a L3T4+ T cell population from 2F10 immune mice was found to increase the effectiveness of transferred T cells to induce inhibition of tumor growth. The inability of 3A4 to induce antitumor immunity could be correlated with the presence of a population of Lyt2+ regulatory T cells. Collectively, these results demonstrate the existence of a regulatory network controlling the expression of effective tumor immunity. Our results demonstrate that selection of binding site-related Ab2 may not be a sufficient criteria for the development of an idiotype vaccine. A better understanding of the regulatory interactions induced by anti-idiotypes is needed for the design of effective antitumor immunotherapy.
Animals↗
[Study of external urethral sphincter in the rabbit. Histochemical analysis by ATP-ase stain].
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Adenosine Triphosphatases↗
Analysis of the expression of H-2K, D and L locus mRNAs by use of an oligonucleotide primer.
By employing an oligonucleotide-dependent cDNA synthesis/HaeIII digestion procedure followed by gel electrophoretic separation of HaeIII digested cDNAs, we have developed a method for analyzing the expression of H-2 mRNAs encoding the K, D and L locus histocompatibility antigens. This method provides unambiguous data as the individual K, D or L specific cDNA bands can be isolated from the gel and partially sequenced. The method is readily applicable to analyzing the relative expression of K, D and L locus mRNAs in normal mouse tissues and their tumors.
Animals↗
Tumor-specific idiotype vaccines. I. Generation and characterization of internal image tumor antigen.
The concept of idiotype vaccines against tumor-associated antigens (TAA) was tested in the DBA/2 L1210 lymphoma subline, L1210/GZL. Monoclonal antibodies against a TAA that cross-reacts with the envelope glycoprotein gp52 of the mammary tumor virus were used to make hybridoma anti-idiotype antibodies (Ab2). In this report we describe the characterization of monoclonal anti-idiotypic antibodies against the combining site of 11C1 (Ab1), which recognizes a shared determinant of gp52 of mouse mammary tumor virus (MMTV) and the TAA of L1210/GZL. Hybridomas expressing the internal image of gp52 were screened by an idiotype inhibition assay. Mice sensitized with radiated L1210/GZL cells produced specific delayed type hypersensitivity (DTH) against the Ab2 hybridoma. Five Ab2 hybridomas were selected and were used to immunize DBA/2 mice. Such immunized animals showed specific DTH reaction against a challenge with the L1210/GZL tumor cells. Similar results were obtained in mice immunized with purified Ab2. Fluorescence-activated cell sorter analysis demonstrated that fluorescence staining of L1210/GZL cells by 11C1 can be completely inhibited with preabsorption on Ab2 hybridoma cells. Mice immunized with 2F10 and 3A4 coupled to keyhole limpet hemocyanin (KLH) contained antibodies binding to MMTV. But only in mice immunized with 2F10-KLH was significant inhibition of L1210/GZL tumor growth observed. Collectively, these results indicate that certain anti-idiotypic antibodies can mimic the MMTV gp52 antigen, as well as the gp52-like epitope expressed on the L1210/GZL tumor cells. These properties of anti-idiotypic antibodies mimicking TAA could be exploited for making idiotype vaccines against tumors.
Animals↗
Clonal variation in tumorigenicity of L1210 lymphoma cells: nontumorigenic variants with an enhanced expression of tumor-associated antigen and Ia antigens.
Clonal variations in the tumorigenicity and in the expressions of tumor-associated antigens (TAA) as well as normal cell surface antigens were studied using clones of a highly tumorigenic DBA/2 lymphoma, L1210, which were isolated by limiting dilution in vitro. The majority of the clones were highly tumorigenic (tum+) in normal syngeneic mice, as was the parent L1210. The rest were nontumorigenic (tum-) in such mice; these clones, however, were tumorigenic in host mice that had been immunosuppressed by irradiation with 450 rads. Moreover, these tum- variants were shown to have an ability to elicit, in syngeneic mice, strong host resistance specifically directed against challenge with the parent L1210 and tum+ cloned cells and an ability to generate an in vitro primary syngeneic cytotoxic T-cell response against L1210 clones, indicating an enhanced immunogenicity in tum- variants. The expression of TAA by tumor clones was defined by determining the reactivity of monoclonal antibody, raised in syngeneic mice against an immunogenic L1210 subline, L1210/GZL. Marked clonal variation in the expression of monoclonal antibody-defined TAA was demonstrated, while no significant variation was seen in the H-2Dd expression. There was an inverse relationship between the TAA expression and the tumorigenicity. Furthermore, the enhanced expression of the TAA and the increased immunogenicity was associated with the I-Ad expression on the tum- variants. The unique characteristics of the tumor variants were very stable and heritable although occasional revertant phenotypes were detected on some clones. The results suggest that the tumor variants bearing distinct immunological properties exist in the parent L1210 line and carry a potential to modulate host immune responses directed against tumor cells.
Animals↗
Three kinds of foamy cells in the spleen: comparative histochemical and ultrastructural studies.
By light and electron microscopy, we observed foamy cells in the spleens from a patient with hemolytic anemia due to red cell adenosine deaminase (ADA) overproduction, a patient with rheumatoid arthritis (RA) treated with gold, and patients with idiopathic thrombocytopenic purpura (ITP). The foamy cells associated with red cell ADA overproduction were essentially similar to Gaucher-like cells described in patients with thalassemia, and it was suggested that the accelerated destruction of red cells was one of the factors responsible for the development of foamy cells. Foamy cells in ITP and RA were closely associated with an increased destruction of platelets in the spleen. Morphologic transitions between phagocytosed platelets and myelin-like materials were traced in these disorders. In RA, however, foamy cells were heterogeneous from an ultrastructural standpoint, with different cytoplasmic inclusions. In addition to myelin-like materials, dense bodies, vacuoles with flocculent materials, and gold were noted in most of foamy cells. As gold compounds are known to inhibit lysosomal enzymes, we surmise that an acquired disturbance in lysosomal digestion is partially responsible for the accumulation of intermediate metabolites. In the pathogenesis of foamy cells associated with blood cell dyscrasia, the accelerated destruction of blood cells and/or acquired disorders in catabolic pathways within the macrophages are suggested to be the underlying mechanism of an intralysosomal accumulation of incompletely degraded cellular debris.
Adenosine Deaminase↗
Immunomodulation of host resistance by tumor variants.
Immunomodulation of host resistance by tumor cell variants has been investigated in the context of immunological effects of tumor cell heterogeneity using a murine tumor model. Clonal variation in the susceptibility to specific T cell-mediated cytotoxicity (TC), which is inversely related to tumorigenicity in syngeneic animals, was demonstrated among clones derived from a cultured line of DBA/2 lymphoma L1210 by limiting dilution. Thus, although a majority of such clones were TC-resistant and highly tumorigenic, some clones were TC-susceptible and non-tumorigenic. Moreover, an inoculation of the variant clones bearing the latter phenotype was shown to elicit protective immunity in host mice against a challenge with the parent L1210, whereas an inoculation of spleen cells (or extracts) from hosts bearing tumorigenic clones would abrogate the priming effects of the non-tumorigenic variants, presumably through splenic suppressor cells. These results suggest that heterogeneity among variant clones may influence the regulation of host resistance against tumors.
Animals↗
Ricin A-chain conjugated with monoclonal anti-L1210 antibody. In vitro and in vivo antitumor activity.
In studies of antitumor antibody-cytotoxic agent conjugates as potential antitumor agents with improved tumor specificity, the toxic subunit A-chain of ricin was conjugated with a monoclonal antibody to a tumor-associated antigen expressed weakly on murine leukemia L1210 cells and strongly on L1210/GZL cells, a guanazole-resistant subline of L1210, employing N-succinimidyl 3-(2-pyridyldithio)propionate as cross-linking agent. The conjugate (anti-L1210 conjugate) exhibited a potent concentration-dependent cytotoxicity against cultured L1210/GZL cells, and inhibited cell growth at concentrations over 0.8 micrograms/ml. The conjugate killed all L1210/GZL cells at a concentration of 100 micrograms/ml. Neither nonimmune conjugate similarly prepared from mouse nonimmune IgG nor unconjugated anti-L1210 IgG alone showed cytotoxicity against L1210/GZL cells. When (BALB/c X DBA/2)F1 mice inoculated with 1 X 10(5) L1210/GZL cells were treated with IP injections of 27 micrograms anti-L1210 conjugate 1 h and 5 days after tumor cell inoculation, a life-prolonging effect was observed. [Lifespan in treated animals as percentage of that in controls (T/C) = 146%]. However, when the dose per injection was increased to 50 micrograms per mouse, survival was the same as in the control group. Postmortem examination of mice that had been treated with 50 micrograms anti-L1210 conjugate revealed lesions with necrosis and hemorrhage in the liver parenchyma and the intestinal epithelium, respectively. A similar toxic effect on the host mice was also observed with nonimmune conjugate.
Animals↗
Differential tumor immunogenicity of DBA/2 mouse lymphoma L1210 and its sublines. III. Control of host resistance to drug-resistant L1210 sublines by H-2-linked and non-H-2-linked genes.
The effects of the host's genetic composition on the host's resistance to the DBA/2 L1210 lymphoma and three drug-resistant L1210 sublines (which show an increased expression of tumor-associated antigens) were investigated. Histocompatible F1 mice between DBA/2 and other mouse strains were given injections ip of graded numbers of these tumor cells, and a marked difference in the resistance of the host to tumor growth was demonstrated. The resistant hybrid mice showed markedly higher resistance to the L1210 sublines than to the L1210 parent lymphoma cells. Experiments with F1 mice between DBA/2 (H-2d) and certain congeneic intra-H-2 recombinant strains showed that the H-2b/d heterozygosity at the H-2K+l-A regions and additional non-H-2 genetic factor(s) confer the resistance to the F1 mice. The resistance was abolished by treating host animals with injections of silica, an antimacrophage agent, or rabbit anti-mouse thymocyte serum. These results suggest that the resistance is immunologic and that the genetically controlled host resistance may be directed to surface changes related to the increased expression of tumor-associated antigens.
Animals↗