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Biomedical subjects

I Nakashima

Publications and source records attributed to I Nakashima.

At least 91 records · Page 5Linked to original sources
PubMed1998

[A case of primary Sjögren's syndrome with CNS disease mimicking chronic progressive multiple sclerosis].

We report a 40-year-old woman with primary Sjögren's syndrome (SjS) with slowly progressive CNS disease. At age 38, she noticed spasticity and very gradual onset of monoparesis in the left leg. She hardly walked by herself at age 40. On admission, neurological examination revealed mild slurred speech, vertical nystagmus, spasticity in the four extremities, spastic monoparesis of the left leg, exaggerated jaw jerk, hyperreflexia in all limbs except right biceps and brachioradialis reflex, and positive bilateral Hoffmann reflexes and Babinski signs. Laboratory examinations disclosed positive anti-nuclear antibody (speckled type) and anti-SS-A/Ro antibody (64x). CSF examination revealed cell count 8/mm3, protein 42 mg/dl, 4 bands of oligoclonal band and the elevation of IgG index. MR-imaging presented multiple plaque-like lesions in white matter of cerebrum and brainstem, which did not show gadolinium enhancement. Additionally she complained of dry eyes. Lacrimal and salivary secretion tests showed hyposecretion of tears and hyposialosis. The biopsied specimen of labial minor salivary gland revealed the destruction of the ducts and periductal lymphocytic infiltrations. The diagnosis of primary SjS was confirmed. We herein report a rare case of primary SjS with CNS disease mimicking chronic progressive multiple sclerosis (MS), and discuss a difficulty in differentiating CNS disease of SjS from MS.

Adult↗
PubMed1997

Protein kinase C alpha-mediated chronic signal transduction for immunosenescence.

In CD2/protein kinase C alpha (PKC alpha)-overexpressing human CD2/rabbit PKC alpha transgenic mice, an aging-dependent increase in PKC alpha expression and a decrease in proliferative responsiveness of splenic T cells were promoted. We found that an aging-associated accumulation of CD44(high) CD45RB(low) memory CD4+ T cells in exchange for CD44(low) CD45RB(high) naive CD4+ T cells was promoted in transgenic mice. A disequilibrium between Ag-dependent generation and subsequent elimination of memory T cells in these mice was shown to underlie this phenomenon. When stimulated with Ag, the PKC alpha transgenic mice responded poorly regarding Ab production and produced cytokines biased for high IFN-gamma/IL-12 and low IL-4/IL-10 levels. These results prove, for the first time, a causal role for chronic signal transduction through PKC alpha in aging-associated immunodysfunction and provide the first animal model for genetically promoted immunosenescence.

Aging↗
PubMed1997

In vitro and in vivo expression of inducible nitric oxide synthase during experimental endotoxemia: involvement of other cytokines.

In this study, we investigated the expression of genes for inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6) of Kupffer cells in the presence of lipopolysaccharide (LPS), and the tissue expression of iNOS in a rat liver after LPS injection at various time intervals. The effects of L-NG-nitroarginine-methyl-esther HCI (L-NAME), a NO inhibitor, also were examined. The mRNA transcripts of TNF-alpha, IL-1 beta, and IL-6 were rapidly detected no more than at 1 h after LPS stimulation, whereas the iNOS transcript was detectable from 3 h after LPS stimulation and maximally increased at 12 h. This fact suggested that these early induced cytokines were related to expression of iNOS. Using an anti-iNOS antiserum raised against recombinant iNOS protein, immunohistochemical analysis was made to reveal kinetics of NO producing cells. The cells immunoreactive for iNOS appeared at 6 h post-LPS injection in the sinusoids of the liver. By structural and immunohistochemical studies, almost all iNOS positive cells were identified as Kupffer cells and endothelial cells. The number of cells immunoreactive for iNOS increased until 12 h post-LPS injection. At 24 h after LPS injection, iNOS positive cells were restricted to the foci of spotty necrosis. Hepatic injury measured by released enzymes was increased by pretreatment of L-NAME before LPS injection.

Animals↗
PubMed1997

Magnitude of protein tyrosine phosphorylation-linked signals determines growth versus death of thymic T lymphocytes.

Using concanavalin A (Con A) as a multireceptor-reactive agonist, we studied the relationship between the growth or death of thymic T lymphocytes and the agonist concentration-dependent magnitude of the intracellularly delivered signal. Both immature and mature thymic T lymphocytes were subjected to a high concentration of Con A-mediated signal for apoptotic cell death. In this model, a number of cellular proteins including mitogen activated protein kinases were phosphorylated at tyrosine depending on the concentration of Con A. This effect was followed by corresponding increase in serine 73 phosphorylation of c-jun and transcription of c-fos. DNA fragmentation and cell membrane disruption developed concomitantly after stimulation with high concentrations of Con A. The addition of inhibitors of protein kinases which completely inhibited the growth of cells stimulated with low concentrations of Con A only partially prevented death, and even promoted DNA fragmentation of cells stimulated with high concentrations of Con A. The dissociated sensitivities of Con A-mediated cell growth and cell death to the inhibitors were, however, shown to be due to the different efficiency of inhibition of high and low levels of intracellularly delivered signals. The results indicate that the magnitude of signaling could be the principal element that determines the growth versus death of thymic T lymphocytes.

Animals↗
PubMed1997

The immunosuppressive effect of fresh allogeneic bone graft in mice.

We investigated the immunosuppressive effect of fresh bone allografts after donor specific spleen cell transfusion in mice. Allografts from major histocompatibility complex incompatible mice were performed one week after the transfusion. Cellular and humoral immune responses were recorded by measuring alloreactive cytotoxic T-lymphocyte activity and antibody activity. Survival in days of a second set skin graft was measured for determining clinical immunity. Alloreactive cytotoxic T-lymphocyte activity was stimulated at 17 days (10 days after bone grafting) and then suppressed at 31 days (24 days after bone grafting). The survival of the second set skin graft was not diminished at this time. This outcome indicates that the spleen cell stimulated cellular immune response was suppressed after fresh bone allografts, suggesting that these allografts have an immunosuppressive effect and induce immunosuppressive actions.

Animals↗
PubMed1997

Differential sensitivities to hyperbaric oxygen of lymphocyte subpopulations of normal and autoimmune mice.

We studied the effect of exposure to hyperbaric oxygen (HBO): 2.8 atm absolute 100% oxygen for 4 h daily over 3-7 days, on the immune system of normal (BALB/c and MRL- +/+) and autoimmune MRL-lpr/lpr) mice. In HBO exposed BALB/c mice, we observed a remarkable decrease in the cell population of the spleen and thymus. We found that the sensitivity to HBO varied among subpopulations of lymphocytes. For example, CD4+ CD8+ double positive cells in the thymus and B220+ B cells in the spleen were more sensitive than CD4+ or CD8+ single positive T cells in the thymus, and Thy-1+ T cells in the spleen, respectively. Accordingly, despite the decrease in total cell number in the spleen, the proliferative response of T cells from the spleen to Con A was not impaired in the HBO exposed mice. Exposure of MRL-lpr/lpr mice to HBO caused a marked reduction of weight and cell population of the otherwise enlarged spleen and lymph nodes, and amongst others of percentages of B220+Thy-1+ double positive abnormal cells. These results suggest the HBO therapy may be applicable for the treatment of some autoimmune diseases.

Animals↗
PubMed1997

A nitric oxide-releasing reagent, S-nitroso-N-acetylpenicillamine, enhances the expression of superoxide dismutases mRNA in the murine macrophage cell line RAW264-7.

Murine interferon-gamma (IFN-gamma) stimulates the murine macrophage tumour cell line RAW264-7 to produce nitric oxide (NO). IFN-gamma induces expression of inducible NO synthase (iNOS), manganese superoxide dismutase (Mn-SOD) and copper zinc SOD (CuZn-SOD) in these cells. To investigate the mechanism of induction of SOD expression, we added S-nitroso-N-acetyl penicillamine (SNAP) to RAW264-7 cells. SNAP enhanced the expression of Mn-SOD and CuZn-SOD. These results suggest that when producing NO, RAW264-7 cells express SOD that might protect them from NO toxicity.

Animals↗
PubMed1997

Differential display analysis of murine collagen-induced arthritis: cloning of the cDNA-encoding murine ATPase inhibitor.

We used the differential display technique in order to detect a new gene involved in murine type II collagen-induced arthritis (CIA). In this study, we have identified a novel gene, IF1, whose expression level is increased during the natural course of CIA. Northern blot analyses suggest that IF1 is involved in the natural course of CIA but is not involved as a trigger of CIA. IF1 is considered to be the murine ATPase inhibitor gene for several reasons. First, IF1 shows an extremely high homology to the rat ATPase inhibitor; the highly conserved region between rat and bovine amino acid residues 22-45, which is the minimum sequence showing ATPase inhibitory activities, is also highly conserved in IF1. Second, IF1 possesses a histidine-rich region in the same area, which is thought to be important for regulation of mammalian inhibitors. Third, the tissue distribution of IF1 is very suggestive. The expression of IF1 was very strong in energetic organs such as the heart, brain and kidney, and the development of arthritis requires great amounts of ATP. As arthritis develops rapidly, the cellular ATP pool may be decreased. Before the ATP pool is exhausted, the ATPase inhibitor may serve as a brake for ATP hydrolysis. If the supply of free energy can be reduced, the inflammation of arthritis may in turn be restored. Our hypothesis is that the ATPase inhibitor is involved in regulating the inflammatory responses.

Amino Acid Sequence↗
PubMed1997

Normal thymic selection, superantigen-induced deletion and Fas-mediated apoptosis of T cells in IL-2 receptor beta chain-deficient mice.

Mice lacking the IL-2 receptor beta chain (IL-2R beta) exhibit an autoimmune reaction characterized by generalized T cell activation, production of autoantibodies, myeloproliferation and severe anemia. T cells of IL-2R beta-/- mice were examined to elucidate the mechanism responsible for their abnormal activation and to determine how such abnormal activation might affect other cell lineages. Elevated levels of IgG, IgE and autoantibodies in IL-2R beta-/- mice were found to be associated with activated CD4+ T cells which secreted elevated levels of IL-4. Thymocytes in IL-2R beta-/- mice showed normal negative and positive selection patterns when analyzed in transgenic mice bearing a TCR specific for HY antigen, suggesting that neither IL-2 nor IL-15 is essential for thymic selection. Peripheral T cells in IL-2R beta-deficient mice underwent normal programmed cell death in response to staphylococcal enterotoxin B superantigen, in contrast to cells from mice deficient for either IL-2 or IL-2R alpha. Activated T cells in IL-2R beta-deficient mice expressed normal levels of Fas antigen and underwent normal apoptosis in response to induction with anti-Fas mAb. Thus, the accumulation of activated T cells in IL-2R beta-/- mice does not appear to be derived from abnormalities in either thymic selection or Fas-mediated apoptosis.

Animals↗
PubMed1997

Mechanism of nitric oxide-dependent killing of Mycobacterium bovis BCG in human alveolar macrophages.

We demonstrated that products of the L-arginine-dependent pathway of human alveolar macrophages (AM) effectively kill the Mycobacterium bovis bacillus Calmette-Guérin (BCG) in vitro. The formation of products was triggered by inoculation with BCG itself. Many reports have shown that activated rodent AM could produce an amount of nitric oxide (NO) sufficient to suppress the growth of mycobacteria. However, there have been no definitive results as to whether human AM might have the NO-dependent mechanism for the killing of mycobacteria. Therefore, we have undertaken some experiments to answer this question. Immunofluorescence assays showed an increased production of inducible nitric oxide synthase (iNOS) and peroxynitrite in BCG-inoculated AM from patients with pulmonary fibrosis. Reverse transcriptase-PCR also revealed the higher expression of iNOS-coding mRNA. Colony assays demonstrated that these human AM effectively killed BCG in their cytoplasm. However, treatment of AM with N(G)-monomethyl-L-arginine monoacetate resulted in markedly reduced killing activity. These results clearly show that BCG-induced NO and its reactive product with the oxygen radical peroxynitrite could play an important role in the killing of BCG in human AM.

Bronchoalveolar Lavage↗
PubMed1997

Nitric oxide as an inflammatory mediator of radiation pneumonitis in rats.

Radiation pneumonitis is a major complication of radiation therapy. To elucidate the mechanisms of radiation-induced pneumonitis, we studied nitric oxide (NO) produced from lung tissues using a model of unilaterally irradiated rats. Our results demonstrated that alveolar macrophages (AM) produced NO after irradiation, and the expression of inducible NO synthase (NOS) in both AM and alveolar epithelial cells was increased. Furthermore, the progression of radiation pneumonitis was reduced with the in vivo treatment of the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). The effect of L-NAME was further confirmed by the inhibition of mRNA expression for procollagen-alpha1 type III of the lung. With these results, NO produced from AM and alveolar epithelial cells after irradiation may be an important mediator in the progression of radiation pneumonitis.

Animals↗
PubMed1997

[A juvenile case of Lambert-Eaton myasthenic syndrome with severe emaciation].

Most of the patients with Lambert-Eaton myasthenic syndrome (LEMS) are over 40 years of age at onset and have a malignant neoplasm, especially pulmonary small cell carcinoma. Juvenile cases of LEMS are rare and have not been reported in Japan. We report a 21-year-old women whose onset of LEMS was at 17 years of age. In the early stage of the disease, she had limb muscle weakness and was diagnosed has having seronegative myasthenia gravis (MG) based on decrementing response in low frequency repetitive nerve stimulation, positive edrophonium test, and negative serum anti-acetylcholin receptor antibodies. Serum anti-voltage-dependent-calcium-channel (VGCC) antibody was negative with an available assay system. She was thymectomized and received anti-cholinesterases, corticosteroids, and cyclophosphamide, but their therapeutic effects were not evident. Two years later, she was confined to bed due to sever emaciation (Her body weight reduced from 47 Kg to 27 Kg.), bulbar palsy, and limb muscle weakness. She needed respiratory support and tube feeding. Type II fiber atrophy, which is non-specific, but is a common finding in LEMS, was seen in the biopsied muscle of the patient. On the other hand, postsynaptic folds and clefts of all seven motor end-plates in the specimen were normal, which is against the diagnosis of MG. Recently, she was found to have anti-VGCC antibody with an improved assay system. Despite vigorous examination, no malignancy or other autoimmune disorders have been found. 3,4-Diaminopyridine was effective to improve limb muscle powers, but she is still bedridden.

Adult↗
PubMed1996

Evidence of a novel redox-linked activation mechanism for the Src kinase which is independent of tyrosine 527-mediated regulation.

The kinase activity of p60c-src has been shown to be basically regulated through phosphorylation and dephosphorylation of Y527. We found that catalytic activity of the immunoprecipitated c-Src kinase from NIH3T3 cells was elevated several folds by exposure to 0.5-50 microM of sulfhydryl-reactive Hg2+. Vmax of the kinase was increased whereas Km was decreased. N-acetylcysteine neutralized this Hg2+ effect, suggesting a critical role of the Hg2+-mediated sulfhydryl modification of the kinase in the mechanism. Addition of protein tyrosine phosphatase inhibitor Na3VO4 into the reaction mixture did not inhibit the Hg2+-mediated activation. Further study revealed that Hg2+ was capable of activating the v-Src kinase lacking Y527 and the c-Src kinase from mutant cells defective of the Y527-phosphorylating Csk kinase. Cyanogen bromide cleavage maps of radiolabeled Src proteins showed that Hg2+ selectively promoted the autophosphorylation at Y416 and that the previously in vivo radiolabeled phosphorous on Y527 was not deleted during the promotion of Y416 autophosphorylation by Hg2+. Phosphoamino acid analysis demonstrated selective promotion of phosphorylation at tyrosine but not at serine/threonine. Not like bivalent Hg2+, monovalent p-chloromercuribenzenesulfonic acid was incapable of activating c-Src kinase. These results suggest a novel Y416 phosphorylation-linked activation pathway for Src kinases which is initially triggered independent of Y527-mediated or serine/threonine phosphorylation-linked regulation, possibly through sulfhydryl-based protein structural modification for functional alteration.

3T3 Cells↗
PubMed1996

Modulation of endotoxin-induced histamine synthesis by cytokines in mouse bone marrow-derived macrophages.

The aim of this study was to examine the roles of various cytokines in histamine synthesis by macrophages in bone marrow. Pure (> 99% nonspecific esterase-, CD14-, and Mac-1-positive) macrophage populations were obtained after long term culture of bone marrow cells (bone marrow-derived macrophages). Culture of the cells in the presence of Escherichia coli LPS caused a slight, but dose-dependent, increase in histidine decarboxylase-associated histamine synthesis with a concomitant increase in the expression of CD14, a LPS receptor, as well as the Mac-1 Ag on their surface. Granulocyte/macrophage CSF (GM-CSF) or IL-3 strongly enhanced LPS-induced histamine formation and expression of CD14 on bone marrow-derived macrophages, without affecting the expression of Mac-1 Ag. GM-CSF and IL-3 also caused a marked accumulation of both histidine decarboxylase and IL-6 mRNAs in the cells. Macrophage CSF and IL-1-alpha also potentiated LPS-dependent histamine formation when it was stimulated with GM-CSF or IL-3. In contrast to these cytokines, IFN-gamma suppressed LPS-induced histamine production regardless of whether it was stimulated by GM-CSF or IL-3, and inhibited CD14 expression. Neither IL-6 nor granulocyte CSF had any appreciable effect on LPS-induced histamine production even in combination with GM-CSF or IL-3. These results suggest that GM-CSF and IL-3 enhance LPS-induced histamine production in bone marrow-derived macrophages and that macrophage CSF and IL-1 alpha augment the actions of GM-CSF and IL-3. Possible implication of CD14 molecule in the reactions is discussed.

Animals↗
PubMed1996

Dynamics of soluble adhesion molecule levels in patients with pollinosis.

OBJECTIVES: To define the dynamics of systemic and local soluble adhesion molecule levels and to discuss the role of these molecules in the pathogenesis of allergic rhinitis. DESIGN: Randomized control trial. SUBJECTS: Twelve volunteers with Japanese cedar pollinosis and 7 healthy volunteers. INTERVENTIONS: The levels of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble E-selectin, and soluble L-selectin in serum samples and nasal epithelial lining fluids (ELF) from 12 patients with pollinosis were measured 5 times throughout the allergy preseason to postseason, and the results were compared with those from 7 healthy subjects. RESULTS: The levels of sICAM-1 (P < .05) and sVCAM-1 (P < .05) in sera were up-regulated, and the levels of soluble L-selectin (P < .01) in sera were down-regulated during the early stage of the season in the allergic subjects. The difference between the levels of sICAM-1 and sVCAM-1 in sera in the early and mid-season was statistically significant in the allergic subjects (P < .05). The levels of sICAM-1 in ELF were up-regulated during the early and mid-season. The levels of sVCAM-1, soluble E-selectin, and soluble L-selectin in ELF were undetectably low throughout the preseason to postseason. CONCLUSION: There is evidence of the unique stage-dependent differential contributions of various soluble adhesion molecules in the pathogenesis of seasonal allergic rhinitis with a small amount of natural allergen provocation.

Adult↗
PubMed1996

Nitric oxide releasing reagent, S-nitroso-N-acetylpenicillamine, enhances the expression of manganese superoxide dismutase mRNA in rat vascular smooth muscle cells.

Cultured rat vascular smooth muscle cells (VSMCs) produce nitric oxide (NO) under stimulation by lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). NO synthase (NOS) and manganese superoxide dismutase (Mn-SOD) mRNA expressions are simultaneously induced by these stimulants in rat VSMCs. In VSMCs, S-nitroso-N-acetyl penicillamine (SNAP), one of the NO releasing reagents, induces Mn-SOD mRNA which may protect the VSMCs themselves. This suggests that NO itself may enhance the expression of Mn-SOD to protect the VSMC themselves against NO radicals in cultured rat VSMCs.

Animals↗