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Biomedical subjects

M Hibi

Publications and source records attributed to M Hibi.

At least 109 records · Page 6Linked to original sources
PubMed1992

Inhibitory effect of NZ-107 on anaphylactic bronchoconstriction in guinea pigs and rats.

We studied the effect of NZ-107 in a number of animal models of anaphylactic bronchoconstriction. In conscious guinea pigs, pretreated with indomethacin, pyrilamine and propranolol, passively sensitized with heterologous anti serum, NZ-107 in doses of 10-30 mg/kg per os inhibited the aerosolized antigen-induced cough and collapse. NZ-107 in a high dose of 100 mg/kg per os significantly prevented aerosolized antigen-induced anaphylactic collapse, but not cough in actively or passively sensitized conscious guinea pigs and also significantly protected aerosolized histamine-induced collapse, but not cough in conscious guinea pigs. This compound had little inhibitory effect on aerosolized acetylcholine-induced cough and collapse. In anesthetized animals, the effect of NZ-107 on bronchoconstriction induced by intravenous administration of antigen and various agonists was examined by the method of Konzett and Rössler. In doses of 10-50 mg/kg per os, NZ-107 inhibited antigen-induced bronchoconstriction in anesthetized guinea pigs. NZ-107 when intravenously administered to the anesthetized guinea pigs inhibited not only leukotriene D4-induced bronchoconstriction, but also thromboxane A2 mimetic U-46619-, platelet-activating factor- and histamine-induced bronchoconstriction. In anesthetized rats, NZ-107 in a dose of 300 mg/kg per os tended to inhibit the antigen-induced bronchoconstriction, but this effect was not significant. These results indicate that NZ-107 acts as a spasmolytic agent which inhibits bronchial responses to antigens or various other bronchoconstrictors in animal models, suggesting that NZ-107 may be potentially beneficial in the treatment of bronchial asthma.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family.

Interleukin 6 (IL-6) signal is transduced through gp130 that associates with a complex of IL-6 and IL-6 receptor. Truncations or amino acid substitutions offe introduced in the cytoplasmic region of human gp130, and the mutant cDNAs were transfected into murine interleukin 3-dependent cells to determine amino acid residues critical for generating the IL-6-mediated growth signal. In the 277-amino acid cytoplasmic region of gp130, a 61-amino acid region proximal to the transmembrane domain was sufficient for generating the growth signal. In this region, two short segments were significantly homologous with other cytokine-receptor family members. One segment is conserved in almost all members of the family, and the other is found especially in granulocyte colony-stimulating factor receptor, interleukin 2 receptor beta chain, erythropoietin receptor, KH97 (a granulocyte/macrophage colony-stimulating factor receptor-associated molecule), and interleukin 3 receptor. gp130 molecules with mutations in either of these two segments could not transduce growth signal. Loss of signal-transducing ability of gp130 with such a mutation coincided with disappearance of IL-6-induced tyrosine phosphorylation of gp130.

Amino Acid Sequence↗
PubMed1991

Effect of NZ-107 on late-phase airway responses and airway hyperreactivity in guinea pigs.

The effect of NZ-107 (4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone) on late-phase airway responses and airway hyperreactivity was investigated in the guinea pig. Challenge with inhaled ovalbumin in conscious guinea pigs actively sensitized with inhaled ovalbumin caused triphasic bronchial obstruction, which peaked at 5-30 min, 6-8 h and 24 h. In this model, airway hyperreactivity to acetylcholine was observed 48 h after antigen challenge. Orally administered NZ-107, given 2 h before ovalbumin challenge significantly inhibited airway responses at 5-30 min (10 mg/kg), 6-8 h (30 mg/kg), 24 h (10 mg/kg) and airway hyperreactivity (30 mg/kg). When NZ-107 (10 mg/kg) was orally administered to the guinea pigs 3 h after ovalbumin challenge, it also inhibited airway responses at 6-8 h and 24 h and airway hyperreactivity. In anaesthetized guinea pigs, intravenous administration of NZ-107 (0.03-1.0 mg/kg) inhibited platelet-activating factor (PAF)- and propranolol-induced airway hyperreactivity to histamine. These results suggest that NZ-107 may be a useful drug for the treatment of bronchial asthma by reducing late-phase airway responses and airway hyperreactivity.

Aerosols↗
PubMed1991

Effect of an anti-SRS-A agent, NZ-107, on airway responses induced by ovalbumin and A23187 in the guinea-pig.

The effects of the anti-SRS-A agent NZ-107 on antigen-(ovalbumin) and calcium ionophore A23187-induced airway responses in the guinea-pig have been investigated. In the presence of 5 microM indomethacin, NZ-107 (3 microM) did not affect the peak response in ovalbumin-induced contraction but did inhibit the prolonged response following the peak response in the tracheal strip. A higher concentration of NZ-107 (10 microM) completely blocked both peak and prolonged responses. Inhibitory effects of NZ-107 on ovalbumin responses were less in the lung parenchymal strip. The potency of NZ-107 in inhibiting ovalbumin-induced tracheal contraction was not changed in the absence of indomethacin but was reduced in the presence of 45 mM serine-borate, an inhibitor of the conversion of LTC4 to LTD4. NZ-107 inhibited A23187-induced contractions in both tracheal and parenchymal strips but in both cases the inhibitory potency was less than that on ovalbumin response. NZ-107 was a more potent inhibitor of ovalbumin-induced SRS-A release than histamine release in lung fragments but was ineffective in inhibiting A23187-induced SRS-A and histamine release. NZ-107 at a concentration of 10 microM more effectively inhibited LTC4- and histamine-induced tracheal contractions than it did LTC4 in the presence of 45 mM serine-borate. These results suggest that NZ-107 selectively inhibits antigen-induced SRS-A responses in airway tissues of the guinea-pig.

Animals↗
PubMed1991

Effects of NZ-107 on tracheal responses to adenosine in the guinea pig.

We have investigated the effect of NZ-107, an inhibitor of bronchoconstriction induced by slow reacting substance of anaphylaxis (SRS-A), on tracheal responses to adenosine in the guinea pig. In the presence of an adenosine uptake inhibitor, dipyridamole (1 microM), NZ-107 (0.3-1 microM) enhanced adenosine-induced relaxation in 30 nM leukotriene D4 (LTD4)-precontracted trachea, whereas aminophylline (AP, 10-30 microM), an adenosine receptor antagonist, markedly inhibited it. NZ-107 (1 microM) also enhanced the relaxation induced by forskolin, an adenylate cyclase activator, but not that by nitroprusside (NP), a guanylate cyclase activator. AP (30 microM) affected neither forskolin- nor NP-induced relaxation. NZ-107 (1 microM) and AP (30 microM) inhibited to about the same extent the contractile response to an adenosine A1 receptor agonist, the R(-)-enantiomer of N6-(2-phenylisopropyl)-adenosine (R-PIA). The R-PIA-induced contraction was completely blocked by 5 microM indomethacin. NZ-107 (1 microM) did not affect the contraction induced by PGD2, but significantly reduced that of PGF2 alpha. AP (30 microM) had no effect on PGF2 alpha- and PGD2-induced contractions. These results suggest that NZ-107 may have a unique profile for adenosine responses in bronchial asthma.

Adenosine↗
PubMed1991

[An operative case of vascular ring (Edwards III B type)].

A 28-year-old female with dysphagia due to the vascular ring (Edwards III B type) was operated successfully. Preoperative chest x-ray film showed a defect of the left first arch and deviation of the lower trachea to the left side. Esophagogram disclosed the upper thoracic esophagus stenotic and deviated left anteriorly. Arch aortogram showed the right aortic arch and aberrant left subclavian artery with the aortic diverticulum. Operation was performed through a left thoracotomy. Esophagus was squeezed by the aortic arch, aortic diverticulum and left ligamentum arteriosum. The left ligamentum arteriosum was divided. Its stump of aortic side was sutured and fixed with paravertebral pleura so that the squeeze by the diverticulum was released. The stenotic esophagus was dissected from surrounding tissue and its satisfactory distensibility was confirmed. Dysphagia disappeared after operation and postoperative esophagogram showed marked improvement of the stenosis. Eleven operated cases of this type of vascular ring in adult have been reported in Japan. Remarkable improvement of dysphagia was observed in all cases. Thus surgical treatment is recommended for cases suffering from severe dysphagia.

Adult↗
PubMed1990

Molecular cloning and expression of an IL-6 signal transducer, gp130.

Interleukin-6 (IL-6) signal is transduced through a membrane glycoprotein, gp130, which associates with IL-6 receptor (IL-6-R). A cDNA encoding human gp130 has been cloned, revealing that it consists of 918 amino acids with a single transmembrane domain. The extracellular region comprises six units of a fibronectin type III module, and part of this region of approximately 200 amino acids has features typical of a cytokine receptor family. A cDNA-expressed gp130 showed no binding property to IL-6 or several other cytokines. Although a transfectant with an IL-6-R cDNA expressed mainly low affinity IL-6 binding sites, an increase in high affinity binding sites was observed after cotransfection with a gp130 cDNA. This confirmed that a gp130 is involved in the formation of high affinity IL-6 binding sites. A cloned gp130 could associate with a complex of IL-6 and soluble IL-6-R and transduce the growth signal when expressed in a murine IL-3-dependent cell line.

Amino Acid Sequence↗
PubMed1990

Interleukin 6 and its receptor in the immune response and hematopoiesis.

Interleukin 6 (IL-6) plays critical roles in the immune response and hematopoiesis. It is a potent B cell differentiation factor inducing antibody-forming plasma cells. It enhances interleukin 3-induced proliferation of hematopoietic stem cells. Furthermore, IL-6 induces maturation of megakaryocytes. In IL-6 transgenic mice, a massive polyclonal plasmacytosis and an increase in the number of mature megakaryocytes in the bone marrow were observed. The data indicated that deregulated expression of the IL-6 gene induced a polyclonal plasmacytosis and could be involved in the oncogenesis of plasma cell neoplasias. IL-6 receptor (IL-6R) was molecularly cloned and found to be an immunoglobulin superfamily having an MW of 80 kDa. Upon the binding of IL-6 to its 80 kDa IL-6R, a second non-binding molecule, gp130 was shown to associate with IL-6R. The complex of IL-6 and soluble IL-6R lacking both transmembrane and cytoplasmic domains could bind gp130 and transduce the signal. The results indicate that the IL-6R system consists of two polypeptide chains: one is an 80 kDa ligand-binding molecule and the other is a possible signal transducer, gp130.

Animals↗
PubMed1990

[T cell blastogenesis in stored blood can induce GVHD in open heart surgery].

We studied T cell blastogenesis in stored blood during the preservation time within 7 days. Blood samples were obtained from 8 adults and stored at 4 degrees C immediately after donation with CPD (citrate-phosphate-dextrose) for 3,5 and 7 days. After each intervals, mitogenic responses of T cells from the samples in the presence of an optimal dose of PHA as a mitogen and MLR (mixed lymphocyte reaction) with lymphocytes prepared by 2000 rad radiation from other 10 donors as stimulating cells were investigated. The stimulation index (S.I.) of PHA as a responsibility of the stored blood was decreasing to 86.7 +/- 24.8%, 44.2 +/- 12.5% and 31.2 +/- 11.1% in proportion of that of fresh blood after 3, 5 and 7 days preservation. The S.I. of MLR were in the same way decreasing to 92.5 +/- 21.8%, 45.9 +/- 9.8% and 33.3 +/- 10.1% after that. These observations suggest that lymphocytes in stored blood within 7 days are able to induce GVHD (graft-versus-host disease) in open heart surgery of which immunological activity is thought to be decreased by extra-corporeal circulation. We concluded that the stored blood within 7 days should be irradiated to 1500 rad or more in order to prevent GVHD.

Adult↗
PubMed1990

[Assessment of primary varicose veins with plethysmographic techniques].

Venous hemodynamics were evaluated by simultaneous strain gauge- and photo-plethysmographic techniques in 40 normal limbs (normal group), 74 limbs with primary varicose veins (varicosis group) and 28 limbs with postthrombotic syndrome (thrombosis group). Furthermore, the venous function of 52 limbs with primary varicose veins was assessed before and after surgical treatment of varicose veins. The mean 1/2-refilling time in varicosis and thrombosis group was significantly shorter than that in normal group. With application of tourniquets, limbs in varicosis group showed improvement in 1/2-refilling time. Varicosis group showed a significantly higher value in expelled volume during exercise than thrombosis group, and no significant difference compared with normal group. With tourniquets, the value in varicosis group was higher than that in normal group. From these results, the pathogenesis of primary varicose veins might be characterized as a high degree of venous congestion of the leg and valvular incompetence of the superficial vein system. Postoperative recording showed the improvement in venous function. However, in early stage after the operation, all parameters were lower than those in normal group. These values normalized 3 months after surgery.

Hemodynamics↗
PubMed1989

Characterization of IL-6 receptor expression by monoclonal and polyclonal antibodies.

mAb and polyclonal antibodies against human IL-6R were prepared by using a murine transfectant cell line expressing the human IL-6R and a synthetic oligopeptide made on the basis of the deduced amino acid sequence as immunogens. Immunoprecipitation of radiolabeled IL-6R with these antibodies showed that the Mr of a mature IL-6R was 80 kDa and its value was reduced to 50K after treatment with O- and N-glycanase and neuraminidase, indicating that IL-6R is a glycoprotein. Two mAb recognizing different epitopes were prepared. One, PM1 inhibited the binding of 125I-IL-6 to the receptor and blocked the IL-6-dependent growth of a T lymphoma line, KT3. PM1 could not bind to IL-6R when it was saturated with IL-6, indicating that this antibody recognizes the IL-6 binding or the adjacent site on IL-6R. The other, MT18 was not inhibited by IL-6 for its recognition of IL-6R, therefore, this could be used for cytofluorometric staining of normal cells. Nonstimulated B cells expressed undetectable amount of IL-6R regardless of the expression of surface IgD. However, after the stimulation with PWM, IL-6R was observed on IgD- B cells with a relatively large size, but subtly on IgD- small B cells and not on IgD+ B cells, fitting the function of IL-6 which acts on activated B cells to induce Ig production. In contrast, IL-6R was detected on non-stimulated CD4+/CD8- and CD4-/CD8+ T cells. The level of IL-6R on both T cell subpopulations was not significantly changed after stimulation with phytohemagglutinin.

Antibodies, Monoclonal↗
PubMed1989

Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130.

Interleukin-6 mediates pleiotropic functions in various types of cells through its specific receptor (IL-6-R), the cDNA of which has already been cloned. We report here that an 80 kd single polypeptide chain (IL-6-R) is involved in IL-6 binding and that IL-6 triggers the association of this receptor with a non-ligand-binding membrane glycoprotein, gp130. The association takes place at 37 degrees C within 5 min and is stable for at least 40 min in the presence of IL-6, but does not occur at 0 degree C. Human IL-6-R can associate with a murine gp130 homolog and is functional in murine cells. Mutant IL-6-R lacking the intracytoplasmic portion is functional, suggesting that the two polypeptide chains interact to involve their extracellular portion. In fact, a soluble IL-6-R lacking the transmembrane and intracytoplasmic domains can associate with gp130 in the presence of IL-6 and mediate its function. These findings indicate that the complex of IL-6 and IL-6-R can interact with a non-ligand-binding membrane glycoprotein, gp130, extracellularly and can provide the IL-6 signal.

Animals↗
PubMed1989

Inhibitory effect of the newly synthesized pyridazinone derivative NZ-107 on bronchoconstriction induced by slow reacting substance of anaphylaxis in the guinea pig.

We have investigated the effect of a newly synthesized compound NZ-107, 4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone, on bronchoconstriction induced by slow reacting substance of anaphylaxis (SRS-A) in the guinea pig. Orally administered NZ-107 (10 mg/kg, 2 hr) inhibited antigen-induced SRS-A-mediated bronchoconstriction in sensitized guinea pigs. NZ-107 (2 mg/kg, i.v., 1 min) prevented the antigen-induced response about as well as the SRS-A antagonist FPL-55712 and rapidly reversed it. This rapid reversal by NZ-107 but not FPL-55712 also appeared with the leukotriene (LT) D4-induced contraction of the isolated trachea. NZ-107 more selectively inhibited the LTD4 response than those of histamine, acetylcholine and KCl. Compared to FPL-55712, NZ-107 was one-fifteenth less potent in inhibiting the LTD4 response, but two-fold more potent in inhibiting the LTC4 response. NZ-107 inhibited the LTD4 response of the trachea 10-fold more potently than that of the ileum (-log IC50: trachea 5.61, ileum 4.56). The combination of NZ-107 (1 microM) with the beta-agonist isoproterenol had no synergistic effect on the LTD4 response, but those of theophylline and papaverine had large effects. From these results, NZ-107 is a selective inhibitor of the SRS-A response and may be useful in the therapy of bronchial asthma and other diseases in which the LTs are thought to be involved.

Animals↗