Vascular endothelial cells (ECs) have various functions such as the maintenance of vascular permeability, control of vascular tonus and resistance to thrombosis.
During inflammation, ECs also play a role in angiogenesis and transmigration of the leukocytes. EC injury induces inflammatory changes, vasculitis and so on. We examined the mechanism of vascular EC injury induced by the leukocytes from the standpoint of active oxygen species and adhesion molecules, CD11/CD18 and ICAM-1, EC jnjury induced by the leukocytes was due to the hydroxyl radical production from xanthine oxidase using hydrogen peroxide from the leukocytes.
In addition, CD11/CD18 and ICAM-1 induced vascular EC injury and the conversion of xanthine dehydrogenase to xanthine oxidase. The conversion might be elicited by tyrosine kinase activation.

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Steroid/thyroid hormones, vitamin A and vitamin D act as a ligand for nuclear receptors, all of which belong to a gene superfamily and are ligand-inducible transcription factors. Most of actions of these ligands is exerted by the nuclear receptor-mediated gene expression. The target enhancer elements referred as hormone response elements are composed of two core hexmer motifs. Homo- and heterodimers of non-steroid hormone receptors bind direct repeated elements, and homodimers of steroid receptors bind inverted repeats. Heterodimer of Fos and Jun, the other transcription factors, is activated as AP1 activity in response to inflammation. In agreement with in vivo observation that vitamin A (retinoid) and glucocorticoid show anti-inflammatory activities, the AP1 activity is inhibited in a liganddependent way by these nuclear receptors upon the DNA binding sites for AP1.
Moreover, we found that the gene expression of platelet-activating factor receptor (PAFR) is regulated by thyroid hormone and vitamin A in intact animal. Functional analysis of two promoters of this gene revealed that the response elements are located in the one of two promoters. Thus, the actions of PAF may be modified by the status of these ligands through the levels of PAFR.

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Cell-cell and cell-matrix adhesive interactions mediated by integrins play crucial roles in leukocyte migration to inflamed tissues, and also in cell migration during embryogenesis.
Mast cells are known to play a central role in regulating inflammatory responses of allergic and chronic immune diseases. The localization of mast cells in normal and inflamed tissues is therefore, an important regulatory process to influence intensity and duration of inflammatory responses. However, little is known about mechanisms that control localization of mast cells.
Here we examined adhesion of extracellular matrix proteins and mast cells stimulated with steel factor (stem cell factor, kit ligand) and FcERI crosslinking. We showed that steel factor and FcεRI crosslinking were potent stimulators of avidity of β1 integrin VLA-5, which mediated a rapid and transient adhesion to fibronectin.

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The present study examined the temporal pattern and localization of interleukin-1 (IL-1), tumor necrosis factor α (TNFα) and inducible nitric oxide synthase (iNOS) expression in lung tissue undergoing foreign-body granuloma formation. Pulmonary granulomas were induced by the intratracheal injection of dextran beads into genetically high granuloma responder, carrying Beg^s, (BALB/c) and low responder, carrying Bcg^γ, (C₃H/HeJ and DBA/2) mice.
In BALB/c mice, IL-1α and iNOS were induced mostly in the cells accumulated around the beads and also in some bronchiolar epithelial cells during the early phase, whereas TNFα was induced in the cells around the beads at later resolution phase. By contrast, in low responder mice, an increase in the expression of IL-lα and iNOS was detected in lung macrophages as well as in alveolar cells and bronchiolar epithelial cells on day 1, but that of TNFα was not detected throughout the period.
These results suggest that IL-1 and nitric oxide produced by recruited macrophages may take part in the early, macrophage-dependent phase of granuloma formation whereas TNFα may be more crucial as a mediator responsible for the difference in innate resistance or susceptibility to granuloma formation.

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In order to clarify whether bone morphogenetic protein (BMP) was effective and useful in periodontal regenerative therapy, three experiments were performed.
(1) Recombinant human BMP-2 (rhBMP-2) was applied in the horizontal alveolar bone defects of beagle dogs. The carrier was complex of gelatin and polylactic acid polyglycolic acid copolymer. The carrier without rhBMP-2 was used as a control. Twelve weeks later, animals were sacrificed and histological observations were performed. Substantial amount of new bone, cementum, and periodontal ligament were regenerated in the rhBMP-2 group. In the control group, little periodontal regeneration was observed.
(2) rhBMP-2 was implanted with three types of ceramic carriers (biphasic calcium phosphate, β-tricalcium phosphate, and hydroxyapatite) under the rat dorsal skin. In the BCP-BMP group, bone like tissue was formed in all 4 rats, and new bone tissue forming lamellae was observed in 2 of the 4 rats. The amounts of new bone were relatively smaller in the TCP-BMP and HAP-BMP groups. No bone like tissue was observed in any rats in the control groups.
(3) Although 500 ng/ml rhBMP-2 were added to the culture wells of human periodontal ligaments' cells, no elevation of ALP activity of the cells was observed.
These results suggest that rhBMP-2 will be a beneficial material in periodontal regenerative therapy.

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We attempted to investigate whether chemotaxis of neutrophils from healthy donors could be enhanced by G-CSF therapy. Two donors for granulocyte transfusions received intravenous administration of 2μg/kg G-CSF 16 hours before leukapheresis. Phagocytic activity of neutrophils from healthy donors after administration of G-CSF increased compared to those taken before G-CSF administration.
In contrast, random mobility and chemotaxis toward Zymosan-activated serum and filtrate of E. coli were unchanged. After G-CSF administration, neutrophils collected by leukapheresis showed augumented chemotaxis and random mobility as compared with those collected by venipuncture. However, leukapheresis procedure had no effect on phagocytosis. Neutrophil function was not affected by irradiation. Concerning the discrepancy between chemotaxis and phagocytosis, an increased neutrophil adhesion may result in depressive chemotaxis and enhanced phagocytosis.
And the fact that random mobility and chemotaxis of neutrophils enhanced after leukapheresis suggests that during the continuous flow centrifugation process, secondary cytokines may be released into circulation in response to G-CSF, which leads to the enhancement in neutrophil migration.

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The suppressive effect of IRA-378 on adjuvant arthritis was evaluated in Lewis rats and compared with that of auranofin and diclofenac-Na. Drugs were orally administered once daily from Day 0 (adjuvant injection) to Day 16.
(1) IRA-378 (3.1-25.0 mg/kg) dose dependently suppressed the swelling in both adjuvant injected and non injected paws. Auranofin (25.0 and 50.0 mg/kg) suppressed the swelling in the adjuvant injected paw only on Day 1. Diclofenac-Na (0.5 mg/kg) inhibited the swelling only in the injected paw. The degree of suppressive effect of diclofenac-Na on the swelling of the injected paw was similar to that of IRA 378 at a dose of 12.5 mg/kg.
(2) IRA-378 (25.0 mg/kg) significantly suppressed the bone damage in the adjuvant non injected paw by radiographic evaluation on Day 24. Auranofin (50.0 mg/kg) exhibited a tendency to inhibit the bone damage. Diclofenac-Na had no effect on this parameter.
(3) IRA-378 (25.0 mg/kg) significantly improved the thymus atrophy on Day 24. Auranofin and diclofenac-Na did not show any such improvement.
These findings suggest that IRA-378 is a useful drug for the treatment of chronic inflammatory diseases such as rheumatoid arthritis.

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The Uhthoff symptom, a transient impairment of visual function, gives a clue to the diagnosis of retrobulbar neuritis and multiple sclerosis.
We examined whether any clinicopathogenical significance of Uhthoff's phenomenon may declare in patients with Behçet's disease.
15 of 72 patients had been suspected of having the Uhthoff symptom.
High signal intensity lesions on T2-weighted MRI preferentially located on subcortico-occipital lobe and posterior horn of the lateral ventricle in patients having the Uhthoff symptom.
PET studies in 4 patients having the Uhthoff symptom showed decreased cerebral blood flow (CBF) in subcortico- and cortico-temporo-occipital lobes.
In PVEP examination, peak latencies of P100 were delayed in 5 of 20 patients, while mean peak amplitude was diminished in 2. However, these results had no bearing on the presence or absence of the Uhthoff symptom.
Our observation suggests that the reduction of CBF in visual center may play an important role in the occurrence of Uhthoff's phenomenon in Behçet's disease besides any disorders of the anterior visual pathways.

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