Autoimmune thyroid disease occurs in a genetically susceptible patients after triggering events including bacterial and viral infections, environmental insults, drugs or hormones. These triggering events may break the tolerance or anergy to self antigen, leading to emergence of autoreactive T cells. One or more T cell clones that recognize the self antigen is (are) assumed to be involved in initiating autoimmune processes. Following thus, T cell clones expand and migrate from the peripheral blood into the thyroid gland. Migration of mononuclear cells is controlled by inflammatory cytokines and adhesion molecules.
Intrathyroidal T cells may interact with dendritic-like cells, thyrocytes expressed with HLA-DR antigens, B cells and extracellular matrix, resulting in the proliferation of T cells, production of cytokines and autoantibodies. These interactions are regulated by inflammatory cytokines and adhesion molecules. When the initial immune response is completed, a secondary immune response ensues, that may be of considerable complexity involving reaction of infiltrating T cells to a variety of tissue-specific and tissuenonspecific antigens.
These immune responses may contribute to the recurring immunologic activity and maintenance of autoantibody overproduction.

View full abstract

We investigated regulatory mechanisms for leukotriene C₄ generation by rat basophilic leukemia-1 (RBL-1) cells. When RBL-1 cells were preincubated with or without retinoic acid (RA) for 16 hours and stimulated with calcium ionophore A23187, the cells under the former condition produced larger amount of LTC₄ than the latter cells. Such the enhanced LTC₄ production was significantly inhibited by up to 93.5% in the presence of DEX.
In the cell free system, the lysates of RA-preincubated cells showed higher LTC₄ synthase activity than the control cell lysates. In the presence of DEX, such the induction of LTC₄ synthase activity was significantly inhibited by up to 66.8%. This discrepancy of inhibition between the intact and cell free systems was attributed to additional inhibition of phospholipase A₂ activity by DEX (26.4%) .
These results indicate that the production of LTC₄ is regulated at a level of LTC₄ synthase. The regulation and the induction of new LTC₄ synthase activity by RA and its inhibition by DEX may operate as an important regulatory mechanism for LTC₄ synthesis in allergic and inflammatory disorders.

View full abstract

We investigated pulmonary vascular injury caused by mechanically activated white blood cells (WBCs) . We assessed the pulmonary vascular injury by measuring pulmonary vascular filtration coefficient using the gravimetric method and changes in the pulmonary vascular resistance, in the isolated perfused rat lungs. We activated WBCs by gently shaking in a glass container for 10 sec. After measuring the filtration coefficient under baseline conditions, we added inactive or activated WBCs into the pulmonary artery and then stopped the perfusion for 90 minutes and then reperfused. The filtration coefficient and the perfusate flow in activated WBC group was changed to about 2.5 times and 1/3 as that in the inactive WBC group, respectively. These results indicate the increase in the pulmonary vascular permeability and resistance. We conclude that WBCs which are increased in adhesiveness induce pulmonary vascular injury and increase in pulmonary vascular resistance. These results suggest that WBC activation by mechanical share stress may be partly involved in the pathogenesis of reexpansion pulmonary edema.

View full abstract

Interleukin 8 (IL-8) is the inflammatory cytokine that activates neutrophils. Recently, it has been reported activated neutrophils contribute to the cartilage degradation. Previous reports have been suggested interleukin-8 (IL-8) exists in high concentration in RA synovial fluid. In vitro study, various cells such as synoviocytes, monocytes/macrophages, fibroblasts and endothelial cells were reported to produce IL-8. We tried to detect IL-8 producing cells on RA synovial tissues by immunohisto-chemistry and in situ hybridization. In RA synovial tissues, IL-8 products and mRNA were detected on synovial lining cells, fibroblastoid cells, monocytes/macrophages, endothelial cells, and neutrophils. Intensity of IL-8 expression was correlated with the inflammation of synovial tissues.
On the other hand, IL-8 scarecely expressed on synovial lining cells and endothelial cells in osteoarthritic synovium. These data suggest IL-8 may play an important role on inflammation and joint destruction in RA synovial tissues.

View full abstract

It has been reported that the intraarticular injection of hyaluronan (HA), especially that of a high molecular weight (M. W.), provides symptomatic relief and improves joint function in arthritic joints. However, neither the mode of action nor the mechanism of the therapeutic effects is fully understood.
We tried to clarify the effects of HA injection from the aspect of histological features, using immunohistochemical markers in the synovial tissues of the knee joints of patients with rheumatoid arthritis (RA) before and after the injection of high molecular HA. Thirteen patients who met the American Reumatism Association criteria for RA were examined in this study. 2.5 ml hyaluronan (10 mg/ml) was injected weekly into the knee joint five times, 125 mg totally.
Histological parameters that we compared were as follows : 1) grade of synovial proliferation ; number of synovial cells in superficial layer demonstrated by hematoxylin-eosin staining, 2) grade of vascular proliferation ; density of small vessels represented by UEA-1, a lectins, 3) grade of inflammatory cell infiltration by, a) density of macrophages (KP-1), b) density of T lymphocytes (UCHL 1) and c) grade of B lymphocytes aggregation (L26), 4) a) density of Matrix Metallo-proteinase-3, b) density of Cathepsin D, and 5) degree of hyaluronan density and distribution by hyaluronan binding protein (HABP) .
Five of the 13 patients were responders and 8 were non-responders clinically. The difference in immunohistochemical study between responders and non-responders, was the decrease of inflammatory cell density such as macrophages, T lymphocytes, and B lymphocytes, while the density of MMP-3 and cathepsin D containing cells did not decreased. As a result of the diagnosis of their knees, the 5 responders were all evaluated as being in grade I of Larsen Classification, and the proteinase production in their synovial membrane was comparatively mild. From these results, it seems that injected HA has a mild effect in decreasing the inflammation of the synovia.

View full abstract

To investigate the role of granulocytes in arthritis, extracorporporeal granulocytapherersis (G-1) was performed using the column containing cellulose acetate beads in rabbits with immune arthritis.
After injection of ovalbumin into the knee joints of ovalbumin-sensitized animals to induce joint swelling, markedly increased number of granulocytes in peripheral blood and granulocytes accumulation into the arthritic joint were shown. Approximately 18% of granulocytes in whole blood were removed by G-1. Effect of G-1 on granulocytes was investigated by flow cytometry. G-1 treated granulocytes showed a significant decrease in active oxygen production (p<0.05) and lost of LECAM-1 expression (p <0.05) compared with pre treatment granulocytes. The joint swelling was significantly lower in the G-1 group than in the control group, as well as the decreased number of infiltrating leukocytes into the arthritic joint (p< 0.001) .
G-1 appeared to prevent a signficant damage to the tissue by actively controlling leukocytes function and distribution in the inflammatory joints. The results suggested that G-1 could be an effective treatment for inflammatory disorders which granulocytes are chronically or heavily involved.

View full abstract

We investigated the effects of Rubus suavissimus (chinese name: Ten-Cha) extract on the inflammatory reactions including ear dermatitis induced by croton oil and tumor necrosis factor (TNF) production in ICR mice. When Ten-Cha extract (200 mg/kg/day) was administered po for five consecutive days, the ear edema and capillary permeability induced by croton oil were markedly suppressed by 51.8 and 76.5%, respectively. Furthermore, single p. o. administration of Ten-Cha extract, also showed a tendency to reduced these parameters of edema, ear weight and capillary permeability.
In vitro TNF production of the peritoneal macrophages obtained from ICR mice that had been treated with both Ten-Cha extract (200 mg/kg/day, p.o., 5 days) and proteose-pepton (i.p.) was significantly reduced when compared with that obtained from the animals treated with only proteose-pepton. In contrast, the TNF production of the alveolus macrophages obtained from the mice that had been treated with the Ten-Cha extract at the same conditions was not different from that obtained from untreated animals. These results indicate that Ten-Cha extract exerts anti-inflammatory effects and improvement of capillary permeability, suggesting that the effects may be, at least, partially explained by the reduction of endogenous cytokine production induced by Ten-Cha extract.

View full abstract

Ergosterol is an essential component of virtually all fungal cells as it is required for membrane integrity and also for growth. Its importance is underlined by the fact that most antifungal agents interfere with ergosterol either by directoly inhibiting its biosynthesis (allylamines, azoles, morpho lines, thiocarbamates) or by interacting with it the cell membrane (polyenes) . HMG-CoA reductase inhibitors also specially inhibits sterol synthesis at the point of 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase. Mode of action and properties of the sterol synthesis inhibition of HMG-CoA reductase inhibitors are similar to those of antifungal agents.
The antifungal activity of HMG-CoA reductase inhibitors (pravastatin Na, simvastatin carboxylate) was studied with the agar dilution mothod.
In the caseAspergillus furnigatus, growth inhibition of pravastatin appears to result from the inhibition of ergosterol biosynthesis. Simvastatin also exhibits a spectrum activity in vitro against dermatophytes (Epidermophyton floccosum, Microsporum audouinii and Trichophyton rubrum) .
Our results suggest that HMG-CoA reductase inhibitors is a useful drug not only the treatment of hyperlipidemia but also a prevention of fungal infection.

View full abstract

To evaluate the role of lymphocytes in bleomycininduced lung fibrosis, we examined the effect of pretreatment with facteur thymique serique (FTS : serum thymic factor), which activates T lymphocytes, on bleomycin-induced lung fibrosis in mice. FTS inhibited the grade and incidence of lung fibrosis induced by intravenous injection of bleomycin (BLM) . These data suggested that inhibitory effect of FTS to BLM-induced lung fibrosis.

View full abstract

The present study was undertaken to clarify the changes of bone metabolism of adjuvant-induced arthritis rats (AA) . After adjuvant inoculation to rats, urinary deoxypiridinoline content was gradually increased with developing AA. The third lumbar vertebra (L₃) was used for determination of morphological change on 28 days after adjuvant inoculation. The trabecular bone number of the L₃ vertebra significantly decreased in comparison with the control group of the same age. The study has shown that AA has a pronounced effect on vertebral bone mass and quality with collagen destruction.

View full abstract