Vascular endothelial cells (EC) have been shown to produce various biologically active substances and play an important role in both physiology and pathology of the blood vessels. EC have been shown to produce metalloproteinases (MMP) and tissue inhibitor of MMP TIMP. Vascular tissue may be composed of type N collagen which is a main conponent of vascular basement membrane and type I or II collagen, a main stromal matrix component. These different matrix conponents are digested by different MMP. Imbalance of MMP and TIMP produced by EC may cause vascular events: for example, increased MMP and decreased TIMP are a predisposing factor leading to vascular damage, inflammatory cell infiltration and metastasis of malignant cells, while decreased MMP and increased TIMP may lead to fibrosis, atherosclerosis or wound healing.
It has been shown that cytokines modulate production of TIMP by EC. Our data imply that IL-1 or tumor necrosis factor inhibit TIMP production by EC, while IL-6 promote it. Therefore, regulation of matrix conponent, MMP and TIMP may be important for tissue repair, wound healing, atherosclerosis and inflammation.

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Release of mediators from mast cells can be induced in a non-cytotoxic way by a number of agents including histamine releasing factors produced by a variety of iriflammatory cells and eosinophil granule-derived cationic proteins. Neuropeptides can cause mast cells to release histamine but they respond differently to the same stimuli among their subtypes. Naturally occurring aliphatic polyamines also induce a histamine release from mast cells.
Two neutral serine proteases, tryptase and chymase, have been shown to be present in human mast cells. Tryptase-positive, chymase-negative mast cells are the predominant type in the lung and intestinal mucosa and the tryptase-positive, chymase-positive cells in skin and intestinal submucosa, whereas rodent mast cell subpopulations are referred to as mucosal mast cells and connective tissue mast cells.
The interactions of mast cells with a variety of stimuli result in the secretion of mediators through intracellular biochemical events. Calcium and cyclic AMP appear to be two major biochemical factors for the control of cellular activities and are known to activate protein kinase C and cyclic AMP-dependent protein kinase, respectively. Another line of evidence indicates that extracellular stimuli induce phospholipid turnover, especially increased metabolisms of inositol phospholipids. GTP-binding protein is not involved in the induction of the antigen-induced triggering signal to phospholipase C which initiates the enhancement of inositol phospholipids turnover.

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It has been shown that immunomodulators are effective as a remittive agent in the treatment of rheumatoid arthritis (RA) . But their modes of action are not fully understood yet although they are significantly different from the effects of the nonsteroidal anti-inflammatory drugs in that they exert minimal nonspecific anti-inflammatory effects. Most of the immunomodulators have been shown to have in vitro and in vivo effects on the immune system which are probably related to their therapeutic effectiveness. In the present study, we investigated in vitro effects of two immunomodulators, lobenzarit (CCA) and bucillamine, on the production of immunoglobulins and class-specific rheumatoid factors (RF) by blood mononuclear cells from normal donors. Mononuclear cells were cultured 7 days with or without varying concentrations of drugs in the presence of PWM, and supernatants were measured for immunoglobulins, IgG and IgM, and IgGRF and IgMRF. Both CCA and bucillamine significantly inhibited the production of IgG and IgM and IgGRF and IgMRF in dose dependent fashion. Both drugs exerted significant inhibitory effects in vitro B lymphocyte dependent immunoglobulin and RF synthesis at pharmacological concentrations. The properties of these inhibitory capacity of CCA and bucillamine did not differ each other. Moreover, there were no differences of inhibitory capacity between these two drugs and gold sodium thiomalate tested as positive control. These results obtained suggest that CCA and bucillamine have immunomodulatory characteristics which may be related to their therapeutic activity in RA.

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The effects of natural and recombinant interferon-α (IFN-α) on osteoclast-like cell formation were tested in human cord blood cultures. Each type of interferon inhibited osteoclast-like cell formation. Natural type IFN-α was a more potent inhibitor of multinucleated cell formation than was recombinant IFN-α. IFN-α also inhibited osteoclast-like cell formation from human cord blood cultures treated with 1, 25-dihydroxyvitamin D₃ [1, 25 (OH) ₂D₃], interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) which are potent stimulators for osteoclasts. These data demonstrate that IFN-α inhibits multinucleated osteoclast-like cell formation, and further suggest that IFN-α may be useful therapeutic agents in diseases such as inflammately bone resorption in which cytokines (IL-1β. IL-6, TNF-α) have been associated.

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Sodium aceneuramate (Neu 5Ac-Na), sodium salt of N-acetylneuraminic acid known as sialic acid, was shown to possess anti-inflammatory effect after intravenous administration to carrageenan-induced paw edema but not effective after oral administration. Half life of Neu 5Ac-Na was within 5 minutes and Neu 5Ac-Na was not detectable in plasma 3 hours after intravenous administration, but anti-inflammatory effect was still observed 3 to 4 hours after intravenous administration of Neu 5Ac-Na.
Accumulation in inflammatory region of Neu 5Ac-Na was investigated. The inflammatory exudates were obtained following the subcutaneous implantation of carrageenan-soaked polyester sponges in rats. The levels of radioactivity in the exudates after intravenous administration of ¹⁴C-labelled Neu 5Ac was 3 to 4 times higher than those in plasma.
Leukotriene B₄ (LTB₄) was detected by radioimmunoassay in inflammatory exudates obtained from the implantation of sponges in rats. Production of LTB₄ was significantly reduced by i.v, administration of Neu 5Ac-Na to rats.

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Prostaglandin (PG) E₂ inhibited CD 4⁺ cell proliferation stimulated with immobilized anti-CD 3 monoclonal antibody (mAb), 64.1 in a dose-dependent fashion. This inhibition was due to the suppression of interleukin 2 (IL 2) production, but not to that of IL 2 receptor expression. PGE₂ decreased IL 2 mRNA level at a pretranslational level in CD 4⁺ cells. Phorbol myristate acetate (PMA) or mAb 9.3, when present in the culture, reversed PGE₂-mediated inhibition of CD 4⁺ cell proliferation almost to the control level. IL 2 production by CD 4⁺ cell was highly increased in the presence of PMA or mAb 9.3 with immobilized mAb 64.1. This increase was also strongly inhibited by PGE₂ in a dose-dependent manner. The level of IL 2 production by PMA or mAb 9.3 even in the presence of the highest concentration of PGE₂ was higher than that of IL 2 produced by non-stimulated CD 4⁺ cells.
It is, therefore, suggested that the reverse effect of PMA or mAb 9.3 on the PGE₂-mediated inhibition of CD 4⁺ cell proliferation may be due to the excess production of IL 2 by the PMA-or mAb 9.3-stimulated cells.

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A multipotent enzyme inhibitor, ulinastatin, was tested for the effect on osteoarthritis (OA) induced by a partial lateral meniscectomy combined with section of the fibular collateral and sesamoid ligaments in knee joints of rabbits. In the control group, treatd with human serum albumin, histopathological oganges quite similar to those in human OA were observed both in the tibial and the femoral cartilage. In addition, biochemical changes such as decrease in keratan sulfate content and increase in collagenase activity were observed in the meniscus and the synovial fluid, respectively. These changes were markedly suppressed by intraarticular injection of ulinastatin at 30 or 300 units/site, given semiweekly for seven weeksf starting from one week after the surgical induction o, OA. These results suggest that ulinastatin is expected to be useful treatment of OA.

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The subsets of peripheral blood lymphocytes in 3 cases with acute type of the fulminant hepatitis (FH) were studied.
The percentage of Leu 2a⁺15^- cell and Leu 2a⁺ HLA-DR⁺ cell in the peripheral blood at the acute stage increased remarkably in death cases due to FH. In survival cases, increase of Leu 2a⁺15^- cell was not noted, while increase of Leu 2a⁺ HLA-DR⁺ was noted. The increase of the percentage of these cells was also noted in the acute viral hepatitis type A (AVH), while ratio of Leu 2a⁺ HLA-DR⁺ cell/Leo 2a⁺15^- cell was higher in FH than in AVH.
These data suggest that activated cytotoxic T lymphocytes may play a role in the pathogenesis of FH.

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The present study was undertaken to investigate the serum levels and penetrability of piroxicam into synovial fluid in patients with rheumatoid arthritis who were treated with ampiroxicam 27 mg once daily over a long period of time.
The serum levels were determined on 120 blood samples withdrawn from 44 patients and synovial fluid concentrations on 4 samples obtained from 3 patients. The results are summarized as follows.
(1) The piroxicam serum concentrations were 5.45±0.34μg/ml (mean±standard error) for 59 samples of patients treated for 14 weeks or less, 5.74±0.37 μg/ml for 38 samples of those treated for 15-26 weeks, 5.73±0.63 μg/ml for 19 samples of those treated for 27-46 weeks and 5.07±0.88 μg/ml for 4 samples of those whose treatment period was 47 weeks or more, all showing about the same levels.
(2) The piroxicam levels in synovial fluid were about 53% of plasma levels indicating a good penetrability of the drug.
(3) The correlation of the piroxicam serum concentrations with the clinical efficacy of ampiroxicam was unclear nor with the safety (in terms of development of side effect or laboratory abnormal values) .
The foregoing results suggest that when ampiroxicam is given as a single dose of 27 mg once daily to the patients with rheumatoid arthritis over a long period of time, the piroxicam levels in serum are maintained within an about fixed range not showing any increase or accumulation enhanced by a long term dosing and once a steady state is reached, the level is sustained over a long period of time.

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The effects of nabumetone, naproxen or loxoprofen were examined for anti-inflammatory activity and for effects on gastric mucosal integrity in a rat model of carrageenan-induced paw oedema. All three compounds produced effective anti-inflammatory activity which was associated with dose-related reductions in PGE₂ concentration of the inflammatory exudate. However, naproxen and loxoprofen markedly inhibited gastric mucosal 6-keto-PGF_1α, production which was accompanied by increases in gastric erosion formation. In contrast, nabumetone inhibited gastric mucosal 6-keto-PGF_1α production by only 47% and did not induce gastric damage.
In experiments designed to detect gastric and intestinal irritancy, nabumetone, naproxen or loxoprofen were administered orally in single high anti-inflammatory doses. At 6, 24 or 48 hr after dosing, none of the three drugs had caused gastric damage but loxoprofen induced significant ileal damage over the course of the experiment. Associated with loxoprofen-induced ileal damage was a significant increase in myeloperoxidase activity of the ileal tissue 6 hr after dosing, indicating that an inflammatory reaction either precedes or accompanies such damage. Gastrointestinal blood loss was unaltered by any of the drugs over a period of 48 hr. In a cold-restraint rat model of gastric damage where mucosal integrity is compromised, nabumetone failed to increase existing gastric damage whereas both naproxen and loxoprofen increased damage signifcantly. The present study shows that nabumetone, unlike naproxen or loxoprofen, does not cause gastrointestinal irritancy in this species when administered in a high anti-inflammatory dose.

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