Progressive degradation of articular cartilage is a major feature of rheumatoid arthritis and osteoarthritis. Attention has focussed in recent years on some cytokines including interleukin 1 (IL-1) and tumor necrosis factor (TNF) . These cytokines caused cartilage to degrade its proteoglycan and inhibited the synthesis of new proteoglycan in explants of cartilage.
We confirmed and extended these observations at the cellular level as follows. (1) Human recombinant IL-1α, IL-1β and TNFα strikingly inhibited the synthesis of glycosaminoglycan (GAG) and stimulated breakdown of proteoglycan in cultured chondrocytes. (2) These effects of IL-1α and TNFα were specifically neutralized by anti-IL-1α and anti-TNFα antisera, respectively. (3) Five different anti-IL-1α monoclonal antibodies, capable of neutralizing LAF activity to a varying degree, also neutralized IL-1α-induced inhibition of GAG synthesis and stimulation of proteoglycan breakdown. (4) The addition of TNFα, but not of IL-1 (α, β) to the cultures of chondrocytes stimulated DNA synthesis.
In this review we related these results to the previous observations by others. Together these results suggest that IL-1 and TNFα may play an important role in the mediation of cartilage damage in chronic arthritis.

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Rat mast cell granules were obtained by homogenation of highly purified rat mast cells and isolated in a Percoll gradient. PI kinase in rat mast cell granules were assayed by measuring the incorporation of ³²P from [γ³²P] ATP into diphosphoinositide (DPI) in the absence of exogenous PI. Lipids were isolated with methanol chloroform/HCl and were separated by thin-layer chromatography on oxalic acid impregnated silica gel plates. DPI areas were identified by staining with iodine, scraped and measured for ³²P radioactivity. The enzyme was inhibited by 50-500μM adenosine, 5-500μM ADP and AMP. Among several anti-allergic drugs investigated, 10-1000μM theophylline and 1-100μM azelastine inhibited the enzyme, but 1-100μM disodium cromoglycate and ketotifen had little effect.

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To determine the precise mechanism of airway hyperresponsiveness induced by prostaglandin F₂α (PGF₂α) and thromboxane A₂ (TXA₂), we investigated the effects of the subthreshold dose of PGF₂α and TXA₂ on smooth muscle contraction evoked by acetylcholine (ACh) and electrical field stimulation (ES) in canine trachea. We found that neither PGF₂α nor TXA₂ have any effects on smooth muscle contraction evoked by these stimuli. These results shows that these prostanoids have no effects on smooth muscle itself and postganglionic vagal efferent nerve. Our present data, together with our previous data, suggest that these prostanoids induce airway hyperresponsiveness by stimulating vagal sensory endings, and by enhancing the vagal reflex pathway.

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Twenty patients with active rheumatoid arthritis were investigated for a period of eight weeks treatment with prednisolone at a daily dose of 5mg or 10mg. There was a significant decrease in serum IgG and IgM rheumatoid factor (RF) levels over the period of study, depending on the administered dosage of prednisolone. Comparison of changes in serum IgG-RF and total IgG levels indicated a selective depression of RF, which paralleled with the clinical improvement. Comparison of changes in serum IgM-RF and total IgM levels showed a downward trend of RF, but this did not reach statistical significance. During the period of this study, the antibody level to Parainfluenza virus type III was also measured, but not changed significantly.
These results indicate either that half-life of IgG-RF is shorter than that of other antibodies or that the suppresion of RF production is more sensitive than others, and the monitering of IgG-RF level is a good parameter for assessing disease activity.

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Lumisphere, luminol-conjugated microspheres, proved to be useful for measuring simultaneously phagocytic function and chemiluminescence (CL) of human blood leukocytes. Phagocytic index (PI) which was calculated by summation of PMNs phagocytized more than 6 Lumisphere particles per 100 PMNs did not correlate well with any of CL responses to phorbol myristate acetate (CL-PMA), opsonized zymosan (CL-OZ), and Lumisphere by itself (CL-Lumi) . Since phagocytosis is modulated by interaction of cell surface receptors such as FcR, C3bR and fibronectin with certain ligands, the present findings suggested no direct correlation or association of phagocytosis with oxygen active metabilisms. Correlation coefficients of CL-Lumi of healthy adults with CL-PMA and CL-OZ was 0.630 and 0.845, respectively. In contrast, the correlation coefficients of the patients were very low, suggesting that each of CL-PMA, CL-OZ, and CL-Lumi reflected the different receptor-mediated oxygen metabilisms. The comparison of these CL responses and phagocytosis gives an insight into monitoring various disease activities associated with phagocytic functions and receptor mediated functions of PMNs.

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Out of numerous factors relating to the pathogenesis and development of inflammation, the roles of plasma serine-proteases including, kallikrein, Clr, Cls, trypsin and plasmin are not thoroughly elucidated. To investigate the role of an enzyme, it is effective to use the selective inhibitor on it.
In the present studies, authors used two pharmacological tools, i.e., FUT-175 (nafamostat mesilate), a selective inhibitor on serine-proteases and indomethacin, a selective inhibitor on cyclooxygenase and investigated the participation of serine-proteases in inflammation.
At first, the pharmacological profile of FUT-175 was investigated in comparison with indomethacin. It was made clear that FUT-175 had selective inhibitory activities only on serine-proteases and no indomethacin-like activities.
In the second, FUT-175 had significant suppressive effects on the representative models of inflammation including carrageenin-induced pleurisy and foot edema and adjuvant-arthritis in rats.
These results suggest that plasma serine-proteases, especially complement system and kallikrein-kinin system play an important part in the processes of either acute or chronic inflammatory reactions.

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Leukotrienes (LT), mediators on allergic asthma and inflammation, are formed from arachidonic acid by 5-lipoxygenase. An attempt was made to develop an orally effective anti-allergic drug. Caffeic acid was found to inhibit 5-lipoxygenase. We synthesized about 200 derivatives of caffeic acid. Among its derivatives, TMK-688, 1- (3- (5- (3-methoxy-4-ethoxycarbonyloxy) -1-oxo-2, 4-pentadienyl) aminoethyl) -4-benzhydryloxy-piperidine, was finally selected to be the most suitable drug. TMK-688 showed significant inhibition in various models of allergic reactions and non-allergic reaction, i.e., 1. Inhibition of IgE-mediated passive cutaneous anaphylaxis in rats. 2. Inhibition of direct passive Arthus reaction in rats. 3. Inhibition of anaphylactic bronchoconstriction in guinea-pig. 4. Inhibition of histamine-induced smooth muscle contraction in guinea-pigs trachea. 5. Inhibition of platelet activating factor-induced bronchoconstriction in guinea-pigs, etc.
Above all results suggest that TMK-688 is a unique orally active anti-allergic drug.

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A morphological and biochemical study of calcifying tendinitis in twy mouse was carried out. Calcification of the aponeurosis plantaris was first observed at the 7th week of age. Thereafter multinucleated giant cells and histiocytes were seen around the calcium deposits. Infiltration of polymorphonuclear leukocytes followed. These inflammatory cell reaction confined to the tendon. Then, proliferation of capillaries and fibroblasts was observed, and lacunar formation around the calcium deposits was sometimes observed. In later stage, inflammatory cell infiltration subsided, and fibrous scar and calcium deposits were recognized in the tendon. Deposition of hydroxyapatite was confirmed in the tendon by X-ray powder analysis.
These changes resemble those of man, and calcifying tendinitis in twy mouse is thought to be a valuable model of the corresponding disease in man.

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Serum free culture medium collected from primary monolayer cultures of human articular chondrocyte wasfound to inhibit human urokinase enzyme activity.
SDS-polyacrylamide gel electrophoresis followed by reverse fibrin autography revealed that the conditioned medium contained an inhibitor immunologically identical to endothelial cell inhibitor. Fibrin overlay showed that the conditioned medium also contained an inhibitor which had no immunological cross-reactivity with known PA inhibitors. This type of inhibitor formed a high molecular weight SDS-stable complex with urokinase in fibrin overlay.

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Effect of Shosaikoto (TJ-9), Hochuekito (TJ-41) and Juzentaihoto (TJ-48) on phagocytic activity of leukocytes in mice was investigated.
When TJ-9, TJ-41 or TJ-48 was given to mice either intraperitoneally or orally, all of these Kampo medicines enhanced the phagocytic activity of peritoneal exudate cells (PEC) .
Oral administration of TJ-41 or TJ-48 also stimulated the phagocytosis of PEC, spleen cells and bone marrow cells. In contrast TJ-9 enhanced only the activity of PEG.

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