Oxygen-derived free radicals are mainly produced by phagocytic cells and hypoxanthine-xanthine oxidase system at inflammatory site. These oxygen metabolites and lipid peroxidation have been implicated in cell damage, interactions with other inflammatory mediators and modulation of vascular response. It is very important to modulate free radical-induced inflammatory reaction in various organs by administration of radical scavengers and antioxidants.

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IL-5 is a cytokine released from T lymphocytes, mast cells, and eosinophils when infection or inflammation takes place. IL-5 is primarily and selectively engaged in eosinophil development. It works as a homodimer of a polypeptide with M. W. of 12, 500. It is heavily glycosylated to give the M. W. of 40 to 55 kDa. Its receptor consists of α and β chains. The IL-5 receptor a chain is 60 kDa glycoprotein that is the only IL-5 binding protein. The IL-5 receptor fi chain is a 130 kDa glycoprotein that does not bind any cytokines described. This β chain, however, is necessary to form the functional IL-5 receptor. In case of murine IL-5 receptor, α chain binds IL-5 with low affinity and becomes functional high affinity receptor when dimerized with β chain. In contrast, human IL-5 receptor a chain binds IL-5 with higher affinity than murine homologue. It is highly possible that soluble from of human IL-5 receptor α chain effciently block the IL-5 binding to its receptor. The IL-5 receptor β chain is also used as R chain for GM-CSF receptor and IL-3 receptor. These three cytokines which share fi chain are able to induce eosinophil hyperadherence to human microvascular endothelial cells. IL-5 and IL-3 also prime eosinophils, basophils and mast cells to produce leukotriene C4 in response to soluble agonists.

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Molecular mechanism (s) involved in adhesive interactions between T lymphocytes and human gingival fibroblasts (HGF) were examined. Both human peripheral blood T lymphocytes and T cell leukemia line, Molt-4 demonstrated significant binding ability to HGF only when the cells were activated with phorbol 12-myristate 13-acetate (PMA) . In order to reveal the molecule (s) responsible for the adherence, a panel of monoclonal antibodies (mAbs) was prepared against PMA-activated Molt-4 and mAb, 4-145 was finally entablished on the basis of its ability to block the adherence of activated Molt -4 to HGF. Biochemical and functional analysis revealed that 4-145 recognizes an epitope on VLAβ1 chain. Furthermore, blocking experiments utilizing mAbs specific for VLAα chains demonstrated that VLA-4 plays an important role for mediating the adhesion of activated T lymphocytes to HGF.
Results demonstrated in this study suggest that VLA integrins play critical roles not only in binding to activated endothelial cells in inflammatory sites but also in retention of activated T lymphocytes in inflamed periodontal lesions by mediating the adhesive interaction between T lymphocytes and HGF.

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The authors previously found that codeine was rather ineffective against coughing and aggravation of coughing due to angiotensin-converting enzyme inhibitors in the presence of airway inflammation and that Bakumondo-to had a marked antitussive effect. In this study, the effects of Bakumondo-to and ophiopogonin isolated/extracted from Bakumondo (ophiopogonin tubes) on airway inflammatory mediators, in particular tachykinin and its cleavage enzyme neutral endopeptidase (NEP), were investigated.
In animals with bronchitis, airway NEP activity decreased to 1/8-1/9 of that in healthy animals, and Bakumondo-to prevented the reduction in NEP activity. Bakumondo-to and ophiopogonin also suppressed tachykinin-and phosphoramidon (an NEP inhibitor) -induced coughing while codeine was almost ineffective.
These results clarified part of the physiology of airway clearance as well as the pathophysiology and the mechanism of repair which have not been well understood. The results suggest that Chinese medicines and their crude drug constituents are useful resources for the development of the next generation of pharmaceuticals contributing to the radical cure of diseases.

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The possibility has been proposed that the vicious cycle which consists of basal diseases, bacterial metabolites and host persistent inflammation affected on intractability of chronic respiratory tract infections (CRTI) . To elucidate the contribution of host inflammation to the intractability of CRTI, we investigated the effect of repeated inhalations of sterilized Escherichia colisuspension on cellular and biochemical parameters in bronchoalveolar lavage fluid (BALF) and lung tissue using rats. An influx of neutrophils, a leakage of albumin and an increase of neutrophil elastase activity in airways were maintained during the repeated inhalations, which confirmed that there arose a chronic pulmonary inflammation. In histological studies, the lung tissue of inhaled rats showed chronic inflammatory features which resembled in diffuse panbronchiolitis. In the model, erythromycin reduced the number of neutrophils, the concentration of albumin, and the elastase activity in BALF. Furthermore, no or weak histological changes were observed in the lung tissue of rats treated with erythromycin, and the deterioration of pulmonary mechanics was suppressed.
These results suggest that host persistent and excessive inflammation contributes markedly to the exacerbation of basal disease caused by CRTI, and that the suppression of such inflammation is promising to its medical care.

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Sixty-four patients with histologically proven idiopathic interstitial pneumonia (IIP) were retrospectively examined in order to assess the corticosteroid therapy. Fifty-one patients received corticosteroids while thirteen did not receive the steroids. A generalized Wilcoxon's analysis revealed that the group without corticosteroids had a better survival. It was suggested that patients with higher activity, who consequently received corticosteroids therapy, had poor prognosis. Among the patients with corticosteroid therapy, those with over 5% neutrophils in bronchoalveolar lavage fluid (BALF) or with alveolitis proven by lung biopsy had shorter survival period than those with under 5% neutrophils in BALF or with fibrotic histology. Pulse therapy against acute exacerbation seemed to have no beneficial effects on survival rate and all of the patients, who received pulse therapy, died. Moreover, the response to corticosteroid therapy did not result in the improvements of survival rate.
It is concluded that corticosteroids have limited values to improve the poor prognosis in patients with IIP. A new therapy or medicine is expected for IIP.

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We identified transfomation-associated cell surface antigens (TAAs) that are expressed on a W31 H-rasoncogene trasformant of WFB rat fibroblast. One of TAAs, defined by mAb067, showed the enhanced expression by physicochemical stressors, and was supposed to be 70 heat shock cognate protein (hsc) itself. It was also shown that this antigen may be a target for CD4^-CD8^- double negative T cell (DNT), since mAb067 completely blocks the cytotoxicity of DNT against W31.
These data strongly suggest that 70 hsc is a tumor antigen, and is a potential target for the host's tumor immunity. The capability of antigenic peptide presentation of 70 hsc was discussed.

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Transforming growth factor (TGF) -β₁is a pluripotent cytokine exerting differential effects on distinct components of the immune responses. The present report demonstrates that TGF-β₁ modulate the immune responses of rheumatoid arthritis (RA) . The plasma from peripheral blood and bone marrow in affected joints by RA, and synovial fluid (SF) contained the detectable levels of TGF-β, and higher levels of TGF-β was observed in bone marrow from RA patients with anemia or active synovitis. In synovial fluids RA patients had higher levels of TGF-β, comparing with osteoarthritis (OA) patients. T and B cells in SF from RA patients had lower mitogenic (PHA, SAC) responses. Exogenous TGF-β prominently suppressed the mitogenic responses of T and B cells. These lower responses were recoverd by adding neutralizing antibodies (polyclonal heterogenous antibodies) . Spontaneous or SAC-stimulated IgM production of B cells in SF from RA were modulated by exogenous TGF-β and its neutralizing antibodies. Adherent cells in SF from RA actively produced IL-1β with or without the stimulation of LPS. However, TGF-β and its neutralizing antibodies never effect the production of IL-1β from adherent cells.

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As it has been known that non-steroidal anti-inflammatory drugs have damaging effect on gastric mucosa which may be related to superoxide production by neutrophils as indicated in recent reports, we evaluated the effect of indomethacin prodrugs (acemetacin, indomethacin-farnesil, prog-lumetacin and CP-331) on the superoxide production in rabbit neutrophils. Superoxide production was measured by chemiluminescence technique using a luciferine analogue (FCLA) . Proglunetacin inhibited PMA-induced, but not f-MLP-induced, superoxide production in a dose dependent manner. CP-331 depressed both f-MLP- and PMA-induced superoxide production. However, acemetacin and indomethacin-farnesil, and also their metabolite, indomethacin, did not inhibit these superoxide productions. All these compounds did not show any inhibitory effect on superoxide production derived from the hypoxanthine-xanthine oxidase system.
The results indicated that proglumetacin and CP-331 did not act as superoxide radical scavenger. CP - 331, but not other compounds, inhibited NADPH oxidase activity in rabbit neutrophils. CP-331 and proglumetacin showed only weak inhibition on the protein kinase C activity. From these results, proglumetacin and CP-331, but not acemetacin and indomethacin-farnesil, expressed inhibitory properties for superoxide production in neutrophils, although we could not decide their target sites.

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Cyclooxygenase (COX) plays a role in inflammatory diseases, but limited data exist on the regulation of COXin vivo. We studied thein vivoexpression of COX in synovia from patients with rheumatoid arthritis (RA) as well as rats with streptococcal cell wall (SCW) and adjuvant arthritis. Extensive and intense COX immunostaining, which correlated with the intensity of mononuclear cell infiltration, was observed in RA synovia. Significantly less staining was noted in OA and normal human synovia. COX immunostaining was equivocal in the joints of normal and arthritis-resistant F344/N rats. In contrast, high level COX expression developed rapidly in female LEW/N rats throughout hindlimb joints preceeding or paralleling experimental arthritis.
COX was expressed in the joints of athymic LEW. rnu/rnu rats 2-4 days after injection of SCW or adjuvant but was not sustained. Physiological doses of glucocorticoids suppressed both arthritis and COX expression in LEW/N rats injected with SCW or adjuvant.
These observations suggest that, in vivo, (a) COX expression is upregulated in inflammatory joint diseases, (b) expression is a biochemical marker of disease activity, and (c) expression is down-regulated by antiinflammatory glucocorticoids.

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Anti-inflammatory effects of TSA-234 (recombinant human superoxide dismutase, rhSOD) were studied in vitroand in vivo. TSA-234, 0.1-100 μg/ ml, significantly inhibited damage of chondrocytes, reduction inviscosity of hyaluronic acid and osteoarthrosis-derived joint fluid, delayed gelation of collagen and inactivation of α₁-proteinase inhibitor (PI) which were induced by active oxygen species generated in the system of hypoxanthine-xanthine oxidase. Intraarticular injection of TSA-234 significantly inhibited both carrageenin-induced arthritis in rabbit knees and sodium urate-induced arthritis in dog knees. Furthermore, TSA-234 significantly inhibited rat carrageenin-induced paw edema and mouse ischemic paw edema by 0.125-1 mg/kg, i. v. and 1 mg/kg, i. v., respectively.
These results suggest that TSA-234 will be useful with an Intraarticular injection on the therapy of osteoarthrosis in knees.

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The effects of Margarita extract on superoxide generation of human PMN were investigatedin vitroby using chemiluminescence method with a 2-methyl-6-phenyl-3, 7-dihydroimidazo [1, 2-a] pyrazin-3-one (CLA) . Superoxide generation stimulated by N-formyl-methionyl-leucyl-phenylalanine (FMLP) or phorbol myristate acetate (PMA) was suppressed with Margarita extract dose dependently with statistic significance at a rate of 67, 41, 34% with FMLP and 42, 33% with PMA in respective dose of 0.5, 1.0, 1.5 mg/2 ml and of 1.0, 1.5 mg/2 ml.
The results suggest that Margarita extract has an anti-oxidative action through suppressing superoxide generation.

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The antiinflammatory and antiallergic effects of CE were evaluated by measuring antigen-induced histamine release from leukocytes and the following results were obtained. (1) CE inhibited his-tamine release from leukocytes at dose dependent manner. (2) Homoaromoline, cepharanoline and aromoline also inhibited antigen-induced histamine release stronger than CE and isotetrandrine sup-pressed histamine release but its suppression was not dose dependent. (3) Cepharanthin, berbamine and cycleanine did not inhibit histamine release from leukocytes with dose dependency.
These results suggest that the main sources of anti-allergic effect of CE were in homoaromoline, aromoline and cepharanoline.

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