A review on the mechanism of anti-inflammatory actions by glucocorticoids, especially focused on the anti-inflammatory protein proposed by Tsurufuji which includes lipocortin, vasoregulin and vasocortin. A prospect concerning on these proteins is discussed.

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Purified chick type II collagen (CII) was cleaved with cyanogen bromide and the resulting CB-peptides isolated and renatured. Sera from collagen-induced arthritic DBA/1 mice and patients with rheumatoid arthritis (RA) were tested for the reactivity with each CB-peptide and mouse or human type II collagens (MII and HII, respectively) . The mouse sera preferentially recognized CB-11, 10 and 8, in that order, and there was a positive correlation between reactivity with CB-11 and MII, but no correlation was found with any other peptides. CB-11, 10 and 8 were also used for immunization to test the immunogenesity and arthritogenesity. Antibodies were detected in response to each of these peptides, but arthritis developed only in mice immunized with CB-11.
RA sera which are reactive with HII crossreacted with CII at a correlation coefficient of 0.97 (P<0.001) . And the sera mainly recognized CB-11 and 10, indicating the common epitopes on HII and CII molecules are located on the region of CB-11 and 10. We conclude that a major immunogenic and arthritogenic epitope on type II collagen resides in the region of the molecule represented by CB-11 in collagen-induced arthritis. And a similar immune-recognition should be involved in pathogenesis of rheumatoid arthritis in human.

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To elucidate the effects of disturbances of the pulmonary circulation on the formation of pulmonary emphysematous bullae, we studied changes in the parenchyma of the lungs insulted by both pulmonary embolization with Sephadex beads and carrageenan-induced pneumonia in rabbits. The treated lobes of the lungs showed severe carrageenan pneumonia and pulmonary embolism in earlier stages (at one or two week), large to small emphysematous bullae, at 1, 2, or 3 month, and small ones and severe irregular emphysema at 4 month. More animals had bullous lesions in the groups given the larger doses of Sephadex and killed at 2 months while a few in the groups given the smaller or none of Sephadex had them. Rabbits given larger doses of Sephadex and killed at 2 months had also giant bullous lesions or multiple bullous lesions, while few animals given smaller doses of it had giant or multiple lesions.
These results suggest that the size and number of bullous lesions forming in the treated lobes depends to a certain degree on the dose of Sephadex. Giant and small bullous lesions are varieties of the same disorder, and disturbances of the pulmonary circulation are associated with the formation of bullous lesions.

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An experimental liver injury was produced in mice by injection of a sub-hepatotosic dose of anti-basic liver protein (BLP) antibody after immunization of rabbit IgG (RGG) . Strain DBA/2 mice indicated the highest susceptability to the disease. Typical histopathological changes in the liver were submassive hepatocellular necrosis and infiltration of granulocytes and lymphocytes into the portal tract and sinusoid in necrosis lesion. Administration of either prednisolone (10 and 20mg/kg), cyclophosphamide (5 and 10mg/kg) or cianidanol (500 and 1000mg/kg) for 10 days prior to injection of anti-BLP antibody suppressed development of liver injury. These results suggest that the experimental liver injury model in DBA/2 mice is useful for immunopharmacological studies of liver diseases.

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Serum sickness nephritis was induced by repeated i.v. injections of rabbit serum albumin into rat. Blood was drawn from abdominal artery and renal vein. In whole blood, platelet aggregability was determined at 2, 6, 8 and 12 weeks after the preimmunization. Nephritic rats were treatment with oral dipyridamole, 100 and 400mg/kg, for 3 days, and then the platelet aggregability was determined. At the beginning of experiment, normal rats showed 9.9 ohms in arterial blood and 9.2 ohms in renal blood as platelet aggregability, respectively. At the 2nd week, the rats challenged with the first antigen had the increased platelet aggregability in arterial blood and decreased one in renal blood. Then, platelet aggregability in both blood gradually augumented with day. In the 12th week, proteinuric rats showed 14.2 ohms in arterial blood and 9.6 ohms in renal blood. Dipyridamole, 400mg/kg, inhibited platelet aggregability by about 50% as compared with the control in both blood.

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Macrophages in synovial fluid of patients with rheumatoid arthritis (RASF-Mφ) released prostaglandin E₂ (PGE₂) when they were stimulated by lipopolysaccharide (LPS), aggregated-IgG (Agg-IgG) and opsonized-Zymosan (Zymosan) . Monocytes in peripheral blood of patients with rheumatoid arthritis (RA-Mo) and normal subjects (healthy-Mo) similarly released PGE₂ when they were stimulated by LPS, Agg-IgG and Zymosan. Healthy-Mo released more amount of PGE₂ than RA-Mo. The reduced PGE₂ release of RA-Mo might be due to the effect of nonsteroidal antiinflammatory drugs taken by RA patients. Polymorphonuclear leukocytes (PMN), in synovial fluid and peripheral blood of patients with rheumatoid arthritis along with PMN of normal subjects, released little PGE₂.

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Human neutrophils exist in blood and take part in defense mechanisms of the body.
In this study the generation of heat produced by neutrophils was measured using thermoactive analyzer ESCO-3000. When neutrophils phagocytyzed zymosans, they generate heat in proportion to the amount of zymosan added. Cytochalasin B could reduced generation of heat from 17.6μW down to 2.8μW. Similar result was obtained when IgG-coated latex was used as an inducer. Phorbol myristate acetate (PMA) and Ca-ionophore A 23187 also could stimulate neutrophils to produce heat, but N-fomyl-L-methionyl-L-leucyl-L-phenylalnine (FMLP), and concanavalin A (Con A), failed to produce heat from neutrophils even when large amounts of FMLP and Con A were challenged. These phenomena suggest FMLP and Con A activate different metabolic pathways from zymosan, PMA or Ca-ionophore.
These results, suggest that cellular membrane of granulocytes can recognize foreign substance electrically and physiologically, and after these foreign substances combine with the ligands of the membrane, structural changes of the membrane occur, and various substances such as Ca ^_??_, phospholipid metabolite and, cyclic nucleotides become transmitter, and produce heat inside neutrophils.

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The regulation of tissue eosinophilia in allergic skin lesions were examined using chemotactic chamber assay. Tissue eosinophilia manifested two phases: early phase peaking at 6hr and delayed phase at 24hr. More potent delayed phase was mediated by two different eosinophil chemotactic factors, delayed ECF-a and b. Delayed ECF-a was shown to be a lymphokine produced by T lymphocytes through antigenic or mitogenic stimulation, whereas delayed ECF-b was produced by reaction with anti-hapten IgG1 antibody. The Delayed eosinophilia was suppressed completly when animals were treated with complete Freund's adjuvant. This suppression was due to the production of eosinophil-directed chemotactic inhibitory factor (ECIF) which selectively inhibit the chemotactic response of eosinophils to delayed ECF-a but not to delayed ECF-b.
On the other hands, tissue eosinophilia was markedly potentiated when animals were treated with alum hydroxy gel or Bordetella pertussis vaccine. This potentiation was ascribed to the potentiation of delayed ECF-a production by T lymphocytes. Macrophage products, named ECF-potentiating factors, could potentiate ECF-production but not macrophage chemotactic factor production. These results suggested that tissue eosinophilia, especially by a lymphokine (delayed ECF-a), is regulated by a lymphokine (ECIF) selectively, and that macrophage products are involved in the ECF production.

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Bradykinin-inactivating activity of mononuclear leukocytes was examined using guinea-pig macrophages and lymphocytes. Intact macrophages rapidly inactivated bradykinin. Bradykinin-inactivating activity of macrophages was present in the membrane and cytosol fractions but not in the nuclear and granular fractions. The bradykinin-inactivating activity of the membrane fraction was inhibited by captopril, whereas that of the cytosol fraction was inhibited by N-ethylmaleimide. Bradykinin-inactivating activity of intact macrophages was inhibited by captopril but not by N-ethylmaleimide, suggesting that the membranebound bradykinin-inactivating enzyme rather than the cytosol bradykinin-inactivating enzyme is responsible for the inactivation of bradykinin by intact macrophages. Although intact lymphocytes hardly inactivated bradykinin, lymphocytes contained a bradykinin-inactivating activity in the cytosol fraction but not in the nuclear and particulate fractions. The bradykinin-inactivating enzyme of the lymphocyte cytosol fraction was inhibited by N-ethylmaleimide, and this enzyme was hardly released extracellularly from intact cells during incubation of lymphocytes with bradykinin.

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Leukotriene (LT) C₄ in the synovial fluid of patient with osteoarthritis deformans (OA) and rheumatoid arthritis (RA) was measured by radioimmunoassay after its extraction with Sep-Pak C₁₈ cartridge. The amounts of immunoreactive LTC₄ (i-LTC₄) in samples from patients with OA and RA were not significantly different, being 0.198±0.018 pmol/ml (n=11) and 0.179±0. 016 pmol/ml (n=12), respectively. By high performance liquid chromatography and radioimmunoassay, the levels of other sulfidopeptide LTs, such as LTD₄ and LTE₄, in synovial fluid from patients with RA were found to be significantly higher than those in fluid from patients with OA. The leukocyte number in synovial fluids was not correlated with the i-LTC₄ level.
The metabolic activities of these synovial fluids were determined by incubating them with ³H-LTC₄ and then separating sulfidopeptide LTs by high performance liquid chromatography. LTC₄ was found to be converted by γ-glutamyltranspeptidase activities to LTD₄ which was further metabolized by dipeptidase of synovial fluid to LTE₄. The conversion of LTC₄ to LTD₄ in synovial fluids of patients with OA and RA were similar, but the dipeptidase activity converting LTD₄ to LTE₄ was higher in fluid from patients with RA. It is suggested that a high level of LTE₄ may play cause exudation of synovial fluid, since LTE₄ has a strong effect in increasing vascular permeability.

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The effect of halothane (2-bromo-2-chloro-1, 1, 1-trifluoroethane), an inhalation anesthetic, on the formation of leukotriene B₄ (LTB₄) was studied in human polymorphonuclear leukocytes stimulated with calcium ionophore A23187. Halothane inhibited the formation of LTB₄ in a dose-dependent manner and the inhibition was restored by the removal of halothane.

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An accelerated (lymphoma-like) phase is characteristic of Chédiak-Higashi syndrome (CHS), and it may develop in consequence of reactive rather than neoplastic response.
The accelerated phase was studied in two children with CHS by the electron microscopic and histological methods. The electron microscopy of the bone marrow in the accelerated phase and the histological examination at autopsy demonstrated prominent phagocytosis of erythrocytes and nucleated cells as well as mononuclear cell infiltration. The phagocytosis of autologous blood cells was particularly prominent in the tissues from the bone marrow, liver, spleen and lungs.
Peripheral neutrophils and monocytes of CHS were demonstrated to ingest autologous leukocytes and erythrocytes when they were mixed with bacteria in vitro. Such distorted phagocytic ability of CHS phagocytes appears to be related to the prominent phagocytosis of blood cells in the accelerated phase, being responsible for pancytopenia.

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In order to disclose the effect of “KANPO-YAKU” on immune responses, we investigated the induction of anti-SRBC response (PFC assay) in the spleen cells of BDF1 female mice which received Tsumura-Juzentaihoto (TJ-48) . TJ-48 induced an augmentation of anti-SRBC response by oral administration once a day for 7 consecutive days in a dose dependent manner. The maximum induction of anti-SRBC response was seen by 7 days-administration of TJ-48 (2 g/kg/day) and no further increase was obtained by longer treatment. After withdrawing TJ-48, the augmentation of anti-SRBC response was maintained for 3 days and disappeared by 7 days after the withdrawal. The anti-SRBC response was enhanced whether immunization with SRBC was done in vivo or in vitro.

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