Inflammation is the succession of changes of a living tissue to injury and to the cause of injury, which can be regarded as host's defensive reaction and repairing process of the injured tissue. On the other hand, cancer represents a pathologic disturbance of growth characterized by an excessive and unceasing proliferation of cells. It is assumed that when progressive growth of tumor injures the normal tissue active host's defensive reaction against the tumor itself and subsequent injury may be expressed locally as inflammatory response.
Our previous experiments with the autochthonous tumor system of the rat showed clearly that the intensity of the lymphocyte infiltration in the tumor tissue correlates with the tumor specific immune resistance. On the basis of the results, lymphocyte subpopulations and subsets infiltrating in various human cancer tissues were identified with antihuman lymphocyte monoclonal antibodies. It was demonstrated that the grade of lymphocyte infiltration, especially of T cells, in cancer tissue correlates with clinical prognosis. Furthermore, we performed functional analysis of tumor infiltrating cells in rat syngeneic tumor-host system. Various tumor infiltrating cells were shown to play an important role in eradicating the transplanted tumor. Killer/suppressor T cells were demonstrated to be the final effector cells recognizing specifically the target tumor cells. Thus the inflammatory response at the site of tumor can be regarded as the manifestation of host resistance against the tumor.

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Generation of subclasses of leukotrienes (LTs) from peritoneal macrophages of rat under stimulation of calcium ionophore A23187 in vitro is strongly influenced by the time elapsed after the intraperitoneal injection of thioglycollate medium. Peritoneal macrophages collected from mouse, rat, and guinea pig three days after the injection showed specific difference in the generation of LTs under the ionophore stimulation. That is, peritoneal macrophages of mouse and rat produced significant amount of LTC₄ and LTB₄ while those of guinea pig produced only LTB₄. Enzyme solutions from macrophages of the three species converted DNCB to a colored product in the presence of glutathione, while only those of mouse and rat converted LTA₄ to LTC₄ in the presence of glutathione. These results suggest that macrophages of guinea pig lack “LTC₄ synthetase” and also that this enzyme is different from the usual GSH Stransferases. On the basis of the enzyme activity, the subcellular distribution of LTC₄ synthetase of mouse is concluded that it is present mainly in the precipitate of 10⁵×g centrifugation. This enzyme activity can be solubilized by Triton X-100.

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A simultaneous measurement of luminol-dependent chemiluminescence (CL) to two different stimulants, such as phorbol myristate acetate (PMA) and opsonized zymosan (OZ) was developed for evaluating acute and chronic bacterial infections. CL response to PMA (CL_-PMA) was sharply increased and CL_-OZ was moderately increased in the patients with acute bacterial infections, evidenced by sputum bacteriology and cytology in accordance with high fever, leukocytosis and positive C-reactive protein. A ratio of CL_-PMA to CL_-OZ during acute bacterial infections was significantly higher than that of normal adults. When the patients with chronic diseases, such as chronic bronchitis, emphysema, bronchiectasis, lung cancer etc., had acute bacterial infections, the CL responses of them were basically the same as that of acute bacterial infections but the CL_-OZ showed much greater increase than that of acute infections, though a ratio of CL_-PMA to CL_-OZ was similar to that of normal adults.
There was very good correlation between CL_-PMA and CL_-OZ and also between peripheral leukocyte counts and either CL_-PMA or CL_-OZ in patients with acute bacterial infections but not in healthy adults nor in patients with other diseases.

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The biosynthesis of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS) by base-exchange reactions, and of PC and PE by the major pathway (ethanolaminephosphotransferase (EPT) and cholinephosphotransferase (CPT) ), was assessed in the membranes of human leukocyte subsets. Among the three base-exchange activities, ethanolamine-exchange was the highest, and choline-exchange the lowest. In major pathway, EPT and CPT had comparable activities. Among leukocyte subpopulations, T lymphocytes showed the highest levels of each enzyme activity, and neutrophils showed the least. Base-exchange activities were increased by addition of Ca⁺⁺ but inhibited by Mg⁺⁺ while EPT and CPT were inhibited by Ca⁺⁺ but enhanced by Mg⁺⁺. However, each base-exchange was also enhanced by calmodulin inhibitors and inhibited by calmodulin, suggesting that base-exchange reaction is dependent on Ca⁺⁺ but inhibited by Ca-calmodulin complex. Among the enzyme activities tested, PE formation alone was increased by the presence of low concentrations of bioactive stimulants. Our recent reports showed increased ethanolamine-exchange activity in the patients with various inflammatory disorders. These postulate that although its biological significance is unknown, base-exchange activities may be related to cell activation and that PE formation in base-exchange is a precursor of N-transmethylation of PE, leading to the production of arachidonic acid cascade through PC by phospholipase A₂ activity.

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Cytotoxic activity of polymorphonuclear leukocytes (PMN) obtained from synovial fluids of patients with rheumatoid arthritis (RA) was tested on synovial cultured cells obtained from synovial tissues of RA patients in counting the remaining numbers of cells attached to the botton of culture dish. The cytotoxic activity of PMN was not inhibited by superoxide dismutase, weakly inhibited by catalase, but strongly inhibited by a combination of trypsin inhibitor and catalase. The result would suggest that proteolytic enzyme released from are major factors which injure the synovial cells.

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Tranilast (TN) is a drug developed in Japan, and its significant efficacy in allergic disorders has been demonstrated in the IgE mediated allergic reactions, which is mediated by chemical mediators from mast cells. TN suppress the release of chemical mediators, but its effects on mononuclea cells has been obscure. We demonstrated the suppressive effects on TN on human mononuclear cells in vitro studies. TN suppressed the DNA synthesis stimulated by phytohemagglutinin (PHA), polyclonal immunoglobulin (Ig) production by pokeweed mitogen (PWM) and killer T cells induction. Both lymphocytes (PBL) and macrophages (Mφ) were affected. Release of interleukin-1 (IL-1) from Mφ and proliferation of cultured fibroblasts enhanced by IL-1 were reduced, and similar results were obtained in the experiments of interleukin-2 (IL-2) from T cells and in the proliferation of IL-2 dependent cells.
These results indicate the TN has suppressive effects not in the IgE mediated allergic reactions but in other allergic or inflammatoric responses.

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The effects of interferon-β (IFN-β) produced by the recombinant DNA were evaluated on oxygen radical production by human neutrophils stimulated with opsonized zymosan. The oxygen radicals measured in the study were superoxide anions, hydrogen peroxide, and hydroxyl radicals. IFN-β augmented oxygen radical production that had been suppressed after neutrophils were incubated in Krebs-Ringer's solution. The potentiating effect of IFN was greatest with incubation for 3 hrs. In contrast, the function of neutrophils that had been incubated in RPMI 1640 supplemented with 10% fetal calf serum (RPMI) for 3 hrs was comparatively well preserved. Although IFN-β had almost no effect on oxygen radical production by neutrophils incubated without any inhibitor, it augmented that of neutrophils incubated with 50μM Endoxan, or 20μM colchicine. The protective role of IFN-β on neutrophil function was suggested. IFN-β elevated hydrogen peroxide production more markedly than that of superoxide anions or hydroxyl radicals. This difference may be due to induction of cellular proteins such as superoxide dismutase by IFN-β. IFN-β may be useful in the treatment of patients with malignancy whose neutrophil function was impaired by chemotherapy.

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Effect of bradykinin (BK) on the release of met-enkephalin (ME) -like peptides from the rat incisor pulp was examined in in vitro experiments using whole pulp. BK dose-dependently increased the release of ME-like peptides and it was antagonized by Des-Arg⁹- [Leu⁸] -BK, a potent BK-antagonist. High K⁺ did not show any influence on the release. The BK effect was not influenced in Ca⁺⁺-free medium. These findings suggested that effect of BK on the release of ME-like peptides from the pulp was mediated through B₁-receptor and was Ca⁺⁺-independent. In addition, the BK effect was not affected in presence of ouabain, suggesting that the release may be not active. Kyotorphin, an enkephalin releaser in central nervous system, also increased the content and the release of ME-like peptides in and from the pulp. Interestingly, the kyotorphin effect was attenuated by BK and vice versa. This fact may be explained as an interaction between BK and kyotorphin which may be different in mechanism of action. From the results in the present and the previous studies, the hypothesis that ME-like peptides in the pulp might control pain in a negative feedback mechanism was presented.

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Variations in the various trace metals and their reciprocation were investigated in adriamycin-induced nephrotic rats. A dose equivalent to 3 mg/kg BW of adriamycin was administered intraperitoneally to rats, which were then sacrificed at 1, 2, 4, 6 weeks after dosage. A quantitative analysis of copper, manganese, iron and zinc in each organ, blood, feces and urea, in addition to biochemical and histo-pathological observation.
(1) The amount of urea nitrogen, serum creatinine and proteinuria showed a significant increase 4 weeks after dosage. Microscopical examination showed minimal glomeruli alterations and focal glomerular sclerosis.
(2) A high copper content was found in the kidneys and blood 1 week after dosage, and an increase in the urea was also recognized.
(3) The amount of manganese significantly increased in the liver, kidneys, spleen and blood 4 weeks after dosage. The tendency was the same in feces and urea.
(4) The amount of iron in the urea increased 1 week after dosage, and the amount in each organ tended to decrease.
(5) No significant variation in zinc content could be found in the organs, blood, feces or urea.

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Nonobese diabetic (NOD) mice aged 30 to 60 days were orally treated with cyclosporin (Cs) at doses of 25, 15 and 2.5 mg/kg every other day until 160 days of age. Diabetes developed in 12 out of 18 non-treated mice with partial to complete Langerhans' islet destruction associated with remarkable lymphocytic infiltration. NOD mice showed plasma glucose concentration of 140.4±25.2 mg/dl (mean±SD) at 30 days of age. Plasma glucose level of non-treated mice gradually increased therafter to reach 290.3±140.1 mg/dl at 160 days of age, while Cs-treated mice showed neither clear increment of plasma glucose level non development of insulitis.
Subsequently an additional adoptive transfer of spleen cells from Cs-treated mice abrogated the acceleration of development of insulitis observed in young NOD mice aged 30 days which received spleen cells alone from old NOD mice with acute diabetes.
These results suggest that Cs has preventive effect for diabetes in NOD mice and suppressor T cells play a role in mechanisms of the preventive effect.

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We have examined effect of superoxide dismutase on prostaglandin E₂ levels in rat gastric mucosa. After injection of superoxide dismutase, gastric mucosal prostaglandin E₂ levels tend to increase. On the other hand, dimethyldithiocarbamate, an inhibiter of superoxide dismutase lowered prostaglandin E₂ levels. These results suggest that superoxide dismutase may regulate prostaglandin synthesis in rat gastric mucosa.

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Thirty-four mongrel dogs were anesthetized with sodium pentobarbital. The inactivation of various vasoactive substances in the lung was investigated by injecting them into the left ventricle (LV) and into the right ventricle (RV) monitoring systemic blood pressure (P_SYST) and femoral artery blood flow (Q_FEM) . The percentage inactivation of various vaso-active substances was calculated from the difference of P_SYST and Q_FEM responses by injecting them into LV and RV.
1) Prostaglandin E₂ (PGE₂), PGF_2α, leukotriene C₄ (LTC₄), LTD₄, acetylcholine and serotonin were inactivated in the lung. The percentage inactivation of these substances was decreased dose-dependently.
2) In canine lungs of pulmonary embolism induced by glass beads injection, the percentage inactivation of PGF_2α and acetylcholine was significantly low in comparison with normal canine lungs.
3) In canine lungs with left pulmonary artery trunk clumping, the percentage inactivation of PGE₂, PGF_2α, LTC₄, LTD₄, acetylcholine and serotonin was significantly low at the low doses in comparison with normal canine lungs.
Above results suggest that the decrease of pulmonary vascular beds might be the cause of decrease in percentage inactivation of various vasoactive substances following the glass beads-induced pulmonary embolism and the left pulmonary artery trunk clumping.

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Isocarbacyclin (TEI 7165), an analogue of prostacyclin, and its methylester (TEI 9090) were incorporated in lipid microspheres (LM) with a diameter of 0.2μm, in an attempt to increase the efficacy, probably by way of targeting the drugs to the vessel wall. When the two LM-preparations were incubated in 2% BSA-saline, it was shown that TEI 9090 was released from LM much more slowly than TEI 7165. It indicates that TEI 9090 in LM, injected intravenously, may not be released largely in plasma, and delivered to the target sites.
Compared with TEI 9090 as such, TEI 9090 incorporated in LM was more than 500 times more potent as an inhibitor of ADP-induce thrombus growth in the hamster cheek pouch model. These data suggest that prostacyclin analogues incorporated in LM may be used safely as potent antithrombotic agents in the clinical application.

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