Urinary trypsin inhibitor (UTI) is glycoprotein which is excreted in urine small amount in healthy subjects. Faarvang reviewed in 1965 that excretion of UTI in urine increased during various disease states, such as, bacterial infection, malignant neoplasma with metastasis, myocardial infarction, surgical operation, normal pregnancy, acute pancreatitis, and renal diseases.
Thereafter, studies were carried out to investigate the apparent polymorphism of UTI, and to determine and characterize the amino acid sequence and cDNA structure of UTI. In addition to trypsin-inhibitory activity, UTI has been elucidated to have many biological activities including; inhibition of proteinases other than trypsin, stabilization of shock, improvement of acute pancreatitis, and endothelial cell growth factor. In recent works, however, UTI seems seldom to be cited in relation to an acute phase reactant.
We were able to carry out the automated measurement of UTI which was suggested to be useful for clinical diagnosis of acute phase of various conditions and renal diseases.

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Clinical effects of methotrexate on rheumatoid arthritis have been repeatedly confirmed by double blind controlled trials. Clinical activities definitely improved as early as 3 weeks of treatment. It was also shown that most of the patients resistant to gold, penicillamine or the other disease modifying drugs, responded to this drug. Although mechanisms of action of methotrexate on rheumatoid arthritis has not been clarified yet, both immunosuppressive and anti-inflammatory effects seems to be involved. Rare but severe side effects include bone marrow suppression, pneumonitis and liver fibrosis, while common but mild side effects are gastrointestinal symptoms and stomatitis.
Indication of methotrexate should be restricted only to severe cases, and careful monitoring of patients is essential during methotrexate administration.

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Experimental liver injury models were produced by the injection of anti-basic liver protein (BLP) antibody into DBA/2 mice, by the injection of bacterial LPS into Corynebacterium parvum-pretreated ddY mice, and by the injection of CCl₄ into ddY mice. In all models, extensive liver cell damage was estimated by the elevation of glutamate transaminase (GOT and GPT) activity and confirmed by significant histopathological changes of liver. Moreover, significant elevation of TxB₂ in the liver was observed in all models.
Administration of OKY-046, a selective TxA₂ synthetase inhibitor, ONO-3708, TxA₂ receptor antagonist, and indomethacin, cyclooxygenase inhibitor, suppressed the elevation of GOT and GPT levels and histopathological changes in almost liver injury models. In addition, when U-46619, a stable TxA₂ mimetic compound, was injected into mice, clear elevation of GOT and GPT was observed. These evidences suggest that TxA₂ play an important role for the onset of liver injury disease in mice.

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The transnasal administration of the extract of a parasite Ascaris suum (Asc) to mice for 3 weeks produced marked eosinophilia in the broncho-alveolar lavage (BAL) fluid. Among several strains of mice, C57BL/6 developed the most eosinophils in the BAL. C57BL/6-nu/nu mice failed to develop the pulmonary eosinophilia.
The oral administration of cyclosporin 50 mg/kg body weight every other day significantly suppressed the accumulation of eosinophils in the lung. These data indicate that the pulmonary eosinophilia caused by Asc is dependent on T lymphocytes. The mast cell deficient (WB×C57BL/6) F₁-W/W^v mice developed marked eosinophilia in the BAL, which shows that mast cells are not necessary in the formation of eosinophils in this model.

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Blood was drawn into a heparinized syringe from healthy human volunteers and leukocytes were isolated by sedimentation in the presence of 6% dextran. After then, neutrophils and eosinophils were purifid on a Conray-Ficoll and Percoll gradient respectively. Rat serosal mast cells were also purified on a Percoll gradient. The cells were incubated with N-formyl-methionyl-leucyl-phenylala-nine (fMLP) and O^-₂ generation was measured by 2-methyl-6- [p-methoxyphenyl] -3, 7-dihydroimidazo [1, 2-a] pyrazin-3-one (MCLA) -dependent luminescence.
Addition of 0.5μM MCLA and 10^-6 M fMLP to a suspension of neutrophils caused a marked luminescence within 1 min, which was inhibited by 0.5μM superoxide dismutase (SOD) . The luminescence intensity was dependent upon the number of neutrophils and the maximal luminescence intensity was given at 10^-6 M fMLP with a fixed numbers of the cells (1×10⁵) .
Biphasic luminescence light intensities were observed by 10^-6 M fMLP-stimulated neutrophils and eosinophils in the presence of 5μg/ml cytochalasin B and either of them was inhibited by 0.5μM SOD.
On the other hand, addition of 0.5μM MCLA and 10^-6 M fMLP to a suspension of rat serosal mast cells showed no significant luminescence even in the presence of cytochalasin B, suggesting the absence of fMLP receptor on the mast cell membranes.

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Adhesion of blood cells to the vascular endothelium with subsequent migration into the vessel wall or the interstitial space is the initial step characterizing the acute inflammation responses. A significant role for the monocyte-macrophages (Mφ) in atherogenesis is now well accepted. To study this phenomenon we examined the interaction of Mφ with cultured vascular endothelial cells as well as Mφ-derived chemotactic activity of Mφ. The interaction could be modulated by temperature and divalent cations. Pretreatment with LDL and VLDL increased adhesion of Mφ to endothelial cells. Mφ from hypercholesterolemic animals showed enhanced attachment to the endothelial cells; they moved more quickly when examined by time-lapse cinephoto-micrography.
Mφ in culture secreted potent chemotactic factors to Mφ; chemotactic properties of Mφ to the autoconditioned media were remarkably increased when animals were exposed to hypercholesterolemia.
Finally, results obtained by an in vitro model of a blood vessel wall consisting of human umbilical vein endothelial cells cultured on human amnion were briefly described. The methods utilized herein to study atherogenesis would also provide useful and relevant models for in vitro study of inflammation.

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The precise role of neutrophils in adult respiratory distress syndrome is not yet clear. Endotoxin administration is known to induce the permeability pulmonary edema with neutrophil migration into alveolar spaces. Leukotriene B₄ is known as a strong chemotactic factor. To clearify the roles of neutrophils on pulmonary microvascular injury, we compared the effects of endotoxin and leukotriene B₄ on lung lymph dynamics and neutrophil migration. Endotoxin caused increase in microvascular permeability and migration of neutrophils into alveolar spaces.
Whereas leukotriene B₄ did not affect lung microvascular permeability. Neutrophils in broncho-alveolar lavage fluid after leukotriene B₄ administration increased to the same value as which after endotoxin administration. These results suggest that the neutrophil migration into alveolar spaces is not essential to develop the permeability pulmonary edema.

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Metabolism of eicosapentaenoic acid (EPA) and effect of EPA on arachidonic acid (AA) metabolism in human blood monocytes in vitro were examined. Highly purified monocytes were preparated by an improved method in which hypertonic treatment was employed. Metabolism of EPA in monocytes stimulated with calcium ionophore A 23187 was studied compared with that of AA. 5-lipoxygenase (5-LO) metabolites of AA or EPA were separated and quantitated by reverse phase-HPLC (RP-HPLC) . Production of leukotriene B₄ (LTB₄) and 5-hydroxyeicosatetraenoic acid (5-HETE), AA derived metabolites, were inhibited and formation of LTB₅ and 5-hydroxyeicosapentaenoic acid (5-HEPE), EPA derived metabolites, were increased dose dependently by the addition of exogenous EPA (1.0-5.0μg/ml) in A 23187 stimulated monocytes.
The current data indicate that EPA is a good substrate for 5-LO and is metabolized to LTB₅ by A 23187 stimulation and also inhibits production of LTB₄ in monocytes. It is well known that monocytes play an important role in inflammation and immune response, so that EPA might exert its antiinflammatory or immunomodulatory effect through the modulation of production of 5-LO metabolites especially LTB₄ and LTB₅ in monocytes.

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Recombinant human granulocyte colony-stimulating factor (Re Hu G-CSF) was prepared and its stimulating effect on granulocytopoiesis was examined in mice. Human G-CSF was purified to homogeneity from conditioned media of a G-CSF producing cell line. The amino-terminal sequence was determined. By using oligonucleotides as probes, which were proposed by the amino acid sequence, a cDNA library preparcd from human macrophages was screened. The cloned G-CSF cDNA was expresscd in E. coli K12MM294, and the mature protein was purified to homogeneity. Mice were given intraperitoneal injections of Re Hu G-CSF everyday for 14 days. Peripheral blood granulocyte counts were examined after 4, 8, 12, and 14 days of injection. Mice were sacrificed on the 14th day for histologic examinations of bone marrow, and spleen. Granulocyte counts began to increase on the 4th day and reached about 80, 000/mm on the 14th day. Cells of granulocyte lineage were markedly increased in the bone marrow and spleen. Granulocyte precursors (CFU-C) were remarkably increased in the spleen. When mice were treated with 5-fluorouracil, cyclophosphamide, or irradiation, the period of granulocytopenia was significantly shortened by subcutaneous injections of Re Hu G-CSF.
These results suggest that human G-CSF play a central role in granulocyte production in vivo. The ability of Re Hu G-CSF to stimulate granulocyte production implies that this factor will be clinically useful in neutropenic patients treated with anti-cancer agents or irradiation.

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We have observed the clinical effects of interleukin 2 (IL-2) therapy for Epstein-Barr (EB) virus infection in two children with immunodeficiency syndrome. A 13-year-old boy with Shwachman's syndrome had chronic active EB virus infection. There were defective lymphokine-activated killer (LAK) cell and cytotoxic T lymphocyte (CTL) activities against autologous EB virus-transformed B cells and a marked decrease in IL-2 production. He received recombinant IL-2 (1, 000 U/day) by intra-venous drip infusion for 14 days. There has been a clinical improvement in the development of pneumonia, splenomegaly and exanthema after the therapy. There were, although transient, a decrease in VCA-IgG antibody titers and sero-conversion of EBNA antibody. A 14/12-year-old boy with fatal EB virus infection was treated by adoptive immunotherapy with his own CTL generated against autologous EB virus-transformed B cells in the presence of recombinant IL-2. There were no LAK cell and CTL activities against the EB virus transformed B cells and no IL-2 production. Unfortunately, he died from the preexisting pneumonia soon after the therapy. However, EB virustransformed B cell lines, which had been easily established from his peripheral blood mononuclear cell cultures, were never established after the therapy.

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We reported in a preceding paper that Lobenzarit-2Na (CCA) affected RNA polymerase-I activity in nuclear suspension prepared from rat hepatocytes. This effect of CCA on RNA polymerase-I was thought to be the secondary effect, that is, CCA primarily modified the reactivity of cytoskeletal components around the nuclei.
Previously it was also reported that CCA inhibited the IL-1 production by LPS-stimulated macrophages. So we studied whether CCA could modify the cytoskeletal re-organization process in LPS-stimulated macrophages or not.
Results reported here show that microfilament system in macrophages changes its configulation in a biphasic manner within 10 min after LPS stimulation. CCA reduced the magnitude of this configurational change without affecting the timing of process.
Because CCA could be transported into macrophages through some kind of carrier in plasma membrane, this effect of CCA on microfilament system was likely to be the direct action in cytoplasm.

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Topical transdermal delivery (absorption) system for flurbiprofen (FP-A) was evaluated with the aim of providing treatment to relieve inflammatory symptoms in localized sites with reduced systemic side effects. The present double dummy method of double blind comparative clinical trial was attempted to study the degree of usefulness of FP-A on acute subjects suffering post-traumatic inflammation and pain. Ibuprofen (IP) tablets were used as the reference drug. All cases studied were housed under the same conditions. Below are the results obtained;
(1) Of the total 185 cases, 154 registered general consequent improvement with overall safety index seen in 176 cases and 155 cases were noted beneficial on analysis of the subjects studied.
(2) For the cnsequent generally improves, 81.5% (66/81 cases) for FP-A group and 76.7% (56/73 cases) for IP tablet group registered above “good improvement”. The improvement was about the same for both groups, confirming hence the efficacious effect on the use of FP-A.
(3) As regards to overall safety index, only 1.2% (1/86 cases) of the IP tablet group and none of FP-A group were categorized as “having problems in safety index”. This confirms the high safety margin on the use of FP-A.
(4) For degree of usefulness, 79.0% (64/81 cases) and 75.7% (56/74 cases) indicated “good useful” in the FP-A and IP tablet groups, respectively. There was no statistical significance between the 2 groups. Though both groups showed somewhat similar effective and beneficial uses, it is believed that the FP-A group can possibly excel over the IP tablet group judging on the side effects induced, number of administrations that can be reduced with improved compliance on the patients' side.

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