The phagocytic leukocytes form the first line of defense against invading pathogens. They find their targets by chemotaxis, a process in which the phagocytes sense the concentration gradients of chemotactic factors released in the vicinity of invading pathogens, and migrate toward their source. Once the phagocytes encounter the targets, phagocytosis begins. During phagocytosis, the phagocytic leukocytes release the lysosomal enzymes, the free radicals of oxygen, and the metabolites of arachidonic acid. These biologically active compounds affect and modulate the inflammatory process. It is the purpose of this article to review the recent advances in this field.

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In this review, some considerations were made on the relationship between bacterial infection and inflammation in the respiratory tract. At first, bacterial pneumonia was discussed comparing the experimental animal models and patients. The lag time was observed between the occurrence of inflammation and the bacterial growth in the lung, and also the inflammatory changes were prolonged after the bacterial clearance by the antibiotic treatment. The use of antiinflammatory drugs may be considered in combination with antibiotics.
Then, chronic bronchiolitis (equall to diffuse panbronchiolitis), which is considered to be representative of chronic respiratory tract infections, was described. The origin and clinical course of this disease were discussed from bacteriological, chemotherapeutical and pathological aspects, and it was shown that our quantitative sputum culture method and inflammatory cytology of sputum were extremely useful for the clinical study of these patients.

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Inflammation in Behçet's syndrome is characterized clinicopathologically by the increase of vascular permeability, the elevated chemotaxis and random mobility of polymorphonuccear leukocytes, and thrombus formation. These findings suggest the possibility that lysosomal enzymes may contribute to the pathogenesis of Behçet's syndrome. The possibility is also supported by the fact that in Behçet's syndrome activities of lysosomal enzymes and protease inhibitors in serum are elevated especially in acute phase. These enzymes are probably released from phagocytic cells, especialy from polymorphonuclear leukocytes. The role of circulating immune complex, lysosomal membrane-labilizing serum factor and accumulation of chemical agent in lysosome has been discussed for abnormal release of lysosomal enzymes.
Colchicine inhibits strongly the mobility of polymorphonuclear leukocytes. It has been administered with satisfactory results, especially on ocular symptoms. Studies of characteristic findings of inflammation in Behçet's syndrome will serve promising roles not only in exploring the pathogenesis but also in establishing the diagnosis and treatment of this syndrome.

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Various cathepsins and other proteases such as plasmin, kallikrein, thrombin and C₁ esterase in the exudate of experimental inflammation with croton oil or carageenan were examined.
The existence of cathepsin D which causes accelration of vascular permiabitity was observed in the exudate. Further, plasmin and kallikrein as a active form were also found. These may be considered as a key enzyme of inflammation, since produce chemical mediators such as kinin or anaphylatoxin.
Various protease inhibitors were examined for a suppressive effect to the above experimental inflammats. Among them, trypsin-like enzyme inhibitors such as FOY or leupeptin showed a suppressive effect. These results strongly suggest that some proteases participate in the process of inflammation.

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Inflammatory models are used for several purposes. Screening of new anti-inflammatory agents is one of the main purposes and the models are commonly used in routine work. For analyses of diseases through inflammatory models and development of new therapy, the models such as rat paw edema, arthrus reaction, Masugi nephritis, adjuvant arthr itis, are useful, but one should realized that one model cannot cover the whole process of one disease and a certain model may simulate a certain phase of the inflammatory process of a disease.
Rheumatoid arthritis is known to be a chronically progressing, proliferative inflammation. In an acute exacerbation phase of the disease, however, plasma kallikrein-kinin system is activated insinovial fluid with signs of acute inflammation. Even in an acute exudative inflammation, such as rat carrageenin-induced pleurisy, mediators which appear in exudate are different from time to time. In the pleurisy, 6-keto-PGF_1α, PGE₂ and TXB₂ appeared successively in the pleural fluid in the first 1-7hr after carrageenin and PGE₂ played the min role in exudation. Plasma kallikreinkinin system also took more important part in an accumulation of the pleural fluid. Thus, analyses of inflammatory models are necessary for development of therapeutic drugs and selection of suitable period in administration of anti-inflammatory agents.

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Among a number of inflammations in experimental animals we selected air-pouch inflammation induced in the subcutaneous tissues on the dorsum of rats as the most suitable type in analysing mechanisms of the inflammatory processes involving acute exudative phase but aslo chronic prolifrative phase of the inflammation. About 8 ml of air is injected on the first day and then various phlogistic stimuli are applied in the air sac already formed. Carrageenin solution, zymosan suspension in carboxymethyl cellulose (CMC) solution and azobenzenearsonate-conjugated acetylbovine serum albumin solution in CMC solution of pre-sensitized animals have been studied as th phlogistic stimuli.
Vascular permeability can be measured with the aid of radioiodinated human serum albumin as a tracer, which is injected intravenously and then leaked into the fluid in the air pouch. Infiltration of leucocyte is measurable by taking the fluid in the locus of air-pouch inflammation. The pouch fluid canbe used as a sample for a variety of chemical analyses. Proliferative processes are also measurable by taking granulation tissues as a capsule growing around the air pouch. Minced granulation tissues are suitable in investigating incorporation of various labeled precursors into macromolecular components of the tissues.

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The localization and appearance of mast cells of acute and chronic inflammatory processes of the paranasal lesions in the cases of chronic sinuitis were examined pathohistologically in this paper.
Mast cells were seen around and/or attached to the small blood vessels in the connective tissue. Mast cells were easily found in the acute exsudative inflammatory foci, but scarcely in the areas of lymphocytic, plasmocytic, and histiocytic infiltration of the chronic inflammatory stage. Mast cells were found scatteredly in the areas of the proliferation of collagen fibers or fibrosis.
In the acute inflammatory process with neutrophilic and eosinophilic infiltration mast cells showed the degranulation and the degrees of the degranulation of mast cells varied. The mast cells were occasionally seen as the clear cells.
It seems that mast cells have active behaviours in the early stage of the inflammatory processes and play an important role in fibrosis in the repair stage of the inflammatory processes human-pathohistologically.

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The significance of inhibitors in the coagulation-fibrinolysis system was examined by inducing experimental inflammation with carrageenin. Fastacting plasmin inhibitor, α₂-plasmin inhibitor (α₂-PI), was recently discovered in human blood and it was stated that such α₂-PI represents the most sensitive and specific inhibitor of plasmin. The possible role of α₂-PI has been studied in detail in vitro and in vivo in relation to the thrombolytic condition and bleeding based on hyperfibrinolysis. However, the significance of α₂-PI has not been clarified for the inflammatory state and diseases. In the present study in order to clarify the possible role of α₂-PI in inflammatory responses, the antiplasmin activity in the plasma and local fluid (exudate) was investigated using an animal model of inflammation. After subcutaneous injection of carrageenin into the dorsum of rats, on day 7 and 21, the antiplasmin activity in the plasma was significantly higher than that in the plasma of non-treated rats (P<0.001) . However, the antiplasmin activity in the plasma on day 7 was not significantly different from that on day 21. On the other hand, the antiplasmin activity in the exudate on day 21 was significantly lower than that on day 7 (P<0.001) . Based on these results, it is suggested that the antiplasmin in the inflammatory exudate was cosumed during the inflammation to form the hard wall of the carrageenin pouch.

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In order to investigate the usefulness of the clamping method as an inflammation model, the healing process of clamp-induced gastric muco-muscular defects in rats were observed. Furthermore, the effects of several antiinflammatory drugs on the healing process were studied quantitatively.
Male Wistar rats weighing 200-250 gm. were used. An acute gastric muco-muscular defect was produced with a special 12 × 4 mm metal clamp applied for 24 hours. Tested drugs were given 7 days after clamping.
Histological findings showed inflammations such as submucosal edema, and infiltration of polymorpho-nuclear cells in the margin of the mucosal defect in the early phase while granulation was observed in the base of the mucosal defect in the late phase.
The tested anti-inflammatory drugs adversely influenced the gastric muco-muscular defect in the following ways. Cortisone acetate inhibited mucosal regeneration and granulation while prednisolone and indomethacine inhibited only the mucosal regeneration. Aspirin and phenylbutazone inhibited regeneration to a lesser degree. D-penicillamine didn't have any adverse effects on either regeneration or granulation.
The clamping method is useful as an inflammation model as well as a way to check the adverse effects of anti-inflammatory drugs.

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The local anti-inflammatory effects and the systemic effects, including the reduction of the thymus weight, of 17α, 21-diacetoxy-2-bromo-6β, 9α-difluoro-11β hydroxy-1, 4-pregnadiene-3, 20-dione (F-2) were compared with those of fluocinolone acetonide and hydrocortisone acetate by granuloma and granuloma pouch methods. Fluocinolone acetonide and hydrocortisone acetate reduced the thymus and adrenal weights and inhibited the body weight gain at the same doses as they inhibited the formation of granuloma or the accumulation of pouch fluid. F-2 showed an intensive loca anti-inflammatory activity with negligible systemic effects at 25-125 times the minimal effective dose.
After the injection of F-2 into the N₂-gas pouch formed on the dorsum of rats, the residual level of F-2 at the injection site was mesured. F-2 showed a marked locally residual property and it's residual per cent was about 75% on the 7 th day and 50% on the 30 th day.

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Alpha₁-Antitrypsin (α₁-AT) level has been studied using the single radial immunodiffusion in 406 children with various infectious or inflammatory diseases from 1976 to 1980.
The level of α₁-AT as a component of acute phase reactant elevated over 600 mg/dl was observed in patients with Kawasaki disease (MCLS) and pyothorax. Only 31 patients in the 406cases had the level over 600 mg/dl and 27 of the 31 patients were MCLS and pyothorax. The α₁-AT level of MCLS was 704.8±114.1 mg/dl (n=19), and that of pyothorax was 719.2±119. 7 (n=13) in contrast to the other levels, 373.5±61. 6mg/dl of pneumonia (n=86), 280.5±60. 6 mg/dl of streptococcosis (n=11) or 254. 8±43. 2 mg/dl of normal children (n=127) .
The high level of α₁-AT in MCLS and pyothorax was apparent and its correlation with each clinical course was clearly observed. We concluded that α₁-AT was useful indicator of acute phase reactant especially in MCLS and pyothorax. The reason of the high level was not determinded but the relation to the lung damage in pyothorax, and the relation to the disseminated vasculitis in MCLS was postulated subsequently.

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In the textbooks of immunology, immune reactions were described in 5 types of allergic or hypersensitivity reaction, i.e. I (anaphylactic), II (antibody-dependent cytotoxic), III (complexmediated), IV (cell-mediated or delayed), and V (stimulatory) . Antigen and antibody involved, reaction time, histopathological characteristics, clinicl test, disease examples are also weiten in each type respectively.
Immunopharmacology is a newly developed science and progressed rapidly as immunology did. Many investigators are analyzing effects of the drugs on each immune responsive cell. Immunomodulators are understood to possess suppressive effect on hyperimmunity state, augmentative effect on hypoimmunity state, and no effect on normal immune state. Thymostimulin (TP-1), and thymopoietin (TP-5), as thymic hormones; levamisole (LMS), D-penicillamine (D-Pc), mercapto-methylpropanoyl cystein (SA-96), gold salt thiomalate (GST), and auranofin, as SH compounds; carboxyphenyl chloroanthranilic acid (CCA), traxanox, and methyocobalamin (CH₃B₁₂), as others; were discussed in this report immunopharmacologically. No paper had described relationship between immunomodulators and 5 types of hypersensitivity reaction. The drugs had suppressive or augmentative or no effect on the 4 types (I, II, III, IV) of hypersensitivity. The effects might not be the yield of single immune responsive cell but the result of the reactions of several immune responsive cells in the respective types of reaction.
Analysis of effects of the immunomodulators on the different types of hypersensitivity reaction possibly elucidate the mechanism of the drugs and diseases to be applied.

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Arthritis, myositis, serositis and fever are regarded as inflammatory manifestations in PSS. The purpose of this study is to clarify the clinical significance and immunological background of those inflammatory manifestations.
Arthritis was observed in 22 of 60 patients with PSS. A group of patients with arthritis revealed significantly higher frequencies of rheumatoid factor and RNP antibody but lower frequency of Og antibody than the other group of patients. Myositis was observed in 6 patients including 2 patients who had Jo-1 antibody which was only detected in polymyositis patients. Pericarditis defined clinically was found in only 2 patients, but pericardial effusion was demonstrated in 8 of 30 patients using echocardiography.
A group of patients with at least one of those inflammatory manifestations was not associated with the manifestations based on fibrotic and severe vascular changes. The high frequencies of the immunological abnormalities including hypergammaglobulinemia, (19/24), rheumatoid factor (21/24) and RNP antibody (12/22) were demonstrated in this group. Those findings suggested that a humoral immune abnormarity may be a factor in the pathogenesis of inflammatory manifestations in PSS.

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[in Japanese]

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[in Japanese]

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