When cells are stimulated by various stimuli, phospholipase A₂gets activated, and it causes liberation of arachidonic acids from phospholipids in cellular membrane. The released arachidonic acids are then converted to various leukotrienes by 5-lipoxygenase as well as being transformed into various prostaglandins and thromboxanes by cyclooxygenase. The leukotriens are produced mainly by various kinds of blood cells, and have been found to be deeply involved not only in allergy and asthma but also in inflammation. Leukotriene C₄, D₄and E₄were disclosed to cause an increase in vascular permeability, while leukotriene B₄ was revealed to have a remarkably strong capacity for leukocyte migration. On the other hand, the action mechanism of glucocorticoids in anti-inflammation was clarified. According to recent studies in this field, glucocorticoids were found to induce certain protein named lipomodulin or macrocortin which possesses anti-phospholipase A₂activity. Therefore, glucocorticoids can block both cyclooxygenase and lipoxygenase pathways of arachidonic acid, and it causes stronger anti-inflammation than that caused by non-steroidal anti-inflammation drugs which can block only cyclooxygenase pathway of arachidonic acid. Recently some new spesific inhibitors for 5-lipoxygenase were reported. These are 5, 6-dehydroarachidonic acid, esculetin, 5, 6-methanoleukotriene A₄, AA-861, caffeic acid, U-60, 275, eupatilin, 4'-demethyleupatilin and so on. Some of these drugs may become useful tool for inflammation study.

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The effect of hydrochloric acid, tetragastrin, and cimetidine, a H₂-receptor antagonist, on endogenous prostaglandin E₂ (PGE₂) and prostacyclin (PGI₂) in rat gastric mucosa was investigated. Intragastric instillation of 0.25 N HCl increased PGE₂by about 2 times in both fundic and antral mucosa, and inhibited ulcer formation induced by subsequent instillation of a necrotizing agent (0.6 N HCl) . Tetragastrin (4 μg/kg, subcutaneously) also increased PGE₂and PGI₂in both fundic and antral mucosa 15 minutes after administration, and also inhibited ulcer formation induced by subsequent instillation of 0.6 N HCl. Cimetidine in a non-antisecretory dose (2 mg/kg, intraperitoneally) exerted no effect on endogenous PGE₂, while in an antisecretory dose (100 mg/kg), the agent decreased PGE₂by 72% in fundic and 84% in antral mucosa. These results suggest that acid induces those cytoprotective PGs and enhances mucosal integrity.

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Recent evidence suggest that renal tissue has a capacity to synthesize prostacyclin (PGI₂) and thromboxane A₂ (TXA₂) as well as clasical prostaglandin (PG), PGE₂and PGF_2α, These metabolites of arachidonic acid influence the renal hemodynamics when applied into the renal artery; PGE₂and PGI₂are renal vasodilators and TXA₂may be renal vasoconstrictor. In this literature, we will review the role of endogenous prostanoids in altering renal blood flow.

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In vitroandin vivoeffect of eicosapentaenoic acid (EPA), a potent anti-platelet aggregatory substance, on arachidonic acid metabolism in rat peritoneal macrophages was studied.In vitrostudy demonstrated that EPA decreased dose-dependently the release of¹⁴Carachidonic acid (AA) from¹⁴C-AA prelabeled macrophages and the conversion of the released¹⁴C-AA to its cyclooxygenase and lipoxygenase metabolites. This may indicate the impairment of release mechanism of AA from macrophage membrane phospholipids. In addition an increased ratio of lipoxygenase products to cyclooxygenase products by addition of EPA suggests that possible inhibition of cyclooxygenase by EPA seems most likely to shunt released AA into lipoxygenase pathway. When 60mg/kg of EPA-ethylester (75% purity) was orally given to rats for 4 weeks, a significant rise in EPA content in macrophage phospholipids was noted while AA content was unchanged. An apparent decrease in the released AA and its both lipoxygenase and cyclooxygenase metabolites indicates that incorporated EPA in macrophage membrane phospholipids may suppress the release of AA from macrophage membrane phospholipids. These evidences described above raise a possibility that EPA may suppress macrophage functions such as migration or lysosomal enzyme secretion. Accordingly EPA may act not only as anti-thrombogenic or anti-atherogenic but also as anti-inflammatory agent.

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Ca ionophore A 23187 (A 23187) -or antigen-induced release of slow reacting substance (SRS) from passively sensitized ocular tissues or from ocular tissues of non-sensitized or actively sensitized guinea pigs was investigated. In non-sensitized guinea pigs, considerable amount of SRS was generated in choroid>conjunctiva>ciliary body, in this order, by A23187. However, the release from iris was negligible, and no release was observed in retina and cornea. In actively sensitized guinea pigs, similar results of the SRS release by specific antigen or A23187 were obtained from each ocular tissue in the same order as the A23187-non-sensitized tissue experiments. Furthermore, when choroid, ciliary body and iris tissue were sensitized passively by injecting antiserum of the guinea pig in vitereous humor and challenged by antigen, large amount of SRS was released from the choroid and ciliary body, less extent from the iris. The ileal contraction of guinea pig induced those SRS was almost completely inhibited by SRS-specific antagonist, FPL 55712. Although we failed to determine the types of leukotriene of the SRS released by chromatography because of very small amount of the tissue employed, it was suggested that SRS plays a role in inflammation or allergy of the uvea.

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To investigate the effect of several anti-inflammatory drugs on cadmium-induced inflammation in the testis of rat, the degree of intratesticular hemorrhage and lipoperoxide level in the testis were measured as a parameter of the inflammation. Alpha-tocopherol and coenzyme Q₁₀which are well known as antioxidative agents had a potent antiinflammatory effect on cadmium-induced inflammation in rat testis. On the other hand, indomethacin and peonol which are supposed to be potent inhibitors of cyclooxygenase activity and prostaglandin synthesis, enhanced cadmium-induced intratesticular hemorrhage in a dose dependent manner. As for glucocorticoid (predonin) which has been reported to be an inhibitory protein on phospholipase A₂activity, a moderate inhibitory effect on inflammatory changes in rat testis induced by cadmium was observed although it was statistically not significant. These results suggest that oxidative and inflammatory reaction induced by cadmium in rat testis may be considered not to be promoted by the accerelation of cyclooxygenase pathway in arachidonic acid cascade, but by the accerelation of lipoxygenase pathway or radical reaction mediated oxygenation of nonesterified polyunsaturated fatty acids, which has been reported to be increased in the inflammation in the testis of rat induced by cadmium.

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It is said that cysts in jaws enlarge when the intracystic fluid pressure in the cyst cavities increases, and the jaw bone is absorbed. The author investigated that LPO and the prostaglandin-like substances generated in the cyst fluids, damaged the cyst walls, that the value of phospholipid in the cyst walls decreased, that the values of TBA, free radical intensity, PGE, PGF_2αincreased, and that the calcification of the jaw bones around the cysts decreased. These facts indicate that PGE generated in the cyst wall when a cyst is infected, acts on the resorption of the jaw bone. It can be regarded that the factor in the jaw cyst enlargement is PGE₂.

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Recently, there have been critics that assessment of phospholipid methylation of microsomal fractions does not necessarily represent membrane fluidity of dynamics. With our improved method, the author assessed the methylation of membrane in neutrophils and lymphocytes from the patients with various diseases including Behçet's disease and systemic lupus erythematosus (SLE) . The methyl assay was also performed with stimulation of opsonized zymosan (0.2 mg/ml) and Con A (2μg/ml) . Overall, [³H] -methyl incorporated to microsomal fractions in lymphocytes is greater than in neutrophils. Methylation of both neutrophils (P<0.001) and lymphocytes (P<0.01) in the patients with active Behçet's disease was most highly enhanced among all the diseases tested. The patients with active rheumatoid arthritis (RA), severe bacterial diseases and mucocutano lymphnode syndrome (within 7 days after its onset) also showed an increase in [³H] -methyl incorporated. The increase in methylation in the patients paralleled to their disease activity. In active SLE patients, methylation was not so highly increased and lymphocyte methylation showed no significant enhancement, compared to healthy controls. No increase in methylation was observed in patients with severe viral diseases. The present study seems to indicate that our original assay of phospholipid methylation of the membrane of neutrophils and lymphocytes is appraisable indicator of inflammation.

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A study representing an attempt to elucidate the immunopharmacological mechanisms of lobenzarit (former name CCA: carboxyphenyl chloroanthranilic acid disodium) has been performed employing as a parameter the hemolytic plaque forming cell (HPFC) assay, hemagglutination (HA) test, rosette forming cell (RFC) assay of mouse spleen and thymus cells with sheep red blood cells (SRBC) antigen. In C57BL/6 mice, CCA at 2, 10, 50, and 100mg/kg caused a suppression of spleen HPFC, HA, spleen RFC, and thymus RFC. C57BL/6, BALB/c, C3H/He, DBA/2, (NZB×NZW) F₁, and BXSB mice had different immune response against SRBC antigen respectively. Each strain had different immunopharmacological response against CCA. CCA stimulated the lower response, suppressed the higher response, and had no effect in some strains of mice. CCA proved to be effective in restoring the impaired immune response pretreated with immunosuppressants. But in some conditions, the agent suppressed the lowered response by immunosuppressants still more. These data suggested CCA has ability of immunomodulation.

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Concomitant effects of CCA with ketoprofen or prednisolone were investigated in the preventive and curative experiments of rat adjuvant arthritis, respectively.
(1) Inhibitory effects of CCA administered with the above each drug on the swelling of rat kind legs were found to be rather weak or almost negative in most cases.
(2) Administration of CCA and ketoprofen concomitantly enhanced the improving effect of each drug on the pathological changes of hemogram (percent increase in neutrophils counts and perceut decrease in lymphocytes counts) in both the prophylactic and curative experients.
(3) Similar improving effects on both the changes of lymphocytes counts in blood and the decrease of albumin/globulin ratio in the serum were shown in the therapeutic experiments treated by CCA and prednisolone.
(4) Concomitant use of CCA and ketoprofen suppressed the increase of tissue weights in adrenals and iliac lymph nodes (treated site) in the therapeutic experients.

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