[in Japanese]

View full abstract

The initial demonstration that soluble mediators Could be liberated by antigen-activated lymphocytes came about as a result of research aimed at elucidating the mechanism of delayed hypersensitivity. Subsequently, various soluble factors were found to involve in the induction of inflammatory responses.
Inflammatory processes stimulate phagocytic cells to synthesize and release various Cytokines including IL-1, TNF, IL-6 and IFN. IL-1 and TNF are known to have chemotactic properties for phagocytic cells. In addition to attracting phagocytic cells into inflamed tissues, these Cytokines also potentiate the activation of phagocytic cells. In vitro these cytokines have been reported to induce synovial cell, chondrocyte and fibroblast PGE₂ and collagenase production and also induce the activation of osteoclast.
IL-1, TNF and IL-6 that are produced peripherally from activated phagocytic cells enter the circulation and affect distant organ systems. These cytokines act on the hypothalamic thermoregulatory center to induce fever. They also induce the release of hypothalamic and pituitary peptides including ACTH. They, particularly IL-6, act on the hepatocytes to induce acute phase proteins. Furthermore, IL-6 is known to activate hematopoietic stem cells to be responsive to IL-3. Although IL-1 has no direct effect on marrow precursors, it acts synergistically with bone marrow growth factors.
IL-1, TNF, IL-6 and IFN participate in a network of cytokine-inducd cytokines. IL-1 induces production of itself, TNF, IL-6, IFN and IL-2. TNF induces production of IL-1, IL-6 and IFN, whereas IL-6 suppresses production of TNF. Such a network may be important for the augmentation or suppression of various biological properties during host responses to infection or inflammation.

View full abstract

Human peripheral blood leukocytes were isolated by sedimentation in the presence of 6% (w/v) dextran and neutrophils were purified on a Conray-Ficoll gradient. Also, human peripheral blood platelets were separated by a gel filtration method with Sepharose 2B. 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^-8 M fMLP or 10 ng/ml PMA to a suspension of platelets caused no significant MCLA-dependent luminescence. O^-₂ generation by neutrophils from healthy human volunteers, activated by 10^-8 M fMLP or 10 ng/ml PMA, was inhibited by their platelets in a concentration-dependent manner.
On the other hand, platelets from a 30 year-old female severe bronchial asthmatic patient (atopic and perennial type), whose peripheral blood platelets were elevated more than 60×10⁴/mm³, failed to cause an inhibition of O^-₂ generation from neutrophils activated by 10^-8 M fMLP. The lack of an inhibition of the luminescence from neutrophils by platelets might be involved in the pathogenesis of bronchial asthma.

View full abstract

Oxyradicaldependent chemiluminescence from granulocytes was visualized in rat mesenteric microvascular beds treated with platelet-activating factor (PAF), leukotriene B₄ (LTB₄) and bacterial chemotactic peptide (FMLP) by means of digital imaging photonic intensified microscopy. The topical application of PAF-acether (100 nM) caused remarkable granulocyte adherence on venular endothelial walls and the subsequent activation of a luminol-dependent photonic burst. Chemilumigenic sites clearly corresponded to the spatial distribution of sticking cells in post-capillary venules. LTB₄ and FMLP, however, did not induce any significant photonic burst at concentrations which caused adherent changes between endothelial cells and granulocytes.
These findings suggest that PAF may play a role in granulocyte-mediated oxidative stress on venular endothelial cells during acute inflammatory processes, and also provide the first evidence of an intravital oxidative burst of granulocytes in microcirculatory disturbances.

View full abstract

Recently, attention has been paid to the possible role of neuropeptides in pathophysiology of the autoimmune disorders. We evaluated plasma opioidpeptide levels in patients with rheumatoid arthritis, and the following results were obtained.
The plasma levels of metionine-enkephalin in RA patients is significantly lower than that of healthy volunteers. The plasma level of opioidpeptides (β-endorphin, leucineenkephalin and methionine-enkephalin) in patients with carcinoma is within normal range. The plasma level of methionine-enkephalin in RA patients increased gradually and reached to the normal range by concumitant treatment with lobenzarit. These results support that opioidpeptides, especially methionine-enkephalin, may be related with the disease activity in RA patients.

View full abstract

In this study, chemotactic activity of heat-killed K. pneumoniae DT-S and lipopolysaccharide (LPS), capsular polysaccharide (CPS) of this strain were investigated in mice pleurisy model. Intrapleural inoculation of heat-killed K. pneumoniae DT-S in carrageenan pretreated mice caused more significant neutrophil accumulation than in control mice. This amplified neutrophil accumulation in carrageenan pretreated mice was mainly induced by LPS of heat-killed K. pneumoniae DT-S. Carrageenan pretreated pleural macrophages produced more marked interleukin-1 (IL-1) than control pleural macrophages when stimulated with LPS of K. pneumoniae DT-S. In contrast, CPS induced little IL-1 production even in carrageenan pretreated pleural macrophages and this IL-1 production may be induced by LPS contaminated in CPS of K. pneumoniae DT-S, because polymyxin-B treatment completely inhibited this IL-1 production of CPS in carrageenan pretreated pleural macrophages. Interestingly, there were no IL-1 inducing effects on CPS of K. pneumoniae DT-S in control pleural macrophages.
The results of this study indicated that carrageenan, usually known as antimacrophage agents, caused pleural macrophages to secrete marked IL-1 after stimulation with LPS of K. pneumoniae DT-S. It is considered that this amplified IL-1 production of carrageenan pretreated pleural macrophages in response to LPS, not to CPS, play an important role in neutrophil accumulation on K. pneumoniae DT-S infection.

View full abstract

We examined the effect of prostaglandin E₁ (PGE₁) on the production of plateletactivating factor (PAF) from human neutrophils. PGE₁ was shown to significantly suppress the production of PAF from human neutrophils in a dose-dependent manner.
This result suggests that PGE₁ may have some influence on an inflammatory or immunological reaction by the suppression of PAF production.

View full abstract

Vascular endothelial cells produce or metabolize vasoactive substances, which regulate or modulate vascular tone. A potent vasodilator, prostaglandin I₂ (PGI₂) is known to be released from vascular endothelium in increased quantities in response to not only various chemical stimuli but also mechanical stimuli such as a increased blood flow. We performed this study to know whether pulmonary hemodynamic forces would affect lung PGI₂ production and PGI₂ acts on pulmonary vessels to maintain a low resistance in the pulmonary circulation. We measured plasma 6-keto-PGF_1α, the metabolite of PGI₂, during pulmonary blood flow alterations in rabbits.
The alterations were made by unilateral complete pneumothorax or pulmonary artery occulusion, which decreased pulmonary vascular bed and increased blood flow in the redisual pulmonary vessels. Plasma 6-keto-PGF_1α level increased during such procedures but the rise of pulmonary arterial pressure was small and transient. Cyclooxygenase inhibition did not affect the change of pulmonary arterial pressure during pulmonary artery occulusion.
These data suggest that PGI₂ is produced by pulmonary vessels in response to the increased blood flow but it may not participate in modulation of pulmonary hemodynamics.

View full abstract

The effect of mizoribine (MZR) on adjuvant and collagen arthritis in rats is investigated. In adjuvant arthritis, twice daily doses of 2.5 and 5 mg/kg of mizoribine showed a marked inhibition of the development of secondary lesions of arthritis comparing to the corresponding single daily doses of 5 and 10 mg/kg.
In the case of collagen arthritis, the treatment for 21 days at dose of 10 mg/kg daily, begun on the next day of the bovine type II collagen immunization, suppressed the development of arthritis as well as humoral antibody response to collagen. Although mizoribine treatment only during the induction phase of immunity proved to be successful, the treatment during the established phase of immunity only delayed the development of arthritis.

View full abstract