The effect of tacrolimus hydrate (FK506) ointment on spontaneous dermatitis in NC/Nga (NC) mice was examined. FK506 ointment (0.1-1%) suppressed the development of dermatitis and was also therapeutically effective against established dermatitis. Increases in CD4-positive T cells (helper T cells), mast cells, eosinophils and immunostaining of interleukin (IL)-4, IL-5 and IgE were confirmed in the skin of the NC mice, and FK506 ointment suppressed all of these changes. Increased plasma IgE was also confirmed in the NC mice, and treatment with FK506 ointment reduced the plasma IgE level. These results suggested that FK506 suppressed the dermatitis by inhibiting the activation of inflammatory cells and by blocking the cytokine network in the skin of the NC mice. The commercially available steroid ointments showed only marginal effect on the development of dermatitis and showed some signs of side effects such as alopecia or atrophy of the skin. The effect of the steroids might have been masked by these side effects because the steroids showed similar inhibitory effects on the skin histopathological changes and the increase of plasma IgE. From these results, FK506 ointment can be expected to be a useful drug for atopic dermatitis.
Heparin (2,000 U/kg, i.v.) increases the plasma superoxide dismutase (SOD) activity by 2-3 times after 5 min. followed by a gradual decrease. A high dose of heparin (4 x 10(3) and 10 x 10(3) U/kg) exhibits a lower increase in the release of SOD. Ischaemic paw oedema in mice was suppressed by various types of SOD and heparin also suppresses this oedema. The dose-dependent curve of heparin of oedema suppression corresponds well with the increased plasma level of SOD. Inducibility with heparin, slow clearance from the bloodstream and blocking of oedema suppression by the copper chelator, diethyldithiocarbamate (DDC), suggest that the oedema suppressing SOD was the extracellular (EC)-SOD C. Other anticoagulants such as citrate and EDTA had no effect. Chondroitin sulphate A and C or carrageenan exhibited weak suppression. A complex of EC-SOD C and heparin appears not to bind to the endothelium in contrast to the injected free EC-SOD C. When heparin is re-injected, more than 1 week was required to get the same degree of oedema suppression. This indicates the necessity of newly synthesized enzyme. A biological role for heparin-induced release of plasma SOD is demonstrated for the first time in this investigation.
Various sources of superoxide dismutases (SOD) suppressed ischaemic paw oedemata (tourniquet poditis) of mice, rats and guinea pigs with different potencies. Intravenous (i.v.) dosing of mouse Cu,Zn-SOD had no effect on mouse ischaemic oedema, yet rat and guinea pig Cu,Zn-SOD suppressed ischaemic oedemata of rats and guinea pigs. Homologous SOD was anti-inflammatory at least in these two models. Guinea pig SOD was one of the most potent in all models, but showed a very narrow range of effective dose. This bell-shape suppressive pattern was ameliorated by concomitant catalase injection. Bovine and human Cu,Zn-SOD had a rather broad range of effective dose. Bacterial Mn-SODs were suppressive in mice, as well as the oxygen radical scavenger MK-447 and cytochrome c. Dexamethasone was effective only when administered more than 3 hrs in advance. As ischaemic paw oedema of mice was not sensitive to cyclooxygenase and lipoxygenase inhibitors, this model could serve for screening new types of anti-inflammatory or anti-ischaemic drugs.
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