Physiological regulation of vascular permeability by endogenous glucocorticoids and active oxygen

Abstract

A copper chelator, diethyldithiocarbamate (DDC), injection and adrenalectomy induce significant paw swelling by low doses of serotonin, histamine, or bradykinin, which can result in mild swelling in non-treated mice. Dexamethasone, Cu,Zn-superoxide dismutase (SOD), and hydroxyl radical scavengers suppressed the DDC-provoked edema, but only dexamethasone suppressed the edema of adrenalectomized mice. Adrenal stimulation by SOD is exclusive in that the suppression of edema by SOD began about 1 h prior to that by glucocorticoid. In order to explain the data obtained, the existence of a vascular permeability inhibitory protein (called "vasoregulin") was assumed. This protein must be synthesized constantly somewhere in the body and continuously inactivated by active oxygen in vivo. Local levels of vasoregulin may limit the responses of vascular permeability against the chemical mediators. This hypothesis was also supported by the edema-enhancing effects of protein/RNA synthesis inhibitors.

Vasoregulin, a glucocorticoid-inducible vascular permeability inhibitory protein

“…Vasoregulin easily lost its anti-inflammatory potency on incubation with a superoxide radical generating system in vitro. Together with results of our previous reports [5,8], we present the site of action of vasoregulin in Fig. 7.…”

“…[13] and pointed out by us [8]. Free arachidonic acid results in the sudden death of rabbits by pulmonary thrombosis which can be efficiently prevented by dexamethasone treatment [14].…”

“…With all these observations, we postulated the existence of an anti-inflammatory protein (X-protein) which can be induced by glucocorticoids and inactivated by active oxygens. Our finding on adrenalectomized and diethyldithiocarbamate (DDC, as an endogenous SOD inactivator)-treated mice, lead us to the hypothesis that such an X-protein must function not only in the pathological state, but also in the physiological state [8]. In this paper, we call the X-protein 'Vasoregulin', because it seems to regulate vascular permeability directly without inhibiting the enzymes of the arachidonate cascade.…”

Mechanisms by which endogenous glucocorticoid protects against indomethacin-induced gastric injury in rats

“…Indeed, the present study showed that a deficiency of glucocorticoids by itself induced a significant increase in gastric microvascular permeability in adrenalectomized rats and that this increase was totally prevented by corticosterone replacement. Glucocorticoids are known to decrease vascular permeability by inducing production of the anti-inflammatory protein vasoregulin (26,27). Because vascular permeability is enhanced by vascular endothelial growth factor (VEGF) (3), and because the expression of VEGF is stimulated by hypoglycemia (31) and inhibited by glucocorticoids (23), it is possible that the effect of corticosterone on gastric microvascular permeability is mediated by downregulation of VEGF expression.…”

Neutral endopeptidase and kininase II mediate glucocorticoid inhibition of neurogenic inflammation in the rat trachea.

“…Mediator-induced plasma extravasation is known to occur in postcapillary venules (7,8) and is believed to be due to conformational changes ofendothelial cells (28). It has been suggested that glucocorticoids inhibit mediator-induced extravasation through the synthesis of inhibitory proteins that oppose the conformational changes of endothelial cells (29)(30)(31)). Our present observation that the same dose of dexamethasone that markedly inhibits substance P-induced extravasation has no effect on PAF-induced extravasation is inconsistent with this hypothesis.…”