Inhibition of some aspects of acute inflammation of guinea-pig lung by intraperitoneal dexamethasone and mifepristone: Demonstration of agonist activity of mifepristone in the guinea-pig

Abstract

We have determined the inhibitory activity of dexamethasone as an inhibitor of histamine-induced plasma protein extravasation (PPE) in guinea-pig lung and skin, and of lipopolysaccharide (LPS)-induced neutrophilia and platelet activating factor (PAF)-induced eosinophilia in guinea-pig lungs. Dexamethasone inhibited PAF-induced eosinophilia in guinea-pig lung (ED50 1.4 mg/kg i.p.). Higher doses of dexamethasone were required to inhibit LPS-induced neutrophilia (ED50 10.8 mg/kg i.p.). However, at doses up to 150 mg/kg i.p. dexamethasone did not inhibit histamine-induced plasma protein extravasation (PPE) in guinea-pig lung, but did inhibit PPE in guinea-pig skin. These preparations have previously been shown to be equally sensitive to inhibition by the beta 2-adrenoceptor agonist salmeterol. Dexamethasone inhibited PAF-induced eosinophilia (5 mg/kg) or LPS-induced neutrophilia (50 mg/kg) when given 3 h or 1 h prior to challenge. Inhibitory activity was lost when dexamethasone was administered 23 h prior to LPS or 1 h after PAF. The glucocorticoid antagonist mifepristone (1-100 mg/kg i.p.) caused dose-related inhibition of PAF-induced eosinophilia but not of LPS-induced neutrophilia. The highest dose of mifepristone used (100 mg/kg) did not reverse the inhibitory actions of dexamethasone (50 mg/kg) on LPS-induced neutrophilia. We suggest that the different inhibitory activity of dexamethasone in the preparations studied indicates differences in the sensitivity of the target cells involved to inhibition by dexamethasone. We also suggest that inhibition of PAF-induced eosinophilia by mifepristone reflects the partial agonist activity of this agent, demonstrated by others in different experimental systems.

Inhibition of PAF-, LPS-, and cytokine-induced granulocyte accumulation in guinea pig lung by dexamethasone: Evidence that inhibition of IL-5 release is responsible for the selective inhibition of eosinophilia by glucocorticoids in guinea-pigs

“…The experiments described in the present study confirm, and extend, previous reports which showed that dexamethasone was approximately 10 times more potent as an inhibitor of PAF-induced eosinophilia than of LPSinduced neutrophilia in guinea-pig lung [7]. In these experiments, PAF and LPS were administered to guineapigs as aerosols generated from a nebuliser [7].…”

“…In man, glucocorticoid therapy appears to show some selectivity for inhibition of asthmatic inflammation over the other forms of airway inflammation, since clinical studies show that 10 fold greater doses of beclomethasone dipropionate (BDP) are required to produce a significant therapeutic effect in bronchitis when compared to asthma [5, 61. Similarly, recent studies in guinea-pigs have shown that dexamethasone is 10 times more potent as an inhibitor of PAF-induced eosinophilia than of LPSinduced neutrophilia [7]. The experiments described below extend these findings by describing the inhibitory potency of dexamethasone, administered intraperitoneally, on eosinophilia induced by intratracheal administration of PAF and interleukin (IL)-5 and on neutrophilia induced by intracheal administration of LPS, TNFc~ and the chemokines IL-8 and CINC.…”

“…In these experiments, PAF and LPS were administered to guineapigs as aerosols generated from a nebuliser [7]. In the present study, methods were used which enabled PAF, LPS or cytokines to be administered directly into the airways from a cannula placed at the bottom of the trachea.…”

Mineralocorticoids and Glucocorticoids Cooperatively Increase Salt Intake and Angiotensin II Receptor Binding in Rat Brain

“…Second, glucocorticoids stimulate the expression of MR [21], which could explain how glucocorticoids augment the salt appetite seen in mineralocorticoid-treated rats [22]. Even a partial agonist activity of a GR antagonist [39, 40, 41, 42, 43]may enhance DOCA-induced salt intake [44]. Thus, although previous studies focused on the interaction between mineralocorticoids and AngII, glucocorticoids may also play an important role in increasing MR and AngII in the brain, thereby promoting behavioral interactions.…”

Goblet Cell Hyperplasia, Airway Function, and Leukocyte Infiltration after Chronic Lipopolysaccharide Exposure in Conscious Guinea Pigs: Effects of Rolipram and Dexamethasone

“…Control groups receiving chronic saline and the drug treatments were, however, included. Doses of dexamethasone (Whelan et al, 1995;Toward and Broadley, 1999) and rolipram (Danahay and Broadley, 1997) were selected based upon the findings from other studies using similar models of inflammation and those that were without adverse effects. No animal appeared to be in respiratory distress or to exhibit other signs of discomfort during the exposure regimens or during any other part of the protocol described.…”