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PubMed2005

Histopathologic alterations following local delivery of dexamethasone to inhibit restenosis in murine arteries.

OBJECTIVE: Dexamethasone-eluting stents are currently under evaluation to prevent post-angioplasty restenosis. The efficacy and safety of dexamethasone as an anti-restenotic agent is still unclear. We assess the effect of perivascular delivery of dexamethasone on vascular pathology in a mouse model of restenosis. METHODS AND RESULTS: In this study we investigate the ability of both systemic and local dexamethasone treatment to inhibit neointima formation after cuff placement around C57BL/6 mouse femoral artery. As in the clinical situation, systemic dexamethasone treatment shows adverse side effects in animals, including weight loss. In contrast, local delivery of dexamethasone using a drug-eluting polymer cuff inhibits neointima formation and has no systemic adverse effects. Pathobiological examination of the experimental arteries, however, reveals a dose-dependent medial atrophy, a reduction in vascular smooth muscle cells and collagen content, an increase in apoptotic cell count and disruption of the internal elastic lamina. CONCLUSIONS: Our results demonstrate that although local dexamethasone delivery is effective as an inhibitor for neointima formation, it is dose-dependently associated with adverse vascular morphological changes pointing to a loss of vascular integrity.

Angioplasty, Balloon, Coronary↗
PubMed2003

Dexamethasone exposure during the neonatal period alters ORL1 mRNA expression in the hypothalamic paraventricular nucleus and hippocampus of the adult rat.

Dexamethasone is commonly used to limit the severity of chronic lung disease in premature infants with severe respiratory distress syndrome. Recent literature has demonstrated an association between dexamethasone exposure in critically ill premature neonates and later development of cerebral palsy. However, the majority of children exposed to dexamethasone in the neonatal period do not develop cerebral palsy or global developmental delay, and other more subtle effects of early life glucocorticoid exposure may go unnoticed. Presently, little is known regarding possible effects of early dexamethasone exposure on development of neuropeptide systems that are sensitive to glucocorticoid modulation. One such system is the pain-related opioid system that interacts with the stress-related limbic-hypothalamic pituitary adrenal (LHPA) axis. In the present study, a neonatal rat model was used to expose newborn rats to dexamethasone. Using a within-litter design, on postnatal days P3 through P6, pups were either handled, or they received a daily intramuscular injection of saline or dexamethasone. Adult animals were sacrificed on day of life P120, their brains were removed and quick-frozen. Using in situ hybridization histochemistry, mRNA expression of the opioid receptor-like (ORL1) receptor was measured in the paraventricular nucleus of the hypothalamus (PVN) and the hippocampal formation. In dexamethasone-treated adult male rats, ORL1 mRNA expression was increased in the PVN and dentate gyrus, but decreased in area CA1, when compared to handled and vehicle controls. These results suggest that prolonged glucocorticoid receptor (GR) occupation in the neonatal period leads to permanent alterations in ORL1 expression in the LHPA stress axis of the adult rat.

Animals↗
PubMed2006

Non-ventilation during early incubation in combination with dexamethasone administration during late incubation: 1. Effects on physiological hormone levels, incubation duration and hatching events.

This study investigated the effect of non-ventilation of the incubator during the first 10 days of incubation and its combination with dexamethasone administration at day 16 or 18 of incubation on hatching parameters and embryo and post-hatch chick juvenile physiology. A total of 2400 hatching eggs produced by Cobb broiler breeders were used for the study. Blood samples were collected at day 18 of incubation, at internal pipping stage (IP), at the end of hatch (day-old chick) and at 7-day-post-hatch for T(3), T(4) and corticosterone levels determination. From 448 to 506 h of incubation, the eggs were checked individually in the hatcher every 2h for pipping and hatching. The results indicate that non-ventilation during the first 10-day shortened incubation duration up to IP, external pipping (EP) and hatch, had no effect on hatchability and led to higher T(3) levels at IP but lower corticosterone levels at 7-day-post-hatch. The injection of dexamethasone at days 16 and 18 of incubation affected hatching and blood parameters in both the ventilated and non-ventilated embryos differentially and the effect was dependent on the age of the embryo. Dexamethasone increased T(3) levels and T(3)/T(4) ratios but the effect was greater with early non-ventilation of eggs. Dexamethasone decreased hatchability but the effect was greater when injected at day 16 and especially in ventilated embryos. The effects of incubation protocols and dexamethasone treatments during incubation were still apparent in the hatched chicks until 7 days of age. The changes in T(3), T(4) and corticosterone levels observed in response to the early incubation conditions and late dexamethasone treatments in this study suggest that incubator ventilation or non-ventilation may influence the hypothalamic-pituitary-adrenal axis (HPA) regulation of stress levels (in terms of plasma corticosterone levels) and thyroid function in the embryo with impact on incubation duration, hatching events and early post-hatch life of the chick. Our results also suggest that some stages of development are more sensitive to dexamethasone administration as effects can be influenced by early incubation protocols.

Animals↗
PubMed2004

Inhibition of ischemia/reperfusion-induced damage by dexamethasone in isolated working rat hearts: the role of cytochrome c release.

We investigated the contribution of dexamethasone treatment on the recovery of postischemic cardiac function and the development of reperfusion-induced arrhythmias in ischemic/reperfused isolated rat hearts. Rats were treated with 2 mg/kg of intraperitoneal injection of dexamethasone, and 24 hours later, hearts were isolated according to the 'working' mode, perfused, and subjected to 30 min global ischemia followed by 120 min reperfusion. Cardiac function including heart rate, coronary flow, aortic flow, and left ventricular developed pressure were recorded. After 60 min and 120 min reperfusion, 2 mg/kg of dexamethasone significantly improved the postischemic recovery of aortic flow and left ventricular developed pressure from their control values of 10.7 +/- 0.3 ml/min and 10.5 +/- 0.3 kPa to 22.2 +/- 0.3 ml/min (p < 0.05) and 14.3 +/- 0.5 kPa (p < 0.05), 19.3 +/- 0.3 ml/min (p < 0.05) and 12.3 +/- 0.5 kPa (p < 0.05), respectively. Heart rate and coronary flow did not show a significant change in postischemic recovery after 60 or 120 min reperfusion. In rats treated with 0.5 mg/kg of actinomycin D injected i.v., one hour before the dexamethasone injection, suppressed the dexamethasone-induced cardiac protection. Electrocardiograms were monitored to determine the incidence of reperfusion-induced ventricular fibrillation. Dexamethasone pretreatment significantly reduces the occurrence of ventricular fibrillation. Cytochrome c release was also observed in the cytoplasm. The results suggest that the inhibition of cytochrome c release is involved in the dexamethasone-induced cardiac protection.

Animals↗
PubMed2004

Prostaglandin E2 and dexamethasone regulate eosinophil differentiation and survival through a nitric oxide- and CD95-dependent pathway.

Apoptosis, involving both CD95/CD95L interactions and their modulation by nitric oxide (NO), is central to regulation of mature eosinophil numbers. However, its role in regulating eosinophil production from bone-marrow precursors is unknown. We examined the effects of prostaglandin E2 (PGE2) and dexamethasone on eosinophil differentiation and survival in murine bone-marrow cultures, and their relationship to: NO production as well as CD95/CD95L-dependent apoptosis. Bone-marrow cultures were established with IL-5, alone or in association with PGE2, dexamethasone or both. PGE2 (10(-7)M) inhibited eosinophil differentiation by selectively inducing apoptosis in developing eosinophils. Dexamethasone (10(-7)M) protected developing eosinophils from PGE2-induced apoptosis. Since dexamethasone prevents induction of nitric oxide synthase (NOS), we evaluated the role of NO in the effects of both PGE2 and dexamethasone. NO donors (SNAP and SNP) down-modulated eosinophil precursor responses to IL-5. SNAP induced apoptosis through a dexamethasone-resistant mechanism. The NOS inhibitors, Nomega-nitro-L-arginine and aminoguanidine, blocked the effects of PGE2 on developing eosinophils. PGE2 was ineffective in bone-marrow from knockout mice lacking inducible NOS. PGE2 up-regulated CD95 and CD95L expression in developing eosinophils. Neither PGE2 nor SNAP were effective in cultures from CD95L-deficient gld mice. These data suggest that PGE2 induces apoptosis in developing eosinophils through inducible NOS, leading to NO-dependent activation of the CD95L/CD95 pathway, while dexamethasone antagonizes the effects of PGE2 on the same targets.

Animals↗
PubMedDate not supplied

Dexamethasone fails to inhibit the induction of cytosolic phospholipase A(2) expression by interleukin-1beta in cultured primary human amnion fibroblasts.

OBJECTIVE: To investigate the interaction of dexamethasone and interleukin-1beta (IL-1beta) on the expression of cytosolic phospholipase A(2) (cPLA(2)), the enzyme catalyzing the first reaction in the formation of prostaglandins, in cultured primary human amnion fibroblasts. DESIGN AND METHODS: Human amnion fibroblasts were prepared from fetal amnion collected at term and were treated with dexamethasone with or without interleukin-1beta for 24h. Prostaglandin E(2) (PGE(2)) output and cPLA(2) expression in cultured amnion fibroblasts were measured with radioimmunoassay, quantitative real-time polymerase chain reaction, Western blotting and cPLA(2) promoter-driven luciferase reporter gene activity. RESULTS: Both dexamethasone and IL-1beta caused a significant increase in prostaglandin E(2) output, cPLA(2) mRNA and protein expression in cultured human amnion fibroblasts. Both dexamethasone and IL-1beta stimulated cPLA(2) promoter-driven luciferase reporter gene activity. There was no obvious antagonistic or synergistic effect of combined treatment of dexamethasone and IL-1beta on PGE(2) output, cPLA(2) expression or cPLA(2) promoter-driven luciferase reporter gene activity in cultured human amnion fibroblasts. CONCLUSION: The above findings suggest that paradoxically dexamethasone is a stimulator for both prostaglandin synthesis and cPLA(2) expression in human amnion fibroblasts. The interaction between dexamethasone and IL-1beta on prostaglandin synthesis and cPLA(2) expression is neither synergistic nor conventionally antagonistic.

Amnion↗
PubMed2006

Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression.

In humans, asphyxic deaths and severe poisonings have been attributed to high-dosage buprenorphine, a maintenance therapy for heroin addiction. However, in rats, intravenous buprenorphine at doses up to 90 mg kg(-1) was not associated with significant effects on arterial blood gases. In contrast, norbuprenorphine, the buprenorphine major cytochrome P450 (CYP) 3A-derived metabolite, is a potent respiratory depressant. Thus, our aim was to study the consequences of CYP3A induction on buprenorphine-associated effects on resting ventilation in rats. We investigated the effects on ventilation of 30 mg kg(-1) buprenorphine alone or following cytochrome P450 (CYP) 3A induction with dexamethasone, using whole body plethysmography (N=24) and arterial blood gases (N=12). Randomized animals in 4 groups received sequential intraperitoneal dosing with: (dexamethasone [days 1-3]+buprenorphine [day 4]), (dexamethasone solvent [days 1-3]+buprenorphine [day 4]), (dexamethasone [days 1-3]+buprenorphine solvent [day 4]), or (dexamethasone solvent [days 1-3]+buprenorphine solvent [day 4]). Buprenorphine alone caused a significant rapid and sustained increase in the inspiratory time (P<0.001), without significant effects on the respiratory frequency, the tidal volume, the minute volume, or arterial blood gases. In dexamethasone-pretreated rats, there was no significant alteration in the respiratory parameters, despite CYP3A induction and significant increase of the ratio of plasma norbuprenorphine-to-buprenorphine concentrations. In conclusion, dexamethasone did not modify the effects of 30 mg kg(-1) buprenorphine on rat ventilation. Our results suggest a limited role of drug-mediated CYP3A induction in the occurrence of buprenorphine-attributed respiratory depression in addicts.

Animals↗
PubMed2006

A combination of a thrombin inhibitor and dexamethasone prevents the development of experimental disseminated intravascular coagulation in rats.

INTRODUCTION: Disseminated intravascular coagulation (DIC) is a serious and potentially lethal complication of severe sepsis. DIC is characterised primarily by widespread platelet aggregation and fibrin deposition, followed by consumption of platelets, coagulation factors, and inhibitors. The aim of the study was to evaluate the efficacy of the active-site thrombin inhibitor melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, in reducing fibrinogen and platelet consumption in blood and fibrin deposition in organs, in an experimental endotoxinaemia rat model. MATERIALS AND METHODS: In this model, DIC was induced by an intravenous injection of endotoxin (1 mg/kg). Melagatran was compared with unfractionated heparin and the synthetic glucocorticoid analogue dexamethasone. Animals were divided into 16 treatment groups in which high and low doses of each agent were tested alone and in combination with melagatran. RESULTS: Fibrinogen consumption was reduced by melagatran, dexamethasone, and heparin, and was completely prevented by melagatran in combination with dexamethasone. Platelet consumption was partially reduced by melagatran, unfractionated heparin, and dexamethasone, but complete protection was observed only with melagatran in combination with dexamethasone. Melagatran in combination with dexamethasone or heparin protected the liver and spleen from fibrin deposition. CONCLUSION: In this experimental DIC rat model, the direct thrombin inhibitor melagatran given together with dexamethasone protected against the consequences of activated haemostasis.

Animals↗
PubMed2006

Enhancement by dexamethasone of the therapeutic benefits of cisplatin via regulation of tumor angiogenesis and cell cycle kinetics in a murine tumor paradigm.

We have investigated in the current study, the possible modulatory effects of dexamethasone on cisplatin cytotoxicity in Ehrlich ascites carcinoma (EAC)-bearing female Swiss albino mice. Cisplatin (3.5mg/kg) was injected IP for 3 consecutive days in mice previously inoculated SC with EAC cells in the right flank. Dexamethasone (2.5mg/kg) was administered SC alone or 24h ahead of cisplatin challenge, and these regimens were given for 3 consecutive days. Dexamethasone enhanced the anti-tumor effects of cisplatin, clearly demonstrated by the increased mean tumor growth time (TGT) and tumor growth delay time (TGDT) values compared to cisplatin alone. The effects of dexamethasone on tumor angiogenesis and cell cycle distribution of EAC cells have been addressed as possible mechanisms, whereby the glucocorticoid could probably augment cisplatin cell-kill. Indeed, dexamethasone enhanced the angiostatic activity of cisplatin by 52.5%. The glucocorticoid also synchronized the EAC cells in the G2/M phase, secondary to its regulatory role on the transcriptional and translational activity in these cells, thus, exposing them to the dramatic cytotoxic potential of cisplatin. One could conclude that dexamethasone enhanced the anti-tumor effects of cisplatin via augmenting its angiostatic activity and modulating cell cycle kinetics. Also, dexamethasone did not alter cisplatin-induced nephrotoxicity, thus demonstrating an improved therapeutic potential.

Animals↗
PubMed2004

Oral dexamethasone attenuates Doxil-induced palmar-plantar erythrodysesthesias in patients with recurrent gynecologic malignancies.

OBJECTIVE: The aim of this study is to evaluate the effect of oral dexamethasone in attenuating palmar-plantar erythrodysesthesias (PPE) in Doxil-treated patients for gynecologic malignancies. METHODS: An IRB-approved prospective case study was conducted in patients with recurrent gynecologic malignancies who were treated with Doxil (50 mg/m(2)) on a 28-day cycle. Patients experiencing grades II-IV PPE were delayed until resolution then retreated without dose reduction and with a tapering oral dexamethasone regimen (8 mg BID days -1 to 4; 4 mg BID day 5; 4 mg day 6). Standard treatment for grades II-IV PPE in those not receiving dexamethasone was weekly dose delay until resolution of symptoms up to 2 weeks. If resolution occurred within 3 weeks of delay, a 25% dose reduction was made. Persistent grades III/IV PPE resulted in withdrawal of Doxil. RESULTS: Twenty-three patients (ovarian-16, uterine-7) were treated between January 1998 and December 2000. The median number of cycles administered was 5 (range 1-20). Nine patients (39%) developed grades II-IV PPE. All nine patients received more than five cycles of Doxil. The median time to PPE was 3 cycles (range 2-5). Six out of nine PPE patients received scheduled dose dexamethasone. All six had complete or near complete resolution of PPE and all continued treatment without subsequent dose modification. All three of the nine PPE patients not receiving dexamethasone required treatment delays and were dose reduced. CONCLUSION: Oral dexamethasone is effective in attenuating or eliminating Doxil-induced PPE. The use of the dexamethasone regimen prevents treatment delay and dose reduction.

Administration, Oral↗
PubMed1997

Better maternal outcomes are achieved with dexamethasone therapy for postpartum HELLP (hemolysis, elevated liver enzymes, and thrombocytopenia) syndrome.

OBJECTIVE: Our purpose was to determine whether the routine initiation of dexamethasone therapy in patients with postpartum HELLP (hemolysis, elevated liver enzymes, and thrombocytopenia) syndrome produces specific and general therapeutic benefits. STUDY DESIGN: In this retrospective, analytic study the puerperal courses of 43 women with postpartum HELLP syndrome who were treated with dexamethasone were compared with those of 237 similar patients who did not receive corticosteroids. Dexamethasone 10 mg intravenously at 12-hour intervals was given until disease remission was noted in treated patients, at which time up to two additional 5 mg intravenous doses were given at 12-hour intervals. RESULTS: The two patient groups were similar in regard to mode of delivery, gestational age, parity, and frequency of eclampsia. Compared with control subjects, dexamethasone-treated postpartum patients were more ill with significantly higher (p < 0.05) admission mean arterial blood pressure, higher serum uric acid level, and severe proteinuria. Dexamethasone administration was associated with a more rapid normalization of platelet counts and lactic dehydrogenase values. Most impressive was a clinically significant reduction of indicated transfusion and respiratory therapy, invasive hemodynamic monitoring, infectious or bleeding-related morbidity, and length of postpartum hospital course. CONCLUSIONS: Patients who received dexamethasone for postpartum-onset HELLP syndrome experienced a shorter disease course, faster recovery, less morbidity, and less need for other interventionist therapy compared with patients with HELLP syndrome who did not receive dexamethasone.

Adult↗
PubMed1997

A placebo-controlled comparison between betamethasone and dexamethasone for fetal maturation: differences in neurobehavioral development of mice offspring.

OBJECTIVE: Our purpose was to determine whether antenatal betamethasone or dexamethasone is the preferred drug by use of neurobehavioral development assessment of exposed mice offspring. STUDY DESIGN: Thirty adult CD-1 mice were randomly assigned to one of three groups (n = 10) to be administered a single subcutaneous dose of either a placebo (0.9% sodium chloride), betamethasone (0.10 mg), or dexamethasone (0.10 mg) on day 14 (74%) of gestation. The offspring then performed a battery of sensory, motor, motivational-anxiety, cognitive, and social tasks. Data were compared with use of analysis of variance, Kruskal-Wallis, or chi2 testing where appropriate. RESULTS: The offspring from the three treatment groups were indistinguishable at birth. Dexamethasone exposure induced a brief developmental delay. Separation anxiety was increased in the dexamethasone-exposed group in the perinatal period, whereas exposure to both corticosteroids decreased anxiety in the juvenile period, continuing into adulthood among male betamethasone-exposed mice. Selective enhancement of a memory process occurred in betamethasone-exposed mice, whereas dexamethasone exposure resulted in a decrement. Socialization as to place preference while awake and asleep varied among the three treatment groups. Corticosteroid treatment did not induce significant changes in sensory, motor, motivation, and learning performances or in reproductive capability and progeny development. CONCLUSION: Subtle differences in offspring performances of neurobehavioral development tasks favored antenatal betamethasone rather than dexamethasone. This finding, along with the knowledge that dexamethasone is less potent in accelerating lung maturity in the fetal mouse, suggests that betamethasone may be the preferred corticosteroid to use when human preterm delivery is imminent.

Animals↗
PubMed2000

Effects of single dose, postinduction dexamethasone on recovery after cardiac surgery.

BACKGROUND: Corticosteroids have been recommended to facilitate rapid recovery after cardiac surgery. We previously reported that dexamethasone given after induction of anesthesia decreases the incidence of postoperative shivering. We performed a post hoc analysis of the data obtained during that study, focusing on secondary outcomes. METHODS: A total of 235 adult patients undergoing elective coronary or valvular heart surgery were randomized to receive dexamethasone 0.6 mg/kg or placebo after induction of anesthesia. Patients who had pharmacologically treated diabetes mellitus, had hypersensitivity to dexamethasone, or were receiving treatment with corticosteroids were excluded. RESULTS: We found that, compared with placebo, patients receiving dexamethasone were more likely to remain tracheally intubated for 6 hours or less (26.4% vs 10.0%, p = 0.020) and had a lower incidence of early postoperative fever (20.2% vs 36.8%, p = 0.009) and new-onset atrial fibrillation during the first 3 days postoperatively (18.9% vs 32.3%, p = 0.027). However, we could not demonstrate a statistical difference in the intensive care unit or hospital length of stay, or in overall morbidity and mortality. The dexamethasone-treated patients were also more likely to have a higher blood glucose on admission to the intensive care unit (186 mg/dL vs 143 mg/dL, p = 0.012). CONCLUSIONS: Dexamethasone facilitates early tracheal extubation and is associated with a lower incidence of early postoperative fever and new-onset atrial fibrillation. Apart from a treatable decreased glucose tolerance, dexamethasone treatment was not shown to affect morbidity or mortality significantly.

Anesthesia↗
PubMed2000

Selective induction of cytochrome P450 3A1 by dexamethasone in cultured rat hepatocytes: analysis with a novel reverse transcriptase-polymerase chain reaction assay section sign.

The study of drug metabolism in cultured rat hepatocytes is hampered by the rapid loss of the expression of cytochrome P450 enzymes. Nevertheless, the activity of cytochrome P450 3A (CYP3A), one of the most important isoenzymes for drug metabolism, can be elevated by chemical inducers. In the present study, we investigated in cultured rat hepatocytes the induction of all four currently identified CYP3A isoforms by dexamethasone, and compared the results obtained in vitro with the induction profile of dexamethasone in vivo. To this end, CYP3A mRNA levels were quantified with a novel, radioactive reverse transcriptase-polymerase chain reaction (RT-PCR) assay, and CYP3A enzymatic activity was measured by a testosterone hydroxylation assay. In the RT-PCR assay, CYP3A isoforms were co-amplified with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the presence of radioactively labeled nucleotides. This resulted in an extremely sensitive and accurate determination of CYP3A expression levels, relative to those of GAPDH. Using this RT-PCR assay, it was found that the expression of all CYP3A isoforms in rat hepatocytes, cultured on a collagen matrix, was decreased by 80-90% within one day of cultivation. After addition of dexamethasone, at one day after isolation, CYP3A1 mRNA levels were elevated to levels comparable to those in freshly isolated hepatocytes within two days. In contrast, CYP3A2, CYP3A9, and CYP3A18 mRNA levels were not affected by dexamethasone treatment, and were hardly detectable after three days of cultivation. CYP3A enzymatic activity was also induced in cultured hepatocytes (approximately 6-fold) after addition of dexamethasone. In vivo, CYP3A1 mRNA levels increased 45-fold after dexamethasone administration. However, in contrast to the situation in cultured hepatocytes, CYP3A2 and CYP3A18 were also induced, albeit to a lesser extent (4- and 7-fold elevated mRNA levels, respectively). We conclude that the selective induction of CYP3A1 in dexamethasone-treated rat hepatocytes allows the study of biotransformation reactions by CYP3A1, without interference by any of the other CYP3A isoenzymes.

Animals↗
PubMed1998

Dexamethasone enhancement of hyperoxic lung inflammation in rats independent of adhesion molecule expression.

Infants and adults on oxygen often are treated with glucocorticoids in an attempt to reduce lung inflammatory injury. However, glucocorticoids hasten the development of hyperoxic lung injury in some animal models. The purpose of this study was to test the hypothesis that dexamethasone alters the lung inflammatory responses to hyperoxia exposure. We studied male Sprague-Dawley rats, placing them in >95% oxygen immediately after administration of 0, 0.1, 1, or 10 mg/kg of dexamethasone. At 0, 24, or 48 hr of exposure to hyperoxia, extravascular lung water contents were measured, and lung inflammatory responses were assessed by lung myeloperoxidase activities, lung neutrophil counts, and lung expression of E-Selectin and intercellular adhesions molecule-1 (ICAM-1). Dexamethasone, independent of exposure to hyperoxia, led to marked increases in lung neutrophil counts, without increases in lung myeloperoxidase activities or increases in the expression of the adhesion molecules. Hyperoxia exposure also enhanced lung neutrophil accumulation, and extravascular lung water increased earlier in animals exposed to hyperoxia and dexamethasone than in those exposed to hyperoxia alone. In conclusion, the increase in lung neutrophils in dexamethasone-treated rats without enhanced expression of E-Selectin or intracellular adhesions molecule-1 suggests that dexamethasone leads to lung neutrophil accumulation by its effect on neutrophils. The more rapid development of hyperoxic lung injury associated with earlier lung neutrophil accumulation suggests that dexamethasone-induced lung neutrophil sequestration primes the lung for the development of hyperoxic lung injury and supports further the conclusion that lung inflammation contributes significantly to the development of hyperoxic lung injury.

Animals↗
PubMed1996

Protection against hypoxic-ischemic damage with corticosterone and dexamethasone: inhibition of effect by a glucocorticoid antagonist RU38486.

We investigated whether the neuroprotection provided by dexamethasone against neonatal hypoxic-ischemic damage can be inhibited by a glucocorticoid antagonist and whether corticosterone, the endogenous glucocorticoid in the rat, also provides protection. Rats (6 days old) were treated with either vehicle (0.1 ml/10 g), corticosterone (3.5-80 mg/kg, s.c.) or dexamethasone alone or in combination with RU38486 (20-80 mg/kg, s.c.) 15 min prior to dexamethasone (0.1 mg/kg, i.p.). At 7 days of age, cerebral hypoxia-ischemia was produced by right carotid artery ligation under anesthesia and subsequent exposure to 2 h of hypoxia. Damage was quantified from brains perfusion-fixed and processed 2 days later. The reduction in somatic growth, thymus weight and the relatively elevated blood glucose levels at the end of hypoxia-ischemia were inhibited by RU38486. The protective effect of dexamethasone was also prevented by RU38486 (P < 0.001). Similar to pre-treatment with dexamethasone, administration of corticosterone (40-80 mg/kg) markedly reduced the extent of infarction compared to vehicle-treated controls (P < 0.0001). Thus, the endogenous glucocorticoid in the rat also provides protection against hypoxic-ischemic damage. RU38486 inhibits the beneficial effects of dexamethasone demonstrating that the neuroprotection observed with dexamethasone is a glucocorticoid receptor-mediated effect.

Animals↗
PubMed1997

Dexamethasone down-regulates the expression of L-selectin on the surface of neutrophils and lymphocytes in humans.

OBJECTIVE: On the basis of previous animal studies, we hypothesized that dexamethasone may reduce the expression of L-selectin on neutrophils and lymphocytes in healthy men. METHODS: A double-blind, randomized, placebo-controlled, and three-way crossover trial was conducted in nine healthy men. Every subject received four identical infusions of saline solution, 0.04 mg/kg dexamethasone, or 1.0 mg/kg dexamethasone during three observation periods of 48 hours each. RESULTS: Dexamethasone time and dose dependently decreased the L-selectin expression on neutrophils and lymphocytes as measured by flowcytometry. This effect occurred with a time lag of 8 hours after start of treatment: the L-selectin binding index of neutrophils decreased by a maximum of -50% (confidence interval [CI], -37% to -63%) and that of lymphocytes by -26% (CI, -8% to -45%) at 32 hours after the start of treatment with high-dose dexamethasone (p < 0.016). Low-dose dexamethasone had only a transient effect on L-selectin expression of lymphocytes and a less pronounced effect on L-selectin expression of neutrophils. CONCLUSION: Dexamethasone time and dose dependently decreases L-selectin expression on neutrophils and lymphocytes in health men, an effect that is less pronounced than that previously reported for animals.

Adult↗
PubMed1999

Effect of dexamethasone on reactive oxygen species generation by leukocytes and plasma interleukin-10 concentrations: a pharmacodynamic study.

After the demonstration that hydrocortisone inhibits reactive oxygen species (ROS) generation by leukocytes in vivo in a highly predictable manner, we investigated the effect of dexamethasone at a dose of 4 mg, which is thought to be roughly equivalent to 100 mg hydrocortisone. We also tested the hypothesis that dexamethasone may increase the plasma concentration of interleukin-10 (IL-10), an immunomodulatory cytokine that inhibits T(H)1 cells. Dexamethasone (4 mg given intravenously) markedly inhibited ROS generation by mononuclear cells and polymorphonuclear leukocytes. The onset of the effect on polymorphonuclear leukocytes occurred at 1 hour (76.3% +/- 9.3% of basal value), and the peak effect occurred at 4 hours (22.9% +/- 6.4% of basal value), with a significant inhibition still persistent at 8 hours (51.3% +/- 14.3% of basal value; F = 66.7; P < .001). ROS generation was restored to baseline at 24 hours (97.6% +/- 9.5%). The inhibitory effect of dexamethasone on mononuclear cells was 78.3% +/- 9.5% of baseline at 1 hour, 11.4% +/- 6.6% at 4 hours, 30.3% +/- 14.1% at 8 hours, and 102.3% +/- 18% at 24 hours (F = 66.5; P < .001). The peak inhibitory effect of dexamethasone on mononuclear cells (11.4% +/- 6.6%) was significantly greater (P < .05) than that on polymorphonuclear leukocytes (22.9% +/- 6.4%). Plasma IL-10 concentrations increased consistently from 4.8 +/- 1.8 pg/mL within 1 hour of dexamethasone injection and peaked at 4 hours (8.8 +/- 2.3 pg/mL), declining to baseline at 8 hours (F = 4.26; P < .004). Dexamethasone (and possibly other glucocorticoids) therefore exerts its immunosuppressive and anti-inflammatory effects by inhibiting ROS generation by leukocytes and by increasing the plasma concentrations of IL-10.

Adult↗