Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “DEXAMETHASONE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 433 records · Page 24Linked to original sources
PubMed1997

Dexamethasone upregulates the Na-K-ATPase in rat alveolar epithelial cells.

Previous studies in kidney, heart, and liver cells have demonstrated that dexamethasone regulates the expression of Na-K-ATPase. In the lungs, Na-K-ATPase has been reported in alveolar epithelial type II (ATII) cells and is thought to participate in active Na+ transport and lung edema clearance. The aim of this study was to determine whether Na-K-ATPase would be regulated by dexamethasone in cultured rat ATII cells. Regulation of the Na-K-ATPase by dexamethasone could lead to a greater understanding of its role in active Na+ transport and lung edema clearance. Rat ATII cells were isolated, plated for 24 h, and exposed to 10(-7) and 10(-8) M dexamethasone. These cells were harvested at 0, 3, 6, 12, and 24 h after dexamethasone exposure for determination of steady-state Na-K-ATPase mRNA transcript levels, protein expression, and function. The steady-state Na-K-ATPase beta1-mRNA transcript levels increased in ATII cells 6, 12, and 24 h after dexamethasone exposure (P < 0.05). However, the steady-state alpha1-mRNA transcript levels were unchanged. The protein expression for the alpha1- and beta1-subunits increased in ATII cells exposed to dexamethasone compared with controls in association with a temporal increase in Na-K-ATPase function after dexamethasone exposure. These results suggest that dexamethasone regulates Na-K-ATPase in ATII cells possibly by transcriptional, translational, and posttranslational mechanisms.

Animals↗
PubMed2006

Prenatal programming of rat proximal tubule Na+/H+ exchanger by dexamethasone.

Prenatal administration of dexamethasone causes hypertension in rats when they are studied as adults. Although an increase in tubular sodium reabsorption has been postulated to be a factor programming hypertension, this has never been directly demonstrated. The purpose of this study was to examine whether prenatal programming by dexamethasone affected postnatal proximal tubular transport. Pregnant Sprague-Dawley rats were injected with intraperitoneal dexamethasone (0.2 mg/kg) daily for 4 days between the 15th and 18th days of gestation. Prenatal dexamethasone resulted in an elevation in systolic blood pressure when the rats were studied at 7-8 wk of age compared with vehicle-treated controls: 131 +/- 3 vs. 115 +/- 3 mmHg (P < 0.001). The rate of proximal convoluted tubule volume absorption, measured using in vitro microperfusion, was 0.61 + 0.07 nl.mm(-1).min(-1) in control rats and 0.93+ 0.07 nl.mm(-1).min(-1) in rats that received prenatal dexamethasone (P < 0.05). Na(+)/H(+) exchanger activity measured in perfused tubules in vitro using the pH-sensitive dye BCECF showed a similar 50% increase in activity in proximal convoluted tubules from rats treated with prenatal dexamethasone. Although there was no change in abundance of NHE3 mRNA, the predominant luminal proximal tubule Na(+)/H(+) exchanger, there was an increase in NHE3 protein abundance on brush-border membrane vesicles in 7- to 8-wk-old rats receiving prenatal dexamethasone. In conclusion, prenatal administration of dexamethasone in rats increases proximal tubule transport when rats are studied at 7-8 wk old, in part by stimulating Na(+)/H(+) exchanger activity. The increase in proximal tubule transport may be a factor mediating the hypertension by prenatal programming with dexamethasone.

Animals↗
PubMed1996

Dexamethasone upregulates ANP C-receptor protein in human mesangial cells without affecting mRNA.

The objective of this study was to examine the role of dexamethasone on the expression of natriuretic peptide B-type and C-type receptors (ANPR-B and ANPR-C) in cultured human mesangial cells, which only possess these two subtypes. Dexamethasone caused concentration- and time-dependent increases in 125I-labeled ANP binding, which were prevented by glucocorticoid receptor inhibition with RU-38486. A lag time of 24 h and a concentration of dexamethasone of at least 1 nmol/l were necessary for this effect to occur. Dexamethasone-induced upregulation of 125I-ANP binding resulted from increased receptor density. No change in dissociation constant (Kd) was observed. Only ANPR-C were affected by dexamethasone. Indeed, dexamethasone did not modify C-type natriuretic peptide (i.e., CNP)-dependent cGMP production by mesangial cells. Moreover, dexamethasone upregulated ANPR-C protein expression as shown by Western blot analysis and by an increase in ANPR-C immunoreactivity at the cell surface. In contrast, dexamethasone did not modify ANPR-C mRNA expression. In conclusion, glucocorticoids increase ANPR-C density on mesangial cells through a mechanism implying, successively, interaction with the glucocorticoid receptor and increase of ANPR-C protein synthesis at a posttranscriptional stage. Thus dexamethasone may influence availability of natriuretic peptides at their glomerular target sites.

Cells, Cultured↗
PubMed2004

2-(8-Hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl)propionic acid, a small molecule isocoumarin, potentiates dexamethasone-induced apoptosis of human multiple myeloma cells.

2-(8-Hydroxy-6-methoxy-1-oxo-1Eta-2-benzopyran-3-yl)propionic acid (NM-3) is a small molecule isocoumarin derivative that has recently entered clinical trials as an orally bioavailable anticancer agent. NM-3 induces lethality of human carcinoma cells by both apoptotic and nonapoptotic mechanisms and potentiates the effects of cytotoxic chemotherapeutic agents. The present studies have evaluated the effects of NM-3 on human multiple myeloma (MM) cells. The results demonstrate that NM-3 potentiates dexamethasone-induced killing of both dexamethasone-sensitive MM1.S and dexamethasone-resistant RPMI8226 and U266 MM cells. We show that NM-3 enhances dexamethasone-induced release of the mitochondrial apoptogenic factors cytochrome c and Smac/DIABLO. The results also demonstrate that NM-3 enhances dexamethasone-induced activation of the intrinsic caspase-9->caspase-3 apoptotic pathway. In concert with these results, NM-3 potentiates dexamethasone-induced apoptosis of MM1.S cells. Moreover, NM-3 acts synergistically with dexamethasone in inducing apoptosis of the dexamethasone-resistant RPMI8226 and U266 MM cells. These findings indicate that NM-3 may be effective in combination with dexamethasone in the treatment of MM.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Effect on growth of two different dexamethasone courses for preterm infants at risk of chronic lung disease. A randomized trial.

A randomized study was designed to evaluate the effects of two different dexamethasone courses on the growth of preterm infants. The first phase included 30 preterm infants at high risk for chronic lung disease (CLD). 15 babies (moderately early dexamethasone group) were treated with dexamethasone for 14 days, from the 10th day of life, and received a total dose of 4.75 mg/kg; 15 babies were assigned to the control group. The second phase included 30 preterm infants at high risk for CLD. 15 babies (early dexamethasone group) were treated with dexamethasone for 7 days, from the 4th day of life, and received a total dose of 2.38 mg/kg; 15 babies were assigned to the control group. All the main clinical baseline characteristics were similar between the groups both in the first and in the second phase. Infants given the two dexamethasone courses showed significantly reduced weight gain during the period of treatment when compared to the respective control group, but they had a weight catch-up soon after the end of treatment. At 30 days of life the weight and length gain of each treated group were similar to those of control infants, but the moderately early dexamethasone group showed a significantly poorer head growth. No differences between the groups were observed at discharge. Dexamethasone treatment induces a slower weight gain which is time-limited to the period of treatment and is followed by a body weight catch-up. However, the poorer head growth detected at 30 days of life in the infants who received a higher dose of dexamethasone could indicate important adverse effects, possibly dose-related, on postnatal brain growth and development.

Anti-Inflammatory Agents↗
PubMed1998

Dexamethasone rapidly regulates TRH mRNA levels in hypothalamic cell cultures: interaction with the cAMP pathway.

The biosynthesis of thyrotropin-releasing hormone (TRH) in the hypothalamic paraventricular nucleus (PVN) is subject to neural and hormonal regulations. To identify some of the potential effectors of this modulation, we incubated hypothalamic dispersed cells with dexamethasone for short periods of time (1-3 h) and studied the interaction of this hormone with protein kinase C (PKC) and PKA signaling pathways. TRH mRNA relative changes were determined by the RT-PCR technique. One hour incubation with 10(-10)-10(-4) M dexamethasone produced a concentration-dependent biphasic effect: an inhibition was observed on TRH mRNA levels at 10(-10) M, an increase above control at 10(-8)-10(-6) M and a reduction at higher concentrations (10(-5)- 10(-4) M). The stimulatory effect of 10(-8) M dexamethasone on TRH mRNA was essentially independent of new protein synthesis, as evidenced by cycloheximide pretreatment. Changes in TRH mRNA levels were reflected by enhanced TRH cell content. Incubation with a cAMP analogue (8-bromo-cAMP, 8Br-cAMP) or with a PKC activator (12-O-tetradecanoylphorbol-13-acetate, TPA) increased TRH mRNA levels after 1 and 2 h, respectively. An increase in TRH mRNA expression was observed by in situ hybridization of dexamethasone or 8Br-cAMP-treated cells. The interaction of dexamethasone, PKA and PKC signaling pathways was studied by combined treatment. The stimulatory effect of 10(-7) M TPA on TRH mRNA levels was additive to that of dexamethasone; in contrast, coincubation with 10(-3) M 8-Br-cAMP and dexamethasone diminished the stimulatory effect of both drugs. An inhibition was observed when the cAMP analogue was coincubated with TPA or TPA and dexamethasone. These results demonstrate that dexamethasone can rapidly regulate TRH biosynthesis and suggest a cross talk between cAMP, glucocorticoid receptors and PKC transducing pathways.

Animals↗
PubMed2004

Effects of dexamethasone, all-trans retinoic acid, vitamin D(3) and interferon-alpha on FO myeloma cells.

BACKGROUND: Since multiple myeloma responds poorly to conventional chemotherapy or radiotherapy, new therapeutic approaches are needed. This study investigated the effects of dexamethasone, all-trans retinoic acid (ATRA), the active metabolite of vitamin D(3) [1,25(OH)(2)D(3)] and interferon-alpha on FO mouse myeloma cells (non-immunoglobulin-secreting myeloma cell line) in single drug or drug combination groups in vitro. METHODS: Apoptosis ratio and change in cell counts in 4 single drug groups (dexamethasone, ATRA, vitamin D(3) and interferon-alpha) and 6 combination drug groups (dexamethasone + vitamin D(3,) dexamethasone + ATRA, dexamethasone + interferon-alpha, vitamin D(3) + ATRA, vitamin D(3) + interferon-alpha, interferon-alpha + ATRA) were compared with the control group. RESULTS: When treatment groups were compared with the control group, there was a significant increase in apoptosis in all, but this was most prominent in the group treated with dexamethasone alone. The apoptosis ratios were 0.10 and 6.82% in the control and dexamethasone-only groups, respectively. We also found that there was a significant decrease in cell count, particularly in the dexamethasone-only, ATRA-only, and ATRA-vitamin D(3) combination groups. CONCLUSION: ATRA, interferon-alpha, vitaminD(3) and particularly dexamethasone have significant effects on FO mouse myeloma cells resulting in a decreased cell count and an increased apoptosis ratio. This study should be repeated with human myeloma cell lines for further information.

Animals↗
PubMed2005

Cardiovascular effects of low-dose dexamethasone in very low birth weight neonates with refractory hypotension.

BACKGROUND: Administration of hydrocortisone and relatively high doses of dexamethasone increase blood pressure in volume- and pressor-resistant hypotensive preterm infants. However, little is known about the temporal relationship of dexamethasone administration and the improvement in blood pressure and the weaning of pressors/inotropes. Furthermore, there are no sufficient data available on whether a smaller dose of dexamethasone would also be effective in treating refractory hypotension. OBJECTIVE: To study the cardiovascular responses to low-dose dexamethasone in very low birth weight neonates with volume- and pressor-resistant hypotension. METHODS: Retrospective database review. Twenty-four preterm neonates (gestational age 26 (23-34) weeks; birth weight 801 (457-1,180) g; postnatal age 2 (1-24) days, medians (ranges)) who remained hypotensive despite volume administration and combined dopamine and dobutamine treatment at >or=30 microg/kg/min received dexamethasone 0.1 mg/kg followed by 0.05 mg/kg intravenously every 12 h for 5 additional doses if still on pressors >or=8 microg/kg/min. RESULTS: Two hours after the first dose of dexamethasone the mean blood pressure increased from 30 +/- 5 to 34 +/- 6 mm Hg (p < 0.001) and remained elevated at 4, 6, 12, and 24 h after treatment was started (p < 0.001). Six hours after the initial dose of dexamethasone the pressor/inotrope requirement decreased from 34 +/- 9 to 24 +/- 13 microg/kg/min (p = 0.001) and continued to decrease at 12 and 24 h (p < 0.001). Urine output also increased significantly during the first 6 h after dexamethasone (p < 0.001). CONCLUSIONS: Low-dose dexamethasone rapidly increases blood pressure and decreases pressor requirements in very low birth weight neonates with volume- and pressor-resistant hypotension.

Cardiovascular System↗
PubMed1995

Dexamethasone suppresses the release of prolactin from the rat anterior pituitary gland by lipocortin 1 dependent and independent mechanisms.

Glucocorticoids have been shown repeatedly to inhibit the release of prolactin (PRL) in the rat but their site and mode of action is unknown. In the present study, we used an in vitro model to examine the requirement for protein synthesis for dexamethasone to suppress the release of immunoreactive (ir)-PRL release from the rat pituitary gland. In addition we have performed a series of in vitro and in vivo experiments to investigate the potential role in this regard of lipocortin 1 (LC1), a protein shown previously not only to mediate aspects of the anti-inflammatory and anti-proliferative actions of the glucocorticoids but also to contribute to the regulatory actions of the steroids in the brain-neuroendocrine system. In vitro, the release of ir-PRL from rat anterior pituitary tissue initiated by submaximal concentrations of VIP (10 nM). TRH (10 nM) or the adenyl cyclase activator forskolin (100 microM) was reduced significantly (p < 0.01) by preincubation (2 h) of the tissue with dexamethasone (0.1 microM). By contrast, ir-PRL release evoked by a submaximal concentration of the L-Ca2+ channel opener BAY K8644 (10 microM) was unaffected by the steroid although readily antagonised (p < 0.01) by nifedipine (1-100 microM). Exposure of the pituitary tissue to dexamethasone (0.1 microM) also caused a pronounced and highly significant increase in de novo protein synthesis, as assessed by the incorporation of 14C-lysine into the tissue (p < 0.001). This response was reduced markedly by the inclusion of the RNA and protein synthesis inhibitors, actinomycin-D (0.5 micrograms/ml) or cycloheximide (1.0 micrograms/ml), in the incubation medium (p < 0.001), both of which also effectively abrogated (p < 0.01) the dexamethasone-induced inhibition of the release of ir-PRL evoked by TRH. VIP and forskolin. Lipocortin I was readily detectable by Western blotting in protein extracts of freshly excised anterior pituitary tissue: a small proportion of the protein was found to be attached to the outer surface of the cells where it was retained by a Ca(2+)-dependent mechanism. Exposure of the tissue in vitro to dexamethasone (0.1 microM) or corticosterone (0.1 microM) but not 17 beta-oestradiol (0.1 microM) caused a pronounced increase in the amount of LC1 attached to the outer surface of the cells and concomitant decrease in the LC1 content of the intracellular LC1 pool. Addition of an N-terminal LC1 fragment. LC11-188 (10 pg-10 ng/ml), to the incubation medium reduced significantly (p < 0.01) the increases in ir-PRL release induced in vitro by VIP (10 nM) and forskolin (100 microM). By contrast, at all concentrations tested. LC11-188 (10 pg-10 ng/ml) failed to influence (p < 0.05) the highly significant (p < 0.01) ir-PRL response to TRH (10 nM). Similarly, the inhibitory actions of dexamethasone (0.1 microM) on the release of ir-PRL induced by VIP (10 nM) or forskolin (100 microM) but not by TRH (10 nM) were substantially reversed (p < 0.01) by a specific monoclonal anti-LC1 antibody while an isotype-matched control antibody was without effect. In vivo, rats pretreated with either a polyclonal anti LC1 antiserum (anti-LC1 pAb, 1 ml/day s.c. for 2 days) or a corresponding volume of non-immune sheep serum (NSS) responded to stress (laparotomy under ether anaesthesia) with significant (p < 0.05) increases in the serum ir-PRL concentration. In the NSS-treated group, the ir-PRL response to stress was effectively inhibited by dexamethasone (100 micrograms/kg i.p.) which had no effect on the pre-stress serum ir-PRL concentration. By contrast, in rats pretreated with anti-LC1 pAb dexamethasone failed to block the stress-induced release of ir-PRL. The results show clearly that the inhibitory actions of dexamethasone on PRL release are dependent on de novo protein synthesis and provide novel evidence for the involvement of both LC1-dependent and LC1-independent mechanisms.

Animals↗
PubMed1990

Reciprocal effects of dexamethasone on vasodilatory responses to arachidonic acid and prostanoids in the isolated perfused rabbit kidney.

We reported that dexamethasone treatment of rabbits causes a reduction in renal vasoconstrictor responses to prostaglandin F2 alpha and U46619, an agonist at the thromboxane-endoperoxide receptor, but not to phenylephrine. The purpose of this study was to examine if dexamethasone treatment can affect the renal vasodilatory responses to prostacyclin (PGI2) and prostaglandin E2 (PGE2) in isolated Krebs-perfused kidneys constricted with phenylephrine. In kidneys from dexamethasone-treated rabbits, the vasodilatory response to PGI2 was reduced by 57%, whereas that to PGE2 was converted to a vasoconstrictor response. This effect of dexamethasone appears to be specific in that the renal vasodilatory responses to forskolin and to sodium nitroprusside were not affected by the steroid. Contrasting with the inhibitory effect of dexamethasone on prostanoid-induced renal vasodilation, treatment with dexamethasone augmented the renal vasodilatory response to arachidonic acid; for example, arachidonic acid, at 10 micrograms decreased perfusion pressure by 24.8 +/- 5.4 and 49.0 +/- 5.6 mm Hg in kidneys from vehicle- and dexamethasone-treated rabbits, respectively. The enhanced vasodilatory effect of arachidonic acid could not be attributed to increased renal formation of PGE2 and PGI2. In conclusion, dexamethasone interferes with prostanoid-mediated renal vasodilation, which is not associated with an impairment in renal responsiveness to direct activators of adenylate cyclase and guanylate cyclase. The reciprocal effect of dexamethasone on the renal vascular responses to arachidonic acid and vasodilatory prostanoids are indicative of a previously unrecognized influence of glucocorticoids on the renal arachidonate-prostaglandin system.

6-Ketoprostaglandin F1 alpha↗
PubMed1975

Effect of dexamethasone on insulin binding, glucose transport, and glucose oxidation of isolated rat adipocytes.

We have studied the in vitro effects of dexamethasone on isolated rat adipocytes at concentrations of dexamethasone therapeutically achieved in man. Glucose oxidation, glucose transport, and insulin binding were assessed. In dexamethasone-treated cells, glucose oxidation was decreased by 30-40% both in the absence of insulin (basal state) and at low insulin levels (less than 25 mu/ML). At maximally effective insulin levels (over 100 muU/ml) no differences existed between control and treated cells. If glucose transport were the rate-limiting step for glucose oxidation in the basal state and at low (submaximal) insulin levels, but not at maximally effective insulin concentrations, then these data could be explained by postulating that dexamethasone has a direct affect on glucose transport and does not affect intracellular oxidative pathways. We tested this hypothesis by directly assessing glucose transport in dexamethasone-treated cells. Glucose transport was assessed by measuring the uptake of [14C]2-deoxy glucose. These studies demonstrated a 30-40% decrease in 2-deoxy glucose uptake by treated cells both in the basal state and at all insulin concentrations. Thus, a direct glucocorticoid effect on the glucose transport system seems to account for the decreased ability of dexamethasone-treated cells to oxidize glucose. Since dexamethasone treatment leads to decreased insulin binding to adipocytes in vivo, we examined the possibility that the in vitro decreases in insulin-mediated glucose transport could be due to decreased insulin receptors. Insulin binding to control and treated adipocytes was measured, and no differences were found. Therefore, in cntrast to previously reported in vivo studies, adipocytes treated in vitro with dexamethasone retain a normal ability to bind insulin. Thus, these studies suggest that all of the in vitro effects of dexamethasone on glucose oxidation are due to direct inhibition of the glucose transport system.

Adipose Tissue↗
PubMed1986

Dexamethasone modulates lipoprotein metabolism in cultured human monocyte-derived macrophages. Stimulation of scavenger receptor activity.

Human monocyte-derived macrophages (HMM) play a key role in the formation of atherosclerotic plaques by accumulating cholesteryl ester (CE) to become foam cells. HMM have receptors for native low density lipoprotein (LDL) and acetylated-LDL (ALDL), and uptake of ALDL can promote substantial cellular CE accumulation. Furthermore, macrophages specifically and saturably bind glucocorticoids, which in turn modulate numerous macrophage functions. Preincubating HMM in dexamethasone-inhibited LDL degradation (230 +/- 12 vs. 515 +/- 21 ng/mg cell protein X 18 h, P less than 0.001) but stimulated ALDL degradation (5.3 +/- 0.5 vs. 2.5 +/- 0.3 micrograms/mg X 18 h, P less than 0.01). These effects were time- and dose-dependent, occurring maximally by 24 h and with 2.5 X 10(-8) M dexamethasone. Dexamethasone increased the maximum velocity for ALDL degradation (16.2 vs. 12.0 micrograms/mg X 18 h, P less than 0.01) without changing the apparent Michaelis constant. Progesterone, 11 alpha-epicortisol, and 17 alpha-OH progesterone (a competitive antagonist of the glucocorticoid receptor) had no effect on HMM ALDL degradation, but 17 alpha-OH progesterone abolished the stimulatory action of dexamethasone. In he presence of ALDL, incorporation of [14C]oleic acid into CE was enhanced over fourfold by dexamethasone (4015 +/- 586 vs. 943 +/- 91 cpm/mg X 2 h, P less than 0.01), and HMM incubated with ALDL and dexamethasone accumulated more free cholesterol (34.6 +/- 1.9 vs. 26.2 +/- 0.8 micrograms/mg, P less than 0.02) and CE (32.8 +/- 2.3 vs. 14.8 +/- 0.8 micrograms/mg, P less than 0.002) than did macrophages without dexamethasone. In cultured human umbilical vein endothelial cells, dexamethasone did not change ALDL degradation, but reduced LDL degradation by 30% (P less than 0.001). In summary, dexamethasone inhibits LDL receptor activity by both macrophages and endothelial cells, but stimulates ALDL receptor activity only in macrophages. These observations provide evidence for the regulation of macrophage endocytic receptors by glucocorticoid hormones.

17-alpha-Hydroxyprogesterone↗
PubMed1995

Dexamethasone enhances insulin-like growth factor-I effects on skeletal muscle cell proliferation. Role of specific intracellular signaling pathways.

IGF-I stimulation of cell proliferation and c-Fos expression in skeletal muscle cells is markedly enhanced by dexamethasone. The effect of dexamethasone is not mediated by changes in IGF-binding proteins, as evidenced by similar effects of dexamethasone on the actions of insulin, PDGF-BB, and the IGF-I analogue long R3IGF-I. Dexamethasone also does not alter autocrine IGF-II secretion by muscle cells. To investigate the mechanism of the augmentation of IGF-I action, the effects of dexamethasone on intracellular IGF-I signaling pathways were determined. In dexamethasone-treated cells, the levels of IGF-I receptor tyrosine phosphorylation and receptor-associated phosphatidylinositol 3-kinase activity were increased. Dexamethasone-treated cells also showed increased and prolonged tyrosine phosphorylation of the Shc proteins. In contrast, dexamethasone decreased both tyrosine phosphorylation and expression of insulin receptor substrate 1 (IRS-1) and IRS-1-associated phosphatidylinositol 3-kinase activity. Thus, distinct signaling pathways activated by the IGF-I receptor in skeletal muscle cells are differentially regulated by dexamethasone. Potentiation of IGF-I action correlates with increased IGF-I receptor-associated phosphatidylinositol 3-kinase activity and tyrosine phosphorylation of Shc, but appears to be independent of activation of the IRS-1/phosphatidylinositol 3-kinase signaling pathway.

Animals↗
PubMed1999

Dexamethasone reduces oxygen induced retinopathy in a mouse model.

Dexamethasone is widely used in the postnatal period. Its impact on retinopathy of prematurity (ROP) is extremely controversial; published studies have found a detrimental, protective, or no effect on ROP. The goal of this study was to test the hypothesis that use of dexamethasone during the injury phase (oxygen exposure) reduces the severity of oxygen-induced retinopathy (OIR) in a mouse model. C57BL6 mice pups were exposed to either room air or hyperoxia (75% FiO2) from postnatal d 7 through 12 (PN7-12) with or without dexamethasone (0.5 mg/kg/d s.c.) and killed on PN17-21. Retinopathy was assessed by a scoring system of retinal flat mount preparations and periodic acid-Schiff (PAS) staining of retinal sections. Pups exposed to dexamethasone and oxygen had a lower median retinopathy score of 5 (4, 6) [median (25th, 75th quartile)] compared with animals exposed to oxygen alone with median score of 9 (6, 10) with p < 0.001. PAS staining for extra retinal neovascularization in the dexamethasone and oxygen treated animals showed a significant reduction in number of nuclei extending beyond the inner limiting membrane when compared with oxygen exposed alone (p = 0.04). Animals treated with dexamethasone had decreased weight gain compared with control animals. Dexamethasone did not appear to affect the normal development of retinal vasculature as assessed by the scoring system when compared with control animals. Thus, dexamethasone decreases severity of OIR without having an adverse effect on normal retinal vascular development in the mouse model. We speculate that dexamethasone decreases the injury response that occurs during the hyperoxic phase, thus protecting the developing vasculature and improving the subsequent retinopathy.

Animals↗
PubMed1999

Energy expenditure and energy intake during dexamethasone therapy for chronic lung disease.

Dexamethasone is commonly administered to ventilator-dependent preterm infants with chronic lung disease. Infants receiving dexamethasone therapy frequently exhibit decreased rates of weight gain. The purpose of this investigation was to determine whether decreased growth in infants receiving dexamethasone therapy is caused by increased energy expenditure. Twelve infants were studied: 6 received dexamethasone treatment at 2 wk of age and crossed over to receive placebo treatment at 4 wk; the treatment order was reversed in the other 6 infants. The doubly labeled water method was used to determine energy expenditure for a 1-wk period during each treatment phase. The rate of weight gain during dexamethasone treatment was 6.5+/-10.6 and 20.0+/-5.7 g/kg/d during placebo treatment. Energy expenditure was 93.1+/-34.6 kcal/kg/d during dexamethasone treatment and 88.3+/-37.1 kcal/kg/d during placebo treatment. Energy intake was 119.2+/-29.0 kcal/kg/d during dexamethasone treatment and 113.8+/-23.7 kcal/kg/d during placebo treatment. The difference between intake and expenditure, or the energy available for growth, was 26.2+/-36.8 kcal/kg/d during dexamethasone treatment and 25.5+/-37.4 kcal/kg/d during placebo treatment. No significant differences were found in energy expenditure or energy intake between the treatment phases. The reduced growth seen in infants receiving dexamethasone treatment cannot be explained by increased energy expenditure or decreased energy intake, but may be due to differences in the composition of newly accreted tissue.

Anti-Inflammatory Agents↗
PubMed2002

Dexamethasone and tumor necrosis factor-alpha act together to induce the cellular inhibitor of apoptosis-2 gene and prevent apoptosis in a variety of cell types.

Using microarray technology, we analyzed 12,000 genes for regulation by TNF-alpha and the synthetic glucocorticoid, dexamethasone, in the human lung epithelial cell line, A549. Only one gene was induced by both agents, the cellular inhibitor of apoptosis 2 (c-IAP2), which was induced 17-fold and 5-fold by TNF-alpha at 2 h and 24 h, respectively, and increased 14-fold and 9-fold by dexamethasone at 2 h and 24 h, respectively. The combination of the two agents together led to an additive increase (34-fold) at 2 h and a more than additive effect (36-fold) at 24 h. The human c-IAP2 promoter contains two nuclear factor (NF)-kappaB sites that have been shown to be required for transcriptional activation by TNF-alpha. To test whether glucocorticoids regulate the c-IAP2 gene at the level of the promoter, a reporter vector containing 947 bases upstream of the start site of transcription of the human c-IAP2 promoter was linked to luciferase [IAP(-947-+54)-LUC] and transfected into A549 cells. Dexamethasone and TNF-alpha each induced reporter activity, whereas the combination of the two agents led to greater induction of luciferase than either one alone. Truncation of the promoter region containing a putative glucocorticoid response element (GRE) at -515 [IAP(-395-+54)-LUC] or mutation of the GRE in the context of the natural promoter [IAP(-947-+54mutGRE)-LUC] resulted in a loss of dexamethasone-mediated induction of reporter activity. Although the functional NF-kappaB sites were retained in the truncated and mutant c-IAP2 promoter constructs, dexamethasone did not inhibit the TNF-alpha induction of luciferase activity, indicating that GR repression through the NF-kappaB sites did not occur. Regulation of the c-IAP2 gene is therefore unique, as GR and NF-kappaB signaling pathways are usually mutually antagonistic, not cooperative. Treatment of A549 cells with TNF-alpha and/or dexamethasone had no effect on cell death, but the two agents were able to inhibit interferon-gamma/anti-FAS antibody-mediated apoptosis. In human glioblastoma A172 cells, TNF-alpha and dexamethasone together elicited a greater than additive increase in c-IAP2 mRNA levels and also inhibited anti-FAS antibody-mediated A172 cell apoptosis. In contrast, in human CEM-C7 leukemic T cells, whereas TNF-alpha and dexamethasone treatment also led to an increase in c-IAP2 mRNA, the two agents were able to induce apoptosis on their own. However, TNF-alpha and dexamethasone were also able to blunt anti-FAS-induced apoptosis in the T cells. These data indicate that the induction of the antiapoptotic protein, c-IAP2, by glucocorticoids and TNF-alpha correlates with the ability of these agents to inhibit apoptosis in a variety of cell types.

Apoptosis↗
PubMed2004

Metabolic consequences of hypoxia from birth and dexamethasone treatment in the neonatal rat: comprehensive hepatic lipid and fatty acid profiling.

Neonatal hypoxia is a common condition resulting from pulmonary and/or cardiac dysfunction. Dexamethasone therapy is a common treatment for many causes of neonatal distress, including hypoxia. The present study examined the effects of dexamethasone treatment on both normoxic and hypoxic neonatal rats. We performed comprehensive hepatic fatty acid/lipid profiling and evaluated changes in pertinent plasma hormones and lipids and a functional hepatic correlate, i.e. hepatic lipase activity. Rats were exposed to hypoxia from birth to 7 d of age. A 4-d tapering dose regimen of dexamethasone was administered on: postnatal day (PD)3 (0.5 mg/kg), PD4 (0.25 mg/kg), PD5 (0.125 mg/kg), and PD6 (0.05 mg/kg). The most significant finding was that dexamethasone attenuated nearly all hypoxia-induced changes in hepatic lipid profiles. Hypoxia increased the concentration of hepatic triacylglyceride and free fatty acids and, more specifically, increased a number of fatty acid metabolites within these lipid classes. Administration of dexamethasone blocked these increases. Hypoxia alone increased the plasma concentration of cholesterol and triacylglyceride, had no effect on plasma glucose, and only tended to increase plasma insulin. Dexamethasone administration to hypoxic pups resulted in an additional increase in plasma lipid concentrations, an increase in insulin, and a decrease in plasma glucose. Hypoxia and dexamethasone treatment each decreased total hepatic lipase activity. Normoxic pups treated with dexamethasone displayed increased plasma lipids and insulin. The effects of dexamethasone on hepatic function in the hypoxic neonate are dramatic and have significant implications in the assessment and treatment of metabolic dysfunction in the newborn.

Animals↗
PubMed1982

The effect of dexamethasone on renal electrolyte excretion in the adrenalectomized rat.

The acute effect of low and high doses of dexamethasone on renal electrolyte excretion was examined in chronically (2--3 weeks) adrenalectomized rats and was compared with that of aldosterone. At the lowest effective dose (2 micrograms/100 g BW) dexamethasone injection produced a 70% increase in urinary potassium (K) excretion (0.99 +/- 0.06 to 1.70 +/- 0.20 mueq/min; P less than 0.005) but had no effect on sodium excretion. In contrast, low doses of aldosterone (2.5 micrograms/100 g BW) caused a significant decrease in urinary sodium excretion (6.23 +/- 1.2 to 2.75 +/- 0.7 mueq/min; P less than 0.01) but had no influence on renal potassium excretion (UKV). Higher doses of dexamethasone (10, 20 and 50 micrograms/100 g BW) produced a greater kaliuresis, increasing UKV by more than 100% over baseline and higher (P less than 0.05) than values after a low dose of dexamethasone, but again failed to lower sodium excretion. The increase in UKV after all doses of dexamethasone occurred in association with a significant increase in urinary K concentration; at higher doses of dexamethasone there was a variable increase in urine flow. The increase in UKV was not secondary to an increase in plasma K concentration nor was it associated with a rise in blood pressure or glomerular filtration rate after dexamethasone administration. These findings demonstrate that, in the adrenalectomized rat, acute administration of low and high doses of dexamethasone increases urinary K excretion without affecting sodium excretion. In contrast, aldosterone has little effect on K excretion but significantly decreases sodium excretion. These results indicate that the kaliuresis observed after dexamethasone cannot be attributed to a mineralocorticoid property of the hormone.

Adrenalectomy↗