Anti-inflammatory Effects Of Dexamethasone Research Articles

Anti-inflammatory effects of dexamethasone in COVID-19 patients: Translational population PK/PD modeling and simulation.

Dexamethasone (DEX) given at a dose of 6 mg once-daily for 10 days is a recommended dosing regimen in patients with coronavirus disease 2019 (COVID-19) requiring oxygen therapy. We developed a population pharmacokinetic and pharmacodynamic (PopPK/PD) model of DEX anti-inflammatory effects in COVID-19 and provide simulations comparing the expected efficacy of four dosing regimens of DEX. Nonlinear mixed-effects modeling and simulations were performed using Monolix Suite version 2021R1 (Lixoft, France). Published data for DEX PK in patients with COVID-19 exhibited moderate variability with a clearance of about half that in healthy adults. No accumulation of the drug was expected even with daily oral doses of 12 mg. Indirect effect models of DEX inhibition of TNFα, IL-6, and CRP plasma concentrations were enacted and simulations performed for DEX given at 1.5, 3, 6, and 12 mg daily for 10 days. The numbers of individuals that achieved specified reductions in inflammatory biomarkers were compared among the treatment groups. The simulations indicate the need for 6 or 12 mg daily doses of DEX for 10 days for simultaneous reductions in TNFα, IL-6, and CRP. Possibly beneficial is DEX given at a dose of 12 mg compared to 6 mg. The PopPK/PD model may be useful in the assessment of other anti-inflammatory compounds as well as drug combinations in the treatment of cytokine storms.

Effect of dexamethasone in two different doses on specific biochemical markers in patients with COVID-19

Background: Severe acute respiratory syndrome coronavirus 2 is the causative agent of coronavirus disease 2019 (COVID-19). The release of alarmins results in a “cytokine storm,” which can be attenuated by the immunomodulatory and anti-inflammatory effects of dexamethasone. Aim: To evaluate and assess the effect of dexamethasone in two different doses, on D-dimer, serum ferritin, C-reactive protein (CRP) levels, and granulocyte/lymphocyte (%) in patients with COVID-19. Patients and methods: A total of 100 patients were randomly divided into two groups; group A patients received a higher dose of dexamethasone than those in group B. Measurements of certain hematological and biochemical markers, including D-dimer, serum ferritin, CRP, and granulocyte/lymphocyte ratio were done for all the patients in both groups. These indices were compared at different times of treatment between the two groups. Results: The D-dimer and granulocyte/lymphocyte ratio measurements were statistically non-significant in both the groups in all three readings. The serum ferritin measurement was significant only on the 6th day of treatment. The results demonstrated that group A patients had significantly lower CRP levels on both the 3rd and 6th days of treatment. Conclusion: Administration of a slightly higher dose of dexamethasone (8 mg per day for three days, then 6 mg per day for another 3 days) in patients hospitalized with COVID-19 effectively reduces the inflammatory and hematological biomarkers in patients who required supplemental oxygen therapy.

Dexamethasone Attenuates the Perioperative Acute Phase Response for Simultaneous Bilateral Total Hip Arthroplasty.

This study aimed to evaluate the effect of perioperative dexamethasone on acute phase response (APR) after simultaneous bilateral total hip arthroplasty (SimBTHA). A retrospective case-control study was performed on 177 SimBTHA procedures. The patients were divided into 2 cohorts: patients receiving perioperative dexamethasone and patients in whom no dexamethasone was administered. We observed the effects of perioperative dexamethasone on the APR following SimBTHA by trending C-reactive protein and interleukin-6. Besides, the incidence of postoperative nausea and vomiting (PONV), postoperative visual analog scale (VAS) score, use of antiemetic and analgesic rescue, and complications were also compared. Compared to the no dexamethasone group, patients receiving dexamethasone yielded a significantly decreased C-reactive protein on postoperative days 1, 2 and 3. Such differences of interleukin-6 were also detected. In addition, the incidence of PONV, postoperative VAS score, and use of antiemetic and analgesic rescue were significantly decreased without increasing the risk of early surgical wound infection and gastrointestinal hemorrhage in patients receiving dexamethasone. The anti-inflammatory effects of dexamethasone can attenuate the APR after SimBTHA as well as decrease the PONV, postoperative VAS score, and use of antiemetic and analgesic rescue.

Repairing Effect of New Dexamethasone Nanoparticles in the Treatment of Acute Lung Injury and Cluster Nursing.

The repairing effect of new dexamethasone nanoparticles in the treatment of acute lung injury was investigated in this study, as well as cluster nursing. In this study, new dexamethasone model drugs were prepared by the aqueous solvent diffusion method, such as anti-ICAM-I monoclonal antibody-modified anionic dexamethasone NLCs and anti-ICAM-I monoclonal antibody-modified cationic dexamethasone NLCs. Besides, the physical and chemical properties and repairing effects of cationic dexamethasone on acute lung injury were compared. A mouse model of acute lung injury was established, and the anti-inflammatory effect of dexamethasone was evaluated by intravenous injection of dexamethasone nanoparticles in the intervention group and normal healthy mice in the control group. A total of 100 patients with acute lung injury in Hai'anPeople's Hospital Affiliated with Nantong University were selected, of which 50 cases were given cluster nursing intervention and the other 50 cases were taken as the control group. A human vascular endothelial cell line was applied to establish the model cells, and a model of inflammatory endothelial cells in acute lung injury was constructed using lipopolysaccharide stimulation, to verify the cytotoxicity of dexamethasone NLCs. It was found that the anion particle size was 250.12 ± 20.15 nm, the cationic particle size was 245.7 ± 2.1 nm; their Zeta potentials were -31 ± 0.5 mV and 38 ± 0.6 mV in turn; their encapsulation rates were 91% and 83%, respectively; the drug loading was 3.7% and 3.4% in sequence; the release lowest rate was 60%. The 50% lethal dose of anionic cells was higher than 600 g/mL, while that of cationic cells was lower. The respiratory function of the cluster nursing intervention group was better markedly than that of the control group, and the lung infection rate was 2.5% in the intervention group and 15% in the control group. In conclusion, dexamethasone nanoparticles had good anti-inflammatory effects. Anionic ICAM NLCs were less toxic than cationic cells and could better bind to lung vascular endothelial cells, which might reduce adverse drug reactions. Therefore, the building of bundled nursing could effectively alleviate respiratory dysfunction and reduce the infection rate of patients.

Evaluation of anti-inflammatory impact of dexamethasone-loaded PCL-PEG-PCL micelles on endotoxin-induced uveitis in rabbits

The aim of this study was to investigate the capability of polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL) micelles in improving the anti-inflammatory effects of dexamethasone (DEX). A film hydration method was used for the preparation of the DEX-loaded PCL-PEG-PCL micelles. In vitro cytotoxicity of the micelles obtained was investigated on L929 cells. Cellular uptake was studied by using flow cytometry and fluorescence microscopy. Anterior uveitis was induced in a group of rabbits by intravitreal injection of endotoxin from Salmonella typhimurium. The severity of inflammation-induced was clinically graded by using Hogan’s classification method. Protein concentration in the aqueous humor was also measured. The micelles exhibited suitable compatibility on L929 cells and were taken up by the cells in a concentration- and time-dependent manner. The DEX-loaded micelles could reduce the clinical symptoms of uveitis after a lag-time. At 24 and 36 h after the LPS injection, the PCL-PEG-PCL micelles showed a better inhibitory effect on uveitis than the marketed eye drop, the differences did not reach significant levels though. This study demonstrated the potential of the PCL-PEG-PCL micelles as carriers for DEX in treating anterior uveitis. However, this concept is still to be further investigated.

Modeling Sex Differences in Anti-inflammatory Effects of Dexamethasone in Arthritic Rats.

Collagen-induced arthritic (CIA) rats are used commonly for preclinical pharmacologic research into rheumatoid arthritis (RA). Dexamethasone (DEX), a potent corticosteroid (CS), remains an important component in combination therapy for RA. Although sex differences in RA and CS pharmacokinetics/pharmacodynamics (PK/PD) have been documented in humans, there has been no such comprehensive evaluation of sex differences in CIA rats. Paw size measurements were obtained for males and females from four groups of animals: healthy controls, non-drug treated arthritic animals, and both 0.225 and 2.25mg/kg DEX-treated arthritic animals. A turnover model for disease progression, minimal PBPK model for drug concentrations, and inhibitory indirect response model were applied using population PK/PD modeling. The clearances of DEX were 43% greater in males, but other PK parameters were similar. The temporal profiles of paw swelling exhibited earlier progression, peak edema times, and disease remission in females. DEX suppressed paw edema well in both males and females with similar capacity (Imax) values (=1.0), but DEX potency was less in females with higher IC50 values (0.101 versus 0.015ng/mL). The pharmacology of DEX was well characterized in CIA rats. This study addresses knowledge gaps about sex differences and can be a guide for more mechanistic assessment of sex, drug, and disease differences in RA.

Do Corticosteroids Attenuate the Peri-Operative Acute Phase Response After Total Knee Arthroplasty?

BackgroundFollowing tissue injury, the acute phase response (APR) functions to survive and then repair injured tissue. An exuberant APR, which can be evoked by total knee arthroplasty (TKA), results in a hyper-inflammatory state, leading to pain, nausea, venous thromboembolism, or potentially life-threatening complications. Here, we observed the effects of peri-operative dexamethasone on the APR following TKA by trending C-reactive protein (CRP, mg/L) and fibrinogen (mg/dL). We hypothesize that the anti-inflammatory effects of dexamethasone can attenuate the APR after TKA and will be associated with decreased post-operative pain and nausea. MethodsA retrospective case-control study was performed on 188 unilateral TKA procedures. The patients were divided into a group receiving dexamethasone (10 mg intra-operatively and on post-operative day [POD] 1) and a group receiving no corticosteroids. Post-operative CRP, fibrinogen, morphine equivalents, and anti-emetic doses were recorded. ResultsCompared to the non-steroid group, patients receiving dexamethasone yielded a significantly decreased CRP on POD0 (5.5 vs 8.3), POD1 (11.8 vs 22.0), and POD2 (85.5 vs 148.9). A significant decrease in fibrinogen in patients receiving dexamethasone was seen on POD2 (460.0 vs 530.2). There was an increase in fibrinogen within the dexamethasone cohort at the 2-week visit (535.4 vs 488.9). Post-operative morphine equivalents administered were significantly decreased in patients receiving dexamethasone, but no difference in anti-emetic use was appreciated. ConclusionThese data support the hypothesis that the APR following TKA can be attenuated pharmacologically by corticosteroids. Further studies are needed to determine whether the attenuation of the APR with the use of corticosteroids prevents complications following TKA.

Evaluation the Effectiveness of Green Zinc Oxide Nanoparticles on The Anti-Inflammatory Effect of Dexamethasone and Its Side Effects in Rats

Green synthesis of nanoparticles is considered an ecofriendly technology because it does not involve toxic chemicals.In this study,green zinc oxide nanoparticles (7-25 nm) were synthesized from olive plant and examined for its anti-inflammatory activities alone or with dexamethasone in rats. Seventy rats were randomly allocated into 7 groups (10 rats/group). Group 1 served as a negative control. Other rats in the six groups were injected with formalin into the intra planter paws of right hind limb (50ul) followed by administration of investigated agents as following; group 2 used as control positive for inflammation. Group 3 and4 were administrated dexamethasone at 2 doses; 2 and 5mg/ kg b.wt. (i.m), respectively. Group 5 was treated with zinc oxide nanoparticles at dose of 25mg/ kg b.wt.(i.p). Groups 6 and 7 were treated with Zinc oxide nanoparticles at dose of 25 mg/kg b. wt. (i.p) and dexamethasone at doses of 2 and 5mg/kg b. wt. (i.m), respectively

Modeling Combined Immunosuppressive and Anti-inflammatory Effects of Dexamethasone and Naproxen in Rats Predicts the Steroid-Sparing Potential of Naproxen.

Dexamethasone (DEX), a widely prescribed corticosteroid, has long been the cornerstone of the treatment of inflammation and immunologic dysfunctions in rheumatoid arthritis. Corticosteroids are frequently used in combination with other antirheumatic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs to mitigate disease symptoms and minimize unwanted effects. We explored the steroid dose-sparing potential of the NSAID naproxen (NPX) with in vitro and in vivo studies. The single and joint suppressive effects of DEX and NPX on the in vitro mitogen-induced proliferation of T lymphocytes in blood and their anti-inflammatory actions on paw edema were investigated in female and male Lewis rats with collagen-induced arthritis (CIA). As expected, DEX was far more potent than NPX in these systems. Mathematical models incorporating an interaction term ψ were applied to quantitatively assess the nature and intensity of pharmacodynamic interactions between DEX and NPX. Modest synergistic effects of the two drugs were found in suppressing the mitogenic response of T lymphocytes. A pharmacokinetic/pharmacodynamic/disease progression model integrating dual drug inhibition quantitatively described the pharmacokinetics, time-course of single and joint anti-inflammatory effects (paw edema), and sex differences in CIA rats, and indicated additive effects of DEX and NPX. Further model simulations demonstrated the promising steroid-sparing potential of NPX in CIA rats, with the beneficial effects of the combination therapy more likely in males than females.

Effects of Platelet-Rich Plasma With Concomitant Use of a Corticosteroid on Tenocytes From Degenerative Rotator Cuff Tears in Interleukin 1β–Induced Tendinopathic Conditions

Background: A corticosteroid injection is commonly used to treat tendinopathy, but it has been associated with negative effects on tendon homeostasis. Platelet-rich plasma (PRP) is known to have proliferative and anabolic effects as well as cytoprotective effects against corticosteroids on tenocytes. However, the combined effects of a corticosteroid and PRP on the anti-inflammatory, matrix synthesis, and cytoprotective potential of tenocytes in conditions simulating tendinopathy have not been investigated. Purpose: To assess the effects of PRP on tenocytes from degenerative rotator cuff tears with the concomitant use of a corticosteroid in interleukin 1β (IL-1β)–induced tendinopathic conditions. Study Design: Controlled laboratory study. Methods: Tenocytes were enzymatically isolated and cultured from patients with degenerative rotator cuff tears. PRP was prepared using a plateletpheresis system, and growth factor concentrations were measured. To evaluate the gene expression of proinflammatory and anti-inflammatory cytokines, enzymes and their inhibitors, and matrix molecules, cells were cultured with 1 ng/mL IL-1β, 1 μM dexamethasone, and 10% (vol/vol) platelet-poor plasma (PPP) and PRP of 200, 1000, and 4000 × 103/μL; quantitative real-time reverse transcriptase polymerase chain reaction was also performed. Western blotting was performed to investigate the protein synthesis of degradative enzymes and their inhibitors. Cell viability, apoptosis, and senescence assays were also conducted. Results: PRP did not interfere with the anti-inflammatory effects of dexamethasone on tenocytes pretreated with IL-1β, but it increased the synthesis of tissue inhibitor of metalloproteinase (TIMP)–1 and -3. Meanwhile, PRP did not induce anti-inflammatory cytokines that had been suppressed with a corticosteroid. It did increase the type I/III collagen ratio mainly through the suppression of type III collagen expression. PRP reversed the decreased viability, increased apoptosis, and induced senescence with IL-1β and a corticosteroid. Conclusion: This study shows that the addition of PRP does not interfere with the anti-inflammatory effects of a corticosteroid on IL-1β–treated tenocytes from degenerative rotator cuff tears but that it does avoid the deleterious side effects of a corticosteroid. Clinical Relevance: PRP can be clinically useful with a corticosteroid as a treatment for tendinopathy.

MUC4 impairs the anti-inflammatory effects of corticosteroids in patients with chronic rhinosinusitis with nasal polyps

Current evidence suggests that membrane-tethered mucins could mediate corticosteroid efficacy, interacting with glucocorticoid receptor (GR) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Mucin 4 (MUC4)-tethered mucin is expressed in nasal polyp (NP) epithelial cells and upregulated under inflammatory conditions. Moreover, MUC4β has the capacity to interact with other intracellular proteins. We hypothesized that MUC4 modulates corticosteroid efficacy of patients with CRSwNP. We sought to analyze the role of MUC4 in corticosteroid effectiveness in different cohorts of patients with CRSwNP and elucidate the possible mechanisms involved. Eighty-one patients with CRSwNP took oral corticosteroids for 15days. Corticosteroid resistance was evaluated by using nasal endoscopy. Expression of MUC4 and MUC4β was evaluated by means of real-time PCR, Western blotting, and immunohistochemistry. BEAS-2B knockdown with RNA interference for MUC4 (small interfering RNA [siRNA]-MUC4) was used to analyze the role of MUC4 in the anti-inflammatory effects of dexamethasone. Twenty-two patients had NPs resistant to oral corticosteroids. MUC4 expression was upregulated in these patients. In siRNA-MUC4 BEAS-2B airway epithelial cells dexamethasone produced higher anti-inflammatory effects, increased inhibition of phospho-extracellular signal-regulated kinase 1/2, increased mitogen-activated protein kinase phosphatase 1 expression, and increased glucocorticoid response element activation. Immunoprecipitation and immunofluorescence experiments revealed that MUC4β forms a complex with GRα in the nuclei of NP epithelial cells from corticosteroid-resistant patients. MUC4β participates in the corticosteroid resistance process, inhibiting normal GRα nuclear function. The high expression of MUC4 in patients with CRSwNP might participate in corticosteroid resistance.

Does dexamethasone act in neuropeptides SP and CGRP in neurogenic inflammation of the skin? An experimental study.

To investigate the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) after subcutaneous injection of dexamethasone prior to skin incision in rats. Twenty seven Wistar-EPM-1 rats were randomly divided into three groups. The sham group (SG) of rats was injected with 0.9 % saline. The second group (Dexa) was injected with 1.0 mg/kg dexamethasone, and the third group (Dexa+) was injected with 10.0 mg/kg dexamethasone. In all groups, the three subcutaneous injections were performed 30 minutes prior to the surgical skin incision and tissue collection. SP and CGRP (15 kDa pro-CGRP and 5 kDa CGRP) were quantified by Western Blotting. No statistically significant differences (p>0.05) were found in pro-CGRP, CGRP and SP values in all three groups. The anti-inflammatory effect of dexamethasone did not occur when the substance P and calcitonin gene-related peptide levels were altered during the neurogenic inflammation process of skin wound healing in rats.

Beneficial effect of annexin A1 in a model of experimental allergic conjunctivitis

Annexin A1 (ANXA1), a 37 kDa glucocorticoid-regulated protein, is a potent anti-inflammatory mediator effective in terminating acute inflammatory response, and its role in allergic settings has been poorly studied. The aim of this investigation was to evaluate the mechanism of action of ANXA1 in intraocular inflammation using a classical model of ovalbumin (OVA)-induced allergic conjunctivitis (AC). OVA-immunised Balb/c mice, wild-type (WT) and ANXA1-deficient (AnxA1−/−), were challenged with eye drops containing OVA on days 14–16 with a subset of WT animals pretreated intraperitoneally with the peptide Ac2-26 (N-terminal region of ANXA1) or dexamethasone (DEX). After 24 h of the last ocular challenge, WT mice treated with Ac2-26 and DEX had significantly reduced clinical signs of conjunctivitis (chemosis, conjunctival hyperaemia, lid oedema and tearing), plasma IgE levels, leukocyte (eosinophil and neutrophil) influx and mast cell degranulation in the conjunctiva compared to WT controls. These anti-inflammatory effects of DEX were associated with high endogenous levels of ANXA1 in the ocular tissues as detected by immunohistochemistry. Additionally, Ac2-26 administration was effective to reduce IL-2, IL-4, IL-10, IL-13, eotaxin and RANTES in the eye and lymph nodes compared to untreated WT animals. The lack of ANXA1 produced an exacerbated allergic response as detected by the density of the inflammatory cell influx to the conjunctiva and the cytokine/chemokine release. These different effects observed for Ac2-26 were correlated with diminished level of activated ERK at 24 h in the ocular tissues compared to untreated OVA group. Our findings demonstrate the protective effect of ANXA1 during the inflammatory allergic response suggesting this protein as a potential target for new ocular inflammation therapies.

The anti-inflammatory efficacy of dexamethasone is protected by (−)-epicatechin

Abstract Dexamethasone and other glucocorticoids (GCs) are used in the treatment of chronic inflammatory diseases. However, in diseases like chronic obstructive pulmonary disease GC resistance can develop. Our study examines (−)-epicatechin, a dietary compound known to display anti-inflammatory action, as adjuvant to prevent GC resistance. The anti-inflammatory potency of dexamethasone was determined in a carefully characterized system of monocytes differentiated to macrophage-like cells. The LPS induced IL-8 release was measured after pre-incubation with H 2 O 2 and (−)-epicatechin. We show that dexamethasone could efficiently suppress LPS induced inflammation and that exposure to H 2 O 2 induced GC resistance. The anti-inflammatory effect of dexamethasone was protected by (−)-epicatechin in the oxidant exposed cells. These results show that the natural antioxidant (−)-epicatechin may be used as an adjuvant therapy to restore or preserve the efficacy of GC drugs and thereby improving the treatment of inflammation.

Diverse stage-dependent effects of glucocorticoids in a murine model of viral myocarditis

BackgroundThe effects of glucocorticoids on viral myocarditis are contentious. The aim of the present study was to determine whether there is a “window of opportunity” for glucocorticoid treatment in a mouse model of acute viral myocarditis induced by Coxsackie group B3 virus (CVB3). MethodsA/J (H-2a) mice were randomly assigned to one of four experimental groups: (1) viral infection without dexamethasone (DEX) treatment; (2) treatment with 0.75mg/kg, i.p., DEX each day for 5 days prior to viral infection; (3) 0.75mg/kg, i.p., DEX treatment for 5 days immediately after viral infection; and (4) 0.75mg/kg, i.p., DEX treatment for 5 days starting on day 7 after infection. ResultsDEX administration before or immediately after viral infection improved survival and attenuated left ventricular dilatation, systolic dysfunction, fibrosis, and infiltration of immune cells in the post-infectious heart. In contrast, late administration of DEX reduced survival (as determined on day 14), and was associated with sustained increases in cardiac tumor necrosis factor-α and interferon-γ levels. The beneficial effects of early DEX administration on survival were completely abrogated by coadministration of a selective cyclooxygenase (COX)-2 inhibitor (NS-398; 5mg/kg per day, p.o.). Notably, the virus titer in the post-infectious heart was significantly suppressed by DEX, but coadministration of NS-398 at the time of viral infection abolished the suppressive effects of DEX and, in fact, increased virus titers. ConclusionsEarly administration of DEX is beneficial in the treatment of fulminant viral myocarditis, whereas late administration of DEX is harmful. The beneficial effects of DEX on survival were completely abolished by simultaneous administration of a selective COX-2 inhibitor. Hence, we speculate that a direct action of DEX on cardiomyocytes, rather than anti-inflammatory effects of DEX on immune cells, confers resistance to myocardial damage induced by viral infection.

Acute anti-inflammatory effects of aspirin and dexamethasone in rats deprived of endogenous prostaglandin precursors.

Paw oedema, induced by carrageenan, was potentiated in normal rats by arachidonic acid and bishomo-gamma-linoleic acid, but not by 5,8,11-eicosatrienoic acid. The latter is not an endogenous prostaglandin precursor, but replaces the other two in essential fatty acid deficient (EFAD) rats. Carrageenan oedema was partially suppressed in these EFAD rats. Aspirin exhibited equal suppression of carrageenan oedema in both normal and EFAD rats, despite the fact that, in the latter, prostaglandins are of negligible importance. The anti-inflammatory effect of dexamethasone was also identical in both normal and EFAD rats. The view that interference with the prostaglandin-system explains the acute anti-inflammatory effects of the two drugs, is discussed, in relation to the present results.

Expression of Na–H exchanger-8 isoform is suppressed in experimental colitis in adult rat: lack of reversibility by dexamethasone

Objectives. Mechanism of the apical transporter Na–H exchanger-8 (NHE-8) regulation was investigated by examining the effects of anti-inflammatory dexamethasone in experimental colitis. In addition, its localization was investigated in the lipid rich membrane domain called membrane rafts. Material and methods. Colitis was induced by trinitrobenzene sulfonic acid (TNBS) and colon segments were removed from 5 day post-TNBS and used to estimate the levels of NHE-8 protein and mRNA using ECL western blot analysis and a competitive RT-PCR method. Myeloperoxidase activity, malondialdehyde levels and histologic changes were evaluated. Results. NHE-8 protein level was decreased in inflamed colon and was not reversed by dexamethasone. However, mRNA levels remained unchanged in inflamed colon. The levels of NHE-8 protein and mRNA were not significantly different in non-colitic control as compared to dexamethasone treated non-colitis. Elevation of myeloperoxidase activity, malondialdehyde and infiltration of inflammatory cells in inflamed colon were suppressed by dexamethasone treatment of colitis significantly. Furthermore, NHE-8 protein was not detected in the detergent resistant membrane (DRM) or lipid rafts, but was present in the detergent sensitive membrane (DRS) fractions. Actin showed its partition similar to NHE-8. On the contrary, NHE-3 was present in both DRM and DRS fractions. Flotillin-1 and caveolin were enriched in the fractions designated as lipid rafts. Conclusions. These findings demonstrate the suppression of NHE-8 protein in inflamed adult rat colon, which seems to be regulated post-transcriptionlly. Furthermore, the absence of NHE-8 in lipid rafts suggests its regulation independent of cAMP or recycling through endocytosis unlike NHE-3 isoform.

Fetal Arrhythmias: A Clinical Review

ABSTRACT Fetal rhythm abnormalities occur in 2% of pregnancies. They are usually identified by the obstetrician or midwifes after 20 weeks. There are four different methods used to assess fetal arrhythmias: scalp electrodes attached to electrocardiographic recordings, magnetocardiography (FMCG), fetal electrocardiographic recordings from the maternal abdomen, and fetal echocardiography (M-mode, pulsed-Doppler, Tissue-Doppler). In everyday practice the Doppler method was found to be the most useful method in the diagnosis and therapy of fetal arrhythmias. Doppler derived mechanical PR interval raised the possibility of refining the prenatal diagnosis of AV conduction abnormalities. A PR interval of >150 ms on Doppler, FMCG or postnatal ECG has been determined to be prolonged. Extrasystoles are most common cause of fetal arrhythmias, and are most often premature atrial contractions (PACs), what are usually identified in third trimester fetuses and their frequency may be highly variable. These are usually benign, resolving just before or shortly after birth. The follow-up is necessary, because some (1-3%) of affected fetuses have intermittent runs of supraventricular tachycardia. Ventricular tachycardia is rare during fetal life. With echocardiography in the setting of fetal tachycardia the findings of atrioventricular dissociation with a ventricular rate that is faster than the atrial rate suggests ventricular tachycardia. If there is 1:1 retrograde conduction it is impossible to distinguish between ventricular and supraventricular tachycardia. Atrial flutter accounted for 26.2% of all cases of fetal tachyarrhythmias and supraventricular tachycardia for 73.2%. Fouron and coworkers proposed to plan the management of the fetal tachyarrhythmia based on analysis of pulsed-Doppler recordings of fetal heart's blood flow. They determined short V-A tachycardia, when V-A (ventriculoatrial period) was shorter than AV (atrio-ventricular period) period. In the therapy of fetal supraventricular tachycardia there are different protocols, the most commonly used drugs are: digoxin, sotalol, amiodarone, flecainide. Persistent fetal sinus bradycardia is a rare condition and has been reported with central nervous system abnormalities, maternal treatment with beta blockers, excessive vagal tone, hydrops, long QT syndrome, intrauterine growth retardation and could be a sign of maternal anti-SSA/Ro antibodies. Prenatal sinus bradycardia or recognition of 2nd degree AV block may lead to early detection and treatment of long QT syndrome. Early detection of incomplete AV block, in cases of maternal anti SSA, SSB autoantibodies, successfully identifies a group at highest risk developing permanent AV block. The anti-inflammatory effects of dexamethasone might have interrupted on-going damage of the conduction system secondary to maternal autoantibodies. If the fetal arrhythmia resulted fetal hydrops, the mortality is high and the risk of late neurological morbidity must be taken into consideration. As a result of close follow-up, transplacentar treatment and well-organized perinatal management, the survival of sustained fetal arrhythmia significantly improved (50% versus 15%).

Impaired TNFα-induced VEGF Expression in Human Airway Smooth Muscle Cells from Smokers with COPD: Role of MAPkinases and Histone Acetylation—Effect of Dexamethasone

The cytokine and potent angiogenic factor vascular endothelial growth factor (VEGF) plays an important role in airway remodelling in various airway diseases such as idiopathic pulmonary fibrosis, pulmonary hypertension, lung cancer, asthma and chronic obstructive pulmonary disease (COPD). The effect of cigarette-smoking on VEGF expression, the modulatory role of extracellular signal-regulated kinase (ERK)-1,-2, p38mitogen-activated protein kinase (MAPK), histone acetylation and the anti-inflammatory effect of dexamethasone on TNFalpha-induced VEGF expression were examined in human airway smooth muscle cells (HASMC) of five non-smokers, 17 smokers without airflow limitation and 15 smokers with COPD. TNFalpha increased VEGF expression 5.4-fold and 4.0-fold in HASMC from non-smokers and smokers without airflow limitation, respectively, but only 2.5-fold in HASMC from smokers with COPD compared with non-stimulated HASMC. VEGF production was dependent on phosphorylation of ERK-1,-2 and p38MAPK, as was shown by examining the effects of PD 098059 (10 microM), an inhibitor of the upstream activator of MAPKkinase (MKK)-1, and SB 203580 (10 microM), an inhibitor of p38MAPK; there were no differences between non-smokers, smokers without airflow limitation and smokers with COPD in this respect. Dexamethasone (DEX; 10(-12)-10(-4) M) reduced TNFalpha-induced phosphorylation of ERK-1/-2 and prevented TNFalpha-induced VEGF generation without differences between non-smokers, smokers with and without COPD. There was an additional inhibitory effect of DEX (10(-12) M) on VEGF-release when PD 098059 was added. The basal and TNFalpha-induced acetylation status of the VEGF-promoter (chromatin immunoprecipitation [ChIP] assay) was increased in HASMC from smokers with COPD compared with smokers without airflow limitation and non-smokers. In comparison to non-stimulated HASMC, TNFalpha decreased the acetylation status of the VEGF-promoter by approximately 46% and approximately 43% in HASMC from non-smokers and smokers without COPD compared with approximately 68% in HASMC from smokers with COPD. The data suggest that HASMC express VEGF in response to TNFalpha and that this may be reduced in HASMC of smokers with COPD in a smoking-independent manner. VEGF expression is directly modulated by phosphorylation of ERK-1,-2 and p38MAPK and by histone acetylation and the acetylation status of the VEGF gene is increased in HASMC of smokers with COPD in a smoking-independent manner. TNFalpha reduced the acetylation status of the VEGF promoter in HASMC.

Treatment with dexamethasone and vitamin D3 attenuates neuroinflammatory age‐related changes in rat hippocampus

Among the changes which occur in the brain with age is an increase in hippocampal concentration of proinflammatory cytokines like interleukin-1beta (IL-1beta) and an increase in IL-1beta-induced signaling. Here we demonstrate that the increase in IL-1beta concentration is accompanied by an increase in expression of IL-1 type I receptor (IL-1RI) and an age-related increase in microglial activation, as shown by increased expression of the cell surface marker, major histocompatibility complex II (MHCII) and increased MHCII staining. The evidence indicates that these age-related changes were abrogated in hippocampus of aged rats treated with dexamethasone and vitamin D3. Similarly, the age-related increases in activation of the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), as well as caspase-3 and PARP were all attenuated in hippocampal tissue prepared from rats that received dexamethasone and vitamin D3. The data indicate that dexamethasone and vitamin D3 ameliorated the age-related increase in IFNgamma and suggest that IFNgamma may be the trigger leading to microglial activation, since it increases MHCII mRNA and IL-1beta release from cultured glia. In parallel with its ability to decrease microglial activation in vivo, we report that treatment of cultured glia with dexamethasone and vitamin D3 blocked the lipopolysaccharide increased MHCII mRNA and IL-1beta concentration, while the IL-1beta-induced increases in activation of JNK and caspase 3 in cultured neurons were also reversed by treatment with dexamethasone and vitamin D3. The data suggest that the antiinflammatory effect of dexamethasone and vitamin D3 derives from their ability to downreguate microglial activation.