Anti-inflammatory Effects Of Steroids Research Articles

Abstract TP551: The Safety and Utility of Steroids in Aneurysmal Subarachnoid Hemorrhage

Background: Hydrocephalus is a common complication in patients with aneurysmal subarachnoid hemorrhage (aSAH) and is one of the predictors of poor outcome. Currently the only treatment modality for hydrocephalus is shunting; there is no known prophylactic therapy. Limited pre-clinical data suggest that anti-inflammatory effect of steroids could be used to prevent arachnoiditis and subarachnoid fibrosis after aSAH, which in turn may reduce the rate of hydrocephalus that requires shunting. Methods: A retrospective study of patients with aSAH admitted to two tertiary care centers from 2009 to 2017 was performed. Age, sex, hypertension, Glasgow coma scale [GCS], Hunt Hess [HH] grade, administration of steroids (dexamethasone [DXM], methylprednisolone [MTP] or none), presence of hydrocephalus and ventriculoperitoneal shunt (VPS) as well as occurrence of adverse events such as hyperglycemia, delirium and infection were recorded for each patient. Results: A total number of 288 patients were included. Mean age was 56.9±13.9 years, 186 (64.6%) patients were female and 145 (50.5%) patients had hypertension. Median GCS score was 14 (IQR 7-15) and median HH grade was 3 (IQR 2-4). 204 (71%) patients received DXM, 23 (8%) patients received MTP and 61 (21%) patients were not administered any steroids during hospital stay. Hydrocephalus was present in 114 (56.4%) patients who received DXM, 13 (56.5%) who received MTP and 37 (61.6%) who did not receive steroids (p>0.05; χ 2 -test). The incidence of VPS placement did not differ between the groups (p>0.05; χ 2 -test). Patients who received steroids were more likely to develop pneumonia (63 [31%] vs. 7 [31.8%] vs. 5 [8.2%] in DMX, MTP and no steroids group, respectively; p=0.008; χ 2 -test). Patients who received DXM (but not MTP) more frequently were treated for a urinary tract infection (48 [23.5%] vs. 6 [9.8%]; p=0.019; χ 2 -test). There was no difference in the ratio of hyperglycemia or delirium between the groups. Conclusion: Our results support the evidence that, although commonly used in clinical practice, steroids administered in patients with aSAH do not decrease the risk of developing hydrocephalus and subsequent VPS. In addition, steroids may increase the risk of infections such as pneumonia and urinary tract infection.

The Conversation Continues, as It Should

In response to the article on using oral steroids as a diagnostic test to distinguish between chronic obstructive pulmonary disease (COPD) and asthma by Broekhuizen and colleagues,1 the discussion turns in part to one of nosology, as Hahn puts it: when, along the continuum of a lifetime of lung disease, do asthma and COPD become part of an overlap syndrome in which “pure” asthma can evolve into “pure” COPD over time?2 Boundaries in clinical medicine are often, if not always, fuzzy, and using steroids to distinguish between 2 clinical entities, where steroids have an effect in both, is not helpful. As Crownover mentions, the situation is particularly vexing when an empirical trial of steroids for treatment, which is recommended in some guidelines, rather than diagnosis confounds the issue.3 The anti-inflammatory effect of steroids can help in infection as well as reactive airway disease. Furthermore, Van Schayck points out that there is very little indication for inhaled steroids, and they should not be confused with oral steroids for management in situations where there is not a clear diagnosis of asthma.4 All respondents agree on 2 points: the standards for management are neither clear or gold, have to do with the populations of patients in whom they are developed, and are not simple in what is often a mixed disease state. More primary care based studies should help management at that level.

Effect of anti-inflammatory steroids on the activity of selected lysosomal hydrolases in serum of rats with experimental liver fibrosis.

Liver fibrosis was produced in rats by subcutaneous injections of carbon tetrachloride. The effect of anti-inflammatory steroids (hydrocortisone, prednisone, dexamethasone) on the activity of serum lysosomal hydrolases (beta-N-acetylglucosaminidase, beta-glucosidase and alpha-mannosidase) was investigated in healthy and CCl4 poisoned rats. The marked increase of enzymatic activity in blood serum was observed in animals with CCl4-induced liver fibrosis. Quite opposite results were found in normal rats treated with glucocorticosteroids. In rats which were given both carbon tetrachloride and corticosteroids the obtained values of serum enzymatic activity did not have a uniform character as compared to controls or CCl4 intoxicated rats. Presumable mechanisms of the results obtained are discussed.

The decrease of hyaluronate synthesis by anti-inflammatory steroids in vitro.

The effect of anti-inflammatory steroids (prednisolone and derivatives of hydrocortisone, dexamethasone and betamethasone) on the synthesis of hyaluronic acid and sulphated glycosaminoglycans in human skin fibroblast culture was studied. The concentrations of steroids varied between 1 x 10(-10)M and 1 x 10(-6)M. All tested steroids decreased the synthesis of hyaluronic acid to the same final level which was about 40--50% of the controls, but the concentrations required varied between different steroids. The relative inhibitory potencies of the steroids were calculated based on concentrations needed to decrease the synthesis of hyaluronate. When the inhibitory potency of hydrocortisone was calculated as one, the values of the other steroids were: prednisolone 5, hydrocortisone 17- butyrate 20, betamethasone alcohol 30, dexamethasone alcohol 38, betamethasone 17-valerate 350--400, dexamethasone monosodium phosphate and betamethasone disodium phosphate over 400. Hydrocortisone sodium succinate was as potent an inhibitor of hyaluronate synthesis as hydrocortisone alcohol. None of the tested steroids affected the synthesis of sulphated glycosaminoglycans at these concentrations. The changes ovbserved in glycosaminoglycans in the medium were in accordance with the changes in the cell layer. The possible significance of hyaluronate synthesis inhibition by anti-inflammatory steroids is discussed.

Dexamethasone Suppresses Expression of Nuclear Factor-kappaB in the Cells of Tracheobronchial Lavage Fluid in Premature Neonates with Respiratory Distress

Nuclear Factor-kappaB (NF-kappaB) plays a central role in regulating the key mediators of inflammation involved in acute lung injury. The anti-inflammatory effect of steroids by suppressing pro-inflammatory cytokines may be mediated by inhibition of transcription factor NF-kappaB. The objective of this study was to determine the effect of glucocorticoid therapy on the expression of NF-kappaB in the cells of tracheobronchial lavage fluid (TBLF) in premature neonates with respiratory distress. Nineteen premature neonates requiring mechanical ventilation and receiving glucocorticoids were enrolled. Their gestational age (mean +/- SD) was 25.0 +/- 1.2 wk, birth weight 714 +/- 105 g and age of starting dexamethasone was 33 +/- 15 d. Tracheobronchial lavage fluid was collected before and 48-72 h after starting dexamethasone. NF-kappaB expression was measured by immunocytochemistry using mouse MAb against the p65 subunit of NF-kappaB on cytospin slides. The percent of cells stained and the intensity staining index were significantly higher before starting dexamethasone compared with after steroid therapy. Localization of NF-kappaB was significantly decreased in the cytoplasm and nuclei of mononuclear cells after initiation of dexamethasone therapy. The concentration of IL-8 was also significantly lower after starting dexamethasone. In conclusion, dexamethasone suppressed the expression of NF-kappaB in the cytoplasm and nuclei of mononuclear cells and decreased levels of IL-8 in TBLF from premature neonates with respiratory distress. The anti-inflammatory effects of corticosteroids may be mediated through NF-kappaB.

Concordance of endogenous cortisol and phospholipase A2 levels in gram-negative septic shock: a prospective study.

Lipocortins, a group of corticosteroid-induced phospholipase-inhibitory proteins, are thought to play a prominent role in the mediation of the anti-inflammatory effects of steroids. The synthesis and release of these proteins may represent a major endogenous mechanism of regulation of extracellular phospholipase A2 (PLA2) activity. Because soluble PLA2 activity has been associated with circulatory collapse in hyperphospholipasemic conditions, such as septic shock and pancreatitis, we examined the relationship between circulating PLA2 activity and adrenocortical function. In a prospective study of 10 episodes of septic shock, serum PLA2 and cortisol levels correlated significantly in all survivors (p less than 0.0001), whereas such a correlation was absent in all nonsurvivors (p less than 0.07). No significant correlation of cortisol and adrenocorticotropic hormone (ACTH), or PLA2 and ACTH, was found in any patient, suggesting that the stimulus for cortisol release arises from outside the hypothalamic-pituitary axis. These data suggest that, in human beings, the regulation of soluble PLA2 activity may be mediated by adrenocortical hormones, perhaps through the intermediary action of lipocortins.

Salvage of ischemic rabbit ear by BW-755C and steroids, but not by indomethacin

The effects of anti-inflammatory steroids and BW-755C (both of which inhibit the formation of prostaglandins and leukotrienes were studied in ischemia-induced edema and necrosis of the rabbit ear utilizing an occlusion reperfusion model. The results were compared with cyclooxygenase inhibitors which selectively block the synthesis of prostaglandins without affecting leukotriene production. Significant inhibition of the progression of necrosis was observed with both methyl prednisolone and BW-755C. The cyclooxygenase inhibitors, naproxen and low-dose indomethacin had no effect on the progression of ear necrosis. By contrast, high-dose indomethacin significantly inhibited edema but accelerated the progression of necrosis.

Inhibition by hydrocortisone of prostacyclin synthesis by rat aorta and its reversal with RU486.

A rat aortic explant culture system was developed for the investigation of the effects of hydrocortisone (HC) and the glucocorticoid antagonist, RU486, on prostacyclin (PGI2 synthesis. HC, but not aldosterone, progesterone, 17 beta-estradiol, or testosterone, inhibited spontaneous, epinephrine-stimulated and U46619 (an analog of thromboxane A2)-stimulated PGI2 synthesis by cultured aortic explants in a concentration- and time-dependent manner. Adequate inhibition of aortic explant PGI2 synthesis by physiological concentrations of HC was achieved after an 18-h culture. An 18-h time course was employed in subsequent experiments. In contrast, HC had no effect on arachidonic acid-stimulated PGI2 synthesis. Protein synthesis inhibitors, actinomycin D and cycloheximide, had no effect on the inhibitory action of HC on epinephrine- and U46619-induced release of PGI2. They exerted a direct inhibitory effect on aortic PGI2 synthesis. Arachidonic acid stimulated PGI2 release by the explants and was unaffected either by HC or by treatment with cycloheximide or actinomycin D. RU486 blocked the inhibitory action of HC on aortic PGI2 synthesis in a dose-dependent manner. Thus, the inhibitory effect of HC on vascular PGI2 synthesis is probably mediated through an inhibition of phospholipase A2 and not cyclooxygenase or other PGI2 synthase systems; furthermore, this inhibitory effect is not dependent upon de novo protein synthesis. RU486 antagonizes the inhibitory effect of HC. The inhibition of vascular PGI2 by hydrocortisone has implications in the pathogenesis of steroid-related hypertension and atherosclerosis and the antiinflammatory effect of steroids.

The effects of antiinflammatory steroids on arachidonate metabolism and prostaglandin synthesis vary according to culture conditions.

The effects of antiinflammatory steroids on arachidonate metabolism and prostaglandin synthesis vary according to culture conditions.

Recent Advances in Renal Transplantation

Recent Advances in Renal Transplantation

The effects of antiinflammatory steroids on the response of the guinea-pig isolated ileum to acetylcholine, histamine, nicotine, 5-hydroxytryptamine and electrical stimulation.

High concentrations of antiinflammatory steroids (2.5-40 microgram/ml) reversibly inhibited the electrically induced contractions of the guinea-pig isolated ileum. At 40 microgram/ml they also reversibly inhibited contractions elicited by acetylcholine, histamine nicotine and 5-hydroxytryptamine. PGE1 (2.5 ng/ml), PGE2 (2.5 ng/ml) and PGF 2 alpha (25 ng/ml) antagonized these effects. The inhibition of contractions elicited by direct agonists were less pronounced than those elicited by indirect or partly indirect agonists. The inhibitory effect of steroids may be related to non-specific actions on biological membranes. An overall sensitization of the smooth muscle by PG's may explain their antagonism to inhibition by steroids.

Inhibition of prostaglandin biosynthesis by corticosteroids requires RNA and protein synthesis

THE finding that aspirin-like drugs act by inhibiting prostaglandin (PG) synthetase was reported by Vane et al.1, and the possible effects of anti-inflammatory steroids on PG production have since been a matter of controversy. Although some studies have indicated no appreciable effect of the corticosteroids on PG synthetase1–4, other investigators have presented evidence that corticosteroids may act by inhibiting the biosynthesis or release of PGs. The latter data were derived from studies on a variety of tissues such as skin5, adipose tissue4, inflamed synovia6,7, cultured fibroblasts8 and fibrosarcoma cells9. No satisfactory explanation for these controversial results has been offered, nor has the mechanism of this possible effect of corticosteroids on PG production been properly elucidated. The mechanism of action of the steroid hormones on their target organs has been clarified in recent years. These hormones are now thought to act primarily by stimulating transcription, thus controlling the rate of synthesis of certain key proteins (see ref. 10 for review). Many of the actions of the colt;rticosteroids on intermediary metabolism are indeed known to involve the induction of synthesis of specific enzyme proteins. We report here that corticosteroids influence PG production by a mechanism involving RNA and protein synthesis.

The effect of certain anti-inflammatory steroids on collagen synthesis in vitro

The effect of some anti-inflammatory steroids (prednisolone, and different derivatives of hydrocortisone, dexamethasone and betamethasone) on the synthesis and extra- and intracellular distribution of collagen was studied using chick embryo tendon cells. The concentrations of steroids varied between 1 × 10 −3 M and 1 × 10 −7 M. All steroids having an effect decreased the synthesis of collagen and the amount of labeled collagen decreased more in the medium than in the cells. Great variations in the inhibitory activity between different derivatives of steroids were noticed. Hydrocortisone was as inhibitory as hydrocortisone butyrate but both decreased collagen synthesis more than succinate or phosphate derivatives of hydrocortisone. Betamethasone-17-valerate was the most potent inhibitor among the steroids tested, whereas its alcohol and phosphate forms were ineffective. Dexamethasone and its phosphate derivative did not affect collagen synthesis in this system. The inhibitory potency of prednisolone on collagen synthesis was about the same as that of hydrocortisone. No steroid caused an accumulation of labeled collagen into cells and the decrease in the amount of collagen followed the decrease in total amount of labeled proteins. The results suggest that the inhibition of collagen synthesis by anti-inflammatory steroids is a consequence of a general inhibition of protein synthesis.

The protective effect of anti-inflammatory steroids on rat-paw necrosis following severance of the common iliac vessels.

Paw necrosis in the adrenalectomized rat was induced by severing the common iliac or ligating the femoral blood vessels. Necrosis did not appear in non-adrenalectomized animals. Administration of either hydrocortisone, 6α, 9α-Difluoro-11β, 16α, 17α, 21-tetrahydroxy-pregna-1, 4-diene-3, 20-dione 16, 17-acetonide or 9α, 11β-dichloro-6α-fluoro-16α, 17α, 21-trihydroxy-pregna-1, 4-diene-3, 20-dione 16, 17-acetonide directly into the paw within two hours after vascular impairment prevented the paw necrosis.

Studies on the prophylaxis and treatment of experimental serum sickness in rabbits

Five or ten days after a single injection with one gram of horse serum globulin, allergic reactions, such as edema and erythema, appeared in both ears of sensitized rabbits and continued to exist for 2 to 6 days. The frequency of occurrence of the reactions was about 60 per cent. Those reactions were also induced immediately after subcutaneous reinjection with one mg of the same antigen into the unilateral ear of rabbits which had been sensitized with a smaller amount of antigen than that which might be necessary to induce such delayed type of reactions as described above.In sensitized rabbits which had developed allergic reactions, the level of antibody against horse serum globulin in the blood stream was proved to be higher than that in rabbits which had failed to develop allergic reactions.These allergic reactions were prevented by subcutaneous injection with cortical steroid hormones for five or ten days after the sensitization of horse serum protein. Both glycyrrhizin and ACTH were also effective to relieve the reactions.From these experimental results, it is suggested that the mechanism of steroid to prevent allergic reactions may not be simple. One of the factors related to this mechanism is to prevent the production of antibody, and another the anti-inflammatory effect of steroid.

Effects of anti-inflammatory steroids on carbohydrate metabolism, with emphasis on hypoglycemic and diabetic states.

Effects of anti-inflammatory steroids on carbohydrate metabolism, with emphasis on hypoglycemic and diabetic states.