Glucocorticosteroids as antioxidants in treatment of asthma and COPD

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Review

Glucocorticosteroids as antioxidants in treatment of asthma and COPD New application for an old medication? A.M. Sadowska a,∗ , B. Klebe b , P. Germonpr´e a , W.A. De Backer a a b

Department of Pulmonary Medicine, University of Antwerp, 2610 Antwerp, Belgium Department of Renal Medicine, Kent and Canterbury Hospital, Ethelbert Road, Canterbury, CT1 3NG Kent, UK

a r t i c l e

i n f o

a b s t r a c t

Article history:

Inhaled corticosteroids (ICS) are the standard of care in asthma and are widely used in

Received 4 April 2006

the treatment of patients with COPD. The influence of steroids on inflammatory processes

Received in revised form

has long been established since glucocorticoids and their receptor belong to the regulatory

4 October 2006

network involved in inhibition of several inflammatory pathways.

Accepted 25 October 2006 Published on line 4 December 2006

Inflammatory processes are usually accompanied by an increased oxidative burden followed by a depletion of antioxidants. Therefore, the effects of steroids on antioxidant status have been investigated revealing possible positive effects on the reduced antioxi-

Keywords:

dant enzyme activity. Nevertheless, the mechanisms of this modulation have not been fully

Glucocorticosteroids

elucidated yet. It is possible that antioxidant enzyme activity is regulated at the level of

Antioxidant enzymes

transcription. Additionally, because of the fact that antioxidant enzymes are trace element

Obstructive lung diseases

dependent, steroids may affect their activity through influence on trace element accumulation. This review summarizes the effects of steroids on the antioxidant enzymes activity in vitro and in vivo in relation to asthma and COPD. © 2006 Elsevier Inc. All rights reserved.

Contents 1. 2. 3.

4. 5.

∗

Oxidative stress and inflammation in asthma and COPD: targets for therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antioxidant enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Steroids: mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Transcription. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Trace element modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Effects of glucocorticosteroids on antioxidant status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antioxidant effects of steroids in relation to lung diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks, future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: +32 38202589/+32 38213447; fax: +32 38202574. E-mail address: [email protected] (A.M. Sadowska). 0039-128X/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.steroids.2006.10.007

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1. Oxidative stress and inflammation in asthma and COPD: targets for therapy The pathogenesis of chronic obstructive lung diseases like asthma and chronic obstructive pulmonary disease (COPD) is complex. It involves both airway inflammation [1] and an oxidant/antioxidant imbalance [2–4]. Pro-inflammatory cytokines released from activated cells stimulate the production of reactive oxygen species (ROS), which act as signaling mediators for a variety of signal transduction pathways and gene expression [5–7]. The transcription factors that have been implicated in many inflammatory responses are the nuclear factor-kappaB (NF-␬B) and activator protein-1 (AP-1) [8–11]. Both NF-␬B and AP-1 are sensitive to many different oxidative stress stimuli. Moreover, NF-␬B is reported to be inhibited by antioxidants like cysteine [12,13] as well as glucocorticosteroids [14]. These observations suggest that inflammation and oxidative stress are co-dependent and strongly interrelated processes. Should the burden of oxidants not be well counterbalanced by the antioxidant systems, the result is systemic oxidative stress [15] and increased inflammatory response [16,17]. Therefore, improving antioxidant capacity in asthma and COPD could provide a future therapeutical approach.

2.

Antioxidant enzymes

Virtually every organism has some form of defense system to counterbalance oxidative stress and detoxify or convert the reactive products. These involve numerous anti-oxidants: endogenous enzymes like glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT), non-enzymatic, metal binding proteins (albumin, lactofferin, transferin), low molecular weight compounds (uric acid, glutathione (GSH), bilirubin, ubiquinone) and exogenous antioxidants (Vitamin C, Vitamin E, beta-carotene). Among the antioxidant enzymes, superoxide dismutase (SOD) is considered fundamental in the process of eliminating ROS because it reduces superoxide (• O2 − ) to form hydrogen peroxide (H2 O2 ). There are several forms of SOD, namely Cu/Zn SOD, Mn SOD, and extracellular SOD (ExSOD). Copper is essential for the activity of the enzyme and half of the copper in the cytosol is reported to be bound to CuZn SOD [18]. Moreover, under condition of copper deprivation, a decrease in CuZn SOD activity and protein content has been reported, also with an increase in Mn SOD activity [19]. Zinc, on the other hand, imparts the stability of the protein structure. CuZn SOD gene contains regulatory elements such as AP-1 and AP-2, plus a glucocorticosteroid and metal responsive elements amongst others [20,21]. The role and regulation of superoxide dismutases has been reviewed before [22]. Glutathione peroxidase (GPx) can reduce lipid peroxides and other organic hydroperoxides, which are highly cytotoxic products. The know forms of GPX are selenoproteins and vary in their localization, structure and nature, comprising of cytoplasmic, phospholipid, gastrointestinal and extracellular GPx [23]. The human GPx gene appears to be regulated not only transcriptionally [24],

but also post-transcriptionally, probably co-translationally, in response to selenium availability [25,26]. Catalase (CAT), on the other hand, is a haem-containing enzyme that also promotes the conversion of hydrogen peroxide to water and molecular oxygen. Its activity is iron-dependent since a decreased CAT was found in iron-deficiency [27] and a correlation was observed between iron and catalase activity in smokers [28]. The respective antioxidants that interact with superoxide and H2 O2 are regulated through a feedback mechanism. Through this system, steady low levels of these enzymes as well as superoxide and H2 O2 are maintained which keeps the entire system in a fully functioning state. Thus, the ability of an individual to prevent the injurious effects of oxidative stress depends on the antioxidant capacity of blood and tissues [29]. The activity of those enzymes can be regulated through several mechanisms, e.g. through increasing transcription of the enzyme and/or through increasing its activity. Enzyme activity may increase in response to elevated usage under condition of acute oxidative stress [30,31] or in response to trace element re-supplementation following their deprivation [26]. The influence of glucocorticosteroids on antioxidant enzyme activity has also been described [32] but the possible mechanisms of this modulation have not been fully elucidated yet. SOD and GPx are reported to be regulated on a transcription level [33] and this fact would correspond to the effects exerted by glucocorticosteroids like dexamethasone with pleiotropic influence on transcription and signaling pathways. Again, due to the fact that the aforementioned enzymes are trace element/iron dependent, glucocorticosteroids might affect them through their influence on trace element accumulation [34].

3.

Steroids: mechanism of action

Glucocorticosteroids are indicated for the treatment of many of diverse conditions. Inhaled corticosteroids (ICS) are the standard of care in asthma and are widely used in the treatment of patients with COPD. They successfully inhibit airway inflammation in asthma, but their effectiveness in COPD remains controversial [35–37]. The desired properties of an inhaled corticosteroid include a high glucocorticoid receptor binding affinity, a high lung deposition, and a long pulmonary residence time. These properties vary between preparations and are also dependent on the device used to deliver the drug into the airway [38,39].

3.1.

Transcription

The efficacy of CS in inhibiting inflammation results from the pleiotropic effects of the glucocorticoid receptor on the multiple signaling pathways. It has been postulated that it modulates the inflammatory response through direct and indirect genomic effects as well as non-genomic mechanisms [40]. The well-known anti-inflammatory effects of glucocorticosteroids are mediated through binding of the intracellular receptor (GR) [41]. The GR affects the transcriptional regulation of specific target genes and inhibits promoter regions of genes such as NF-␬B and AP-1, which are potent transcription factors for both inflammatory cytokines [42] and antioxidant

3

MLN: mesenteric lymph nodes, S: spleen, T: thymus, GC: skeletal muscle (gastrocnemius), AT: all tissues studied, IP: intraperitioneally, GR: glutathione reductase, BALF: bronchoalveolar lavage fluid.

[56] [73] (–) CAT, SOD, GPx () GPx, CAT, SOD, () lipid hydroperoxide SOD, CAT, GPx SOD, CAT, GPx, lipid hydroperoxide BALF Lung tissue Lung tissue Piglets Preterm lambs

0.7 mg/kg 0.5 mg/kg betamethasone

[47] () GPx, () Se () GPx, () Se Se, GPx Plasma Liver Mice

0–5–50 mg/L, 1 week (drinking water)

[72] () GPx, CAT, SOD GPx, SOD, CAT 0.2 mg/kg Lung tissue

GPx, SOD, CAT, GR 3 mg/kg IP

Pregnant rats

GPx, SOD, CAT activity 0.2 mg/100 ␮L subcutaneously

Lung tissue Fibroblasts RBC

Rat

Cell type Subjects

Table 1 – In vitro and in vivo studies

Dose (DEX)

3.3. Effects of glucocorticosteroids on antioxidant status The effects of glucocorticosteroids on antioxidant enzyme activities are summarized in Table 1. In vitro studies show that glucocorticosteroids may inhibit GSH synthesis by inhibiting both ␥-GCS and ␥-GT activity. The plausible explanation for this down-regulation would be their modulation of AP-1, which plays an important role in the regulation of antioxidant enzyme activities [52]. Moreover, a decrease in GPx and MnSOD was observed in rat macrophages after incubation with 2 mg/mL dexamethasone [53]. However, a high concentration of glucocorticosteroid used in this study may have significantly affected the membranes obscuring the studied effect. In contrary to in vitro reports, positive effects of glucocorticosteroids are observed in vivo. Firstly, dexamethasone through direct inhibitory effect on ROS production, decreased oxidant burden in Kupffer cells in vivo [54]. Secondly, the increased GPx and CAT activity was found after 8 days of dexamethasone administration [53]. These observations are supported by other studies showing increases in GPx, SOD and CAT and accompanied by decrease in lipid peroxidation products in rats. Interestingly, the aforementioned increase was not unanimous in all studied organs [55]. On the contrary, some groups observed no change [56] or even a decrease of antioxidant enzymes activity [53] and concomitant decrease in blood and muscle GSH levels [57]. Question arises if the dose

[33] [70] [71]

[55] SOD, GPx, CAT, TBARS 1 mg/kg, 3 days Spleen, thymus, muscle

() GPx, () catalase, () Mn SOD () Mn SOD, () GPx, (–) catalase, Cu/Zn SOD () TBARS (MLN, T, S), () TBARS (GC), () Cu/Zn SOD (AT), () CAT (LN, T), () CAT (S, GC), () GPx (LN, T, S), () GPx (GC) () GPx, CAT, SOD () GPx, CAT, SOD () GPx, (–) GR, () CAT GPx, SOD, CAT GPx, SOD, CAT

Effect studied

Another pathway of action for glucocorticosteroids is the modulation of trace element transport, which is not very well described. Dexamethasone has been reported to induce zinc accumulation in primary cultures of rat liver cells [46]. This observation was supported by Weiner et al. who observed both zinc and copper accumulation in rat liver parenchymal cells after dexamethasone [47]. As far as selenium is concerned, dexamethasone administered to mice for a period of 1 week, increased selenium levels in plasma and cerebrum resulting in concomitant GPx increase in plasma [48]. Furthermore, prednisone used in the treatment of steroid sensitive nephritic syndrome (SSNS) led to an increase in selenium that was also accompanied by enhanced GPx activity [47]. This was supported by yet another study, where methylprednisolone caused a dose-dependent increase in selenium levels [49]. Furthermore, in diabetes, supplementation of selenium results in increased plasma selenium together with GPx activity in red blood cells [50]. Additionally, the importance of selenium was elucidated by Chanoine et al. reporting selenium deficiency resulting in a marked decrease in GPX activity [51].

5 mg/kg, 8 days 2 mg/mL

Trace element modulation

Macrophages Macrophages (cultured)

Results

3.2.

Ref.

enzymes [43]. Therefore, through acting on the glucocorticosteroid response element or AP-1 on the SOD and GPx gene they might modulate the transcription of these enzymes. Moreover, recent reports suggest that glucocorticosteroids can affect inflammation without inducing changes in the gene expression. Furthermore, they may act on inflammatory response by decreasing the stability of RNA for pro-inflammatory genes [44]. The molecular mechanisms of steroids have been reviewed before [40,45].

[53]

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Table 2 – Clinical studies Subjects Asthma patients

COPD patients SSNS patients

Steroids and dose Flunisolide 1000 ␮g/day, 3 weeks Beclomethasone 500 ␮g b.i.d. MDI, 6 weeks Beclomethasone 750 ␮g b.i.d. MDI, 4 weeks Prednisolone 15–10–5–5 mg, 4 weeks Fluticasone propionate (1000 ␮g) 10 weeks Prednisolone

Cell type

Parameter

Effects

Ref.

Bronchial epithelium

SOD, GPx activity

() Cu/Zn SOD, (–) GPx

[67]

RBC

CAT, SOD, GPx, total glutathione GPx, SOD activity Se

() CAT, () total glutathione, (–) GPx, SOD (–) GPx, SOD, (–) Se

[74]

RBC, plasma RBC, plasma RBC

[70]

(–) GPx, SOD, () Se SOD, GPx

() GPx, (–) SOD

[68]

GPx, Se

() GPx, () Se

[48]

SSNS: steroid sensitive nephrotic syndrome, Se: selenium, SOD: superoxide dismutase, GPx: glutathione peroxidase, CAT: catalase, RBC: red blood cells.

may play a role in modulating oxidative stress response. It has been described that high concentrations of dexamethasone may have different effects on inflammatory response than lower doses [58]. Moreover, a cell-type may also be an important effect-determining factor as it is the case in modulation of cell apoptosis. Namely dexamethasone induced apoptosis in monocytes and eosinophils in concentration-dependent manner [59,60]. On the other hand, dexamethasone was found to block ROS-induced neutrophil apoptosis at concentration 10−6 to 10−9 M [61]. It has been reported that variation in the glucocorticosteroids responses exists and involves GR-␤ level [62]. Therefore, it would be plausible that different effects of glucocorticosteroids are seen in different cell-types.

an increase in CAT while GPx and SOD remained unchanged. These studies are supported by a study in stable COPD patients where fluticasone administered for the period of 10 weeks increased GPx activity in comparison with the baseline [68] and significantly influenced relationships between inflammatory markers and antioxidant enzymes [69] but did not affect SOD activity. Other studies, on the other hand, did not find any effects on SOD, GPx and CAT after beclomethasone (750 ␮g b.i.d. MDI) or oral prednisolone [70]. Interestingly, the concentrations used in animal studies are much higher than those used in clinical studies and yet we still may observe the modulation of antioxidant enzymes activity. Therefore it might be postulated that very low concentration of steroids may have the potential to affects the enzymes activity (Table 2).

4. Antioxidant effects of steroids in relation to lung diseases

5.

In asthma patients, antioxidant enzymes activity is observed to be low because of the increased oxidative burden [63]. The depletion of consumable antioxidants like ␣tocopherol further augments the existing imbalance [64]. Therefore, restoring the oxidant/antioxidant balance may prevent/decrease the detrimental effects caused by increased oxidative stress and accompanying inflammation. First of all, glucocorticosteroids steroids may have direct effects on oxidative stress by decreasing the number and/or activity of cells involved in ROS production such as granulocytes. An example is the reduction of superoxide anion production by monocytes in asthma [65] and additionally a decrease in the number of neutrophils in COPD [66]. The last however is still controversial [36]. Secondly, they may act on the antioxidant enzyme activities. By acting on transcription and/or through posttranslational mechanisms, glucocorticosteroids may be capable of elevating the antioxidant enzyme activity. It has been reported that the low antioxidant status in asthma patients is corrected by administration of inhaled steroid [67]. The data on the up-regulation of particular enzymes, however, are not unanimous. In study by Raeve et al., 3 weeks of flunisolide (1000 ␮g/day) increased Cu/Zn SOD with no influence on GPx and Mn SOD [67]. Similarly, Pennings et al. showed

At present there are several anti-inflammatory therapies under investigation that are meant to replace glucocorticosteroids and achieve better disease control with less side-effects. Moreover, while glucocorticosteroids are quite successful in controlling inflammatory response in asthma, their potency in COPD is debatable. Glucocorticosteroids may play a role here, and although studies have been performed in order to examine the properties of steroids in that matter, there have been variability in the positive outcomes. There is an urgent need for the new developments in the area of antioxidant therapy in COPD and glucocorticosteroid form an interesting approach. The efficiacy of glucocorticosteroids as inhibitors of diverse inflammatory diseases guarantees their continued use. The possibility of additional regulatory mechanisms on the antioxidant enzymes and influencing oxidative stress needs further investigation with the use of specific antagonists in vitro. Moreover, the question that requires further investigation is if the antioxidant effects of steroids are independent from their anti-inflammatory actions. More clinical studies should be performed in order to assess the usefulness of these observations in the clinical practice and relate it to possible antioxidant effects of medications that increase thiol status (N-acetylcysteine) and antioxidant enzymes derivatives.

Concluding remarks, future directions

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