Chemical and biological activity of free radical ... · Chemical and biological activity of free...

Clinica Chimica Acta 296 (2000) 1–15www.elsevier.com/ locate /clinchim

Review

Chemical and biological activity of free radical‘scavengers’ in allergic diseases

a , a b*´ ´ ´ ´Jose M. Mates , Cristina Perez-Gomez , Miguel Blancaa ´Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Malaga,

Ćampus de Teatinos, s /n, 29071 Malaga, Spainb ´ Állergy Unit of Hospital Carlos Haya, Pabellon C, Plaza del Hospital Civil, 29009 Malaga, Spain

Received 30 November 1999; received in revised form 3 February 2000; accepted 10 February 2000

Abstract

Reactive oxygen species (ROS) are generated constantly in vivo. They can lead to lipidperoxidation and oxidation of some enzymes, as well as protein oxidation and degradation. Cellspossess several biological systems, defined as ‘scavengers’, to protect themselves from theradical-mediated damage. Immune cells may discharge their arsenal of toxic agents against hosttissues, resulting in oxidative damage and inflammation. Therefore, free radical production anddisturbance in redox status can modulate the expression of a variety of immune and inflammatorymolecules, leading to inflammatory processes, both exacerbating inflammation and effecting tissuedamage. Recently, abnormal immunity has been related to oxidative imbalance, and antioxidantfunctions are linked to anti-inflammatory and/or immunosuppressive properties. Currently, allergyis one of the most important human diseases. We studied the role of the primary antioxidantdefence system, constituted by the antioxidant enzymes superoxide dismutase, catalase andglutathione peroxidase, protecting cells from toxic oxygen. We analyzed how they are involved inblood cells detoxification, and how the imbalance of reactive oxygen species is related toinflammation in allergic diseases by affecting immune cells. Finally, we discuss the published datathat relates anti-free radical therapy to the management of human allergic diseases. 2000Elsevier Science B.V. All rights reserved.

Abbreviations: CAT, catalase (EC 1.11.1.6); EPO, eosinophil peroxidase (EC 1.11.1.2); FMLP, N-formyl-methionyl-leucyl-phenylalanine; GM-CSF, granulocyte-macrophage colony-stimulating factor; GPX, gluta-thione peroxidase (EC 1.11.1.19); GSH, glutathione; IFN-a, interferon alpha; IFN-g, interferon gamma; IgE,immunoglobulin E; NADPH, reduced nicotinamide-adenine dinucleotide phosphate; NFkB, nuclear factorkappa-B; NOS: nitric oxide synthase (1.14.13.39); PAF, platelet-activating factor; PMA, phorbol 12-myristate13-acetate; PMNs, polymophonuclear leukocytes; ROS, reactive oxygen species; SOD, superoxide dismutase(EC 1.15.1.1); TNF-a, tumor necrosis factor alpha

*Corresponding author. Tel.: 134-95-213-1930; fax: 134-95-213-2000.É-mail address: [email protected] (J.M. Mates)

0009-8981/00/$ – see front matter 2000 Elsevier Science B.V. All rights reserved.PI I : S0009-8981( 00 )00215-1

´2 J.M. Mates et al. / Clinica Chimica Acta 296 (2000) 1 –15

Keywords: Allergy; Catalase; Glutathione peroxidase; Oxidative stress; Reactive oxygen species;Superoxide dismutase

1. Introduction

The principal physiological function of the immune system is the removal ofinfectious agents. In this process, cells can be damaged. Therefore, the organismhas evolved different ways of eliminating actively its own potentially harmfulproducts, so that the host may survive. Potentially injurious immune reactionsmay be prevented either by inactivating functionally the responding lympho-cytes, or by eliminating the harmful radical reaction products [1]. Cells possessdifferent systems, defined as ‘scavengers’, to protect themselves from theradical-mediated damage and, among these, some enzymes or chemical struc-tures have the role of antioxidants.

?Reactive oxygen species (ROS), including hydroxyl radicals ( OH), superox-?2ide anion (O ), hydrogen peroxide (H O ) and nitric oxide (NO) are very2 2 2

transient species due to their high chemical reactivity that leads to lipidperoxidation and oxidation of some enzymes, and a massive protein oxidationand degradation [2,3].

Neutrophils constitute 60 per cent of the circulating leukocytes and they arethe most abundant cellular components of the immune system. They maydischarge their arsenal of toxic agents against host tissues, resulting in oxidativedamage and inflammation. The combination of phagocytosis of bacteria andsecretion of proteolytic enzymes and immuno-modulatory compounds that assistin the killing and digestion of bacteria, are accompanied by respiratory burst,involving a sudden stimulus-induced increase in non-mitochondrial oxidativemetabolism which results in the production of ROS [4].

ROS generation through normal cellular metabolism and by exogenous insultsis a constant problem for which cells have developed multiple protectivemechanisms to survive [5,6]. ROS are mainly generated by mitochondria at theportion of the electron transport chain as the toxic by-products of oxidativephosphorylation, their energy generating pathway [7]. The interruption ofoxidative phosphorylation results in decreased levels of ATP. Whatever thecause(s) and sequence of events are, respiratory chain deficiencies appear to playan important role in the pathogenesis of many diseases [8]. In addition, freeradical production and disturbance in redox status can modulate the expressionof a variety of immune and inflammatory molecules [9–11], leading toinflammatory processes, both exacerbating inflammation and effecting tissuedamage [12]. Recently, it has been suggested that abnormal immunity has been

´J.M. Mates et al. / Clinica Chimica Acta 296 (2000) 1 –15 3

related to oxidative imbalance [13–17], and antioxidant functions are linked toanti-inflammatory and/or immunosuppressive properties [18–20].

Since tissue injury and inflammation lead to increased oxidative stress, itseems logical that good antioxidant status might diminish tissue damage inallergic diseases [6–8]. Herein, we will see the role of the primary antioxidantdefence system which is constituted by the antioxidant enzymes, protecting cellsfrom toxic oxygen. We will analyze how they are involved in blood cellsdetoxification, and how the imbalance of reactive oxygen species is related toinflammation in allergic diseases by affecting immune cells. A further in-vestigation in antioxidant enzymes may open a new pathway in the knowledgeof allergic diseases.

2. Reactive oxygen species and free radical scavengers

Generation of hydrogen peroxide takes place through the dismutation of?2superoxide. Therefore any biological system generating O will produce H O .2 2 2

However, there are enzymes localized in peroxisomes that produce H O2 2?2 ?2without intermediation of O . Contrary to O , H O is able to cross cell2 2 2 2

21 1membranes and inside the cells it can react with Fe or Cu to form hydroxylradicals via the Fenton reaction [21]:

21 31 ? 2Fe 1 H O → Fe 1 OH 1 OH (Fenton reaction)2

?2 ? 2O 1 H O → O 1 OH 1 OH (Haber–Weiss reaction)2 2 2 2

The metal-catalysed Haber–Weiss reaction may involve the participation ofeither free iron (or copper) or iron sequestered in the form of nucleotide ironcomplexes, ferritin, lactoferrin, hemoglobin, and myoglobin.

The wide array of enzymatic and non-enzymatic antioxidant defences includessuperoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT),ascorbic acid (vitamin C), a-tocopherol (vitamin E), glutathione (GSH), beta-carotene, vitamin A, NADPH, adenosine, coenzyme Q, urate, methionine,cysteine, phenols and flavonoids [22,23].

Superoxide dismutase (EC 1.15.1.1) destroys the highly reactive radicalsuperoxide by conversion into the less reactive peroxide (H O ), that can be2 2

destroyed by catalase or glutathione peroxidase reactions [21]:

SODO 1 O 1 2 H → H O 1 O2 2 2 2 2

Catalase (EC 1.11.1.6) is a highly reactive enzyme, reacting with H O to2 2


form water and molecular oxygen; and with hydrogen donors such as methanol,ethanol, formic acid or phenols [22]:

CAT2H O → H O 1 O2 2 2 2

CATROOH 1 AH → H O 1 ROH 1 A2 2

Glutathione peroxidase (EC 1.11.1.19) catalyses the reduction of a variety ofhydroperoxides (ROOH and H O ) using GSH, thereby protecting mammalian2 2

cells against oxidative damage and, reducing, among others, cellular lipidhydroperoxides [22]:

GPXROOH 1 2 GSH → ROH 1 GSSG 1 H O2

The flavin containing thioredoxin reductase (EC 1.6.4.5) is an ubiquitous?2enzyme able to reduce O and NO by using thioredoxin as a substrate [23].2

Transferrin and ferritin sequester iron ions, while ceruloplasmin sequesterscopper ions so that these ions are not available to catalyse the Haber–Weiss

?reaction generating OH or to perform the decomposition of hydroperoxides.21 31Ceruloplasmin has also ferroxidase activity: it oxidizes Fe to Fe and so

?inhibits OH formation from H O and iron dependent lipoperoxidation [24].2 2

a-Tocopherol is concentrated inside the membranes, in blood lipoproteins and1 ?adrenal glands. It quenches and reacts with O and is a scavenger of OH, able2

to protect membranes from these extremely reactive species. However, its majorantioxidant action in biological membranes is to act as a chain breakingantioxidant, donating labile hydrogen to peroxy and alkoxy radicals, thereby

?breaking the radical chain. It has been proposed that a-TO may be reduced byascorbic acid or reduced glutathione. These are scavengers of ROS and other

1reactive free radicals. b-Carotene is a powerful scavenger of O . Urate binds2? 1iron and copper and scavenges OH, O and peroxy radicals [25].2

Animal studies have shown that circulating cells exhibit membrane alterationswhen there is a lack of vitamin E in the diet. In fact, the mitochondrialmembranes of the reticulocytes and lymphocytes appear bloated and dis-integrated; the number of platelets, which are more adhesive, increases andproduces more thromboxanes in comparison with those of normal rats. Theresponse of T and B lymphocytes to mitogenic stimuli, the mixed lymphocytereaction and the number of cells forming plates are considerably depressed. Onthe contrary, carotenoids and in particular beta-carotene either directly orindirectly as precursor of vitamin A, enhance T cell proliferation and cytotoxici-ty, macrophage killing, and TNF-a secretion [24].


3. ROS generation and histamine and nitric oxide release

All allergic diseases are characterized by a specific pattern of inflammationthat is largely driven by IgE-dependent mechanisms. Although allergen avoid-ance is, by far, the most effective way against allergic reaction, immunotherapyis the only clinical treatment to effectively prevent the allergic manifestations.Not only does Immunotherapy act only producing blocking antibodies, but italso favors the transformation of lymphocytes T helper 2 (Th ) into Th . At the2 1

same time, the production of interferon gamma (IFN-g) increases and there is aninhibition in the production of IgE by B lymphocytes (Fig. 1). In these processesstimulated cells generate a considerable amount of reactive oxygen species.Thus, we will describe antioxidant enzymes appearing to work with immuno-therapy in order to effect some immune-like functions against inflammation andallergic manifestations (Fig. 2).

Mast cells exist throughout most tissues although they are more prevalent inareas that come into contact with the external environment, such as the skin,

Fig. 1. Immunotherapy favors the transformation of lymphocytes Th into lymphocytes Th . By2 1

avoiding this transformation, IFN-a production and inhibition of B lymphocytes that secrete IgE,is achieved. The alternative pathways for lymphocytes Th transformation and some of the2

cytokines involved are shown.


Fig. 2. Antioxidant defence might block histamine (and other chemicals and molecules) releasedfrom mast cell. The production of ROS has been detected in cells stimulated with cytokines suchas transforming growth factor-b (TGF-b), interleukins (IL-x), granulocyte macrophage colonystimulating factor (GM-CSF) and tumor necrosis factor-a (TNF-a) with peptide growth factorssuch as platelet derived growth factor (PDGF) and basic fibroblast growth factor (BFGF), withagonists of receptors such as angiotensin II (AGII) and lysophosphatidic acid (LPA), or with drugsas phorbol 12-myristate 13-acetate (PMA).

lungs, and gastrointestinal tract. They have a recognized pathophysiologic roleas effector cells in immediate hypersensitivity reactions [24]. Such mast cells,when activated by either immunologic or non-immunologic stimuli, release andgenerate chemical mediators such as histamine, protaglandins, bradykinins,platelet activating factors (PAF) and leukotrienes which then act on surroundingtissues (Fig. 2).

Hydrogen peroxide stimulates histamine release. It is reduced by addition ofcatalase and flavonoids, showing a relationship and a balance among antioxidantenzymes, active oxygen and histamine release [26].

IFN-a and IFN-g enhance monocyte-mediated activity. IFN-a directlyactivates blood monocyte superoxide anion release in allergic patients [27].Superoxide generation correlates with the degree of bronchial hyperresponsive-ness to inhaled histamine. These results hint that polymorphonuclear leukocytes(PMNs) in asthmatic children, especially in those with attacks, generate more


active oxygen species than those in control subjects, and that airway inflamma-?2tion caused by O may be closely related to bronchial hyperresponsiveness2

[28].During phagocytosis, neutrophilic and eosinophilic granulocytes undergo

metabolic activation and degranulation. This leads to accumulation of H O in2 2

the extracellular environment in inflammation with release of histamine. Thisrelease reaction was inhibited by azide and catalase [29].

On the other hand, asthmatic patients show an increased expression ofinducible nitric oxide synthase (iNOS) in airway epithelial cells and anincreased level of NO in exhaled air. The NO derived from airway epithelialcells may be a mechanism for amplifying and perpetuating asthmatic inflamma-tion, through inhibition of Th cells and their production of IFN-g. This would1

result in an increase in the number of Th cells and the cytokines IL-4 and IL-5.2

Thus, it has been argued that the development of specific iNOS inhibitors mayalso represent a novel therapeutic approach for asthma and other allergicdiseases [30].

Another issue is the molecular mechanisms of ROS in affecting these immunoand inflammatory cell activities. It can be driven by secondary cytokine release.More information on the effects at the transcriptional level, such as on NF-kBare needed [31]. This might be a clinically relevant pathway in the case ofexposure to pollutants or respiratory tract infections, and it seems to occur inbronchial epithelial cells [32].

4. Free radical scavengers and blood detoxification

Neutrophil populations have the innate property of generating highly reactive?2 ?oxygen free radical species such as O , HO and H O , and they produce them2 2 2

during inflammatory reactions [33]. CAT, but not SOD, prevented neutrophilactivation measured as (1) induction of cytotoxic responses, (2) increase ofneutrophil adhesiveness to cell-free surfaces, and (3) inhibition of chemotacticresponses to N-formyl-methionyl-leucyl-phenylalanine (FMLP). These findingssuggest that H O may play a major role in neutrophil activation [34].2 2

When neutrophils were blocked from direct attachment to endothelial cells,endothelial cell damage was ameliorated. SOD partially inhibited this endotheli-al cell injury [35]. The respiratory burst is a coordinated series of metabolicevents that take place when PMNs and other phagocytes are exposed to anappropiate stimulus such as phorbol 12-myristate 13-acetate (PMA), thechemotactic peptide FMLP or leukotriene B4. In fact, stimulation of PMNsrapidly increases oxygen consumption and produces superoxide [36].

Ig-stimulated eosinophils can also induce damage to respiratory epithelium.Granule basic proteins and reactive oxygen radicals may be responsible for the


injury. Peripheral blood eosinophils and neutrophils obtained from allergicpatients, and stimulated with PMA, displayed a significantly higher superoxidegeneration [37]. CAT inhibited partially the appearance of irregularities on thesurface of the epithelium. Moreover, the addition of either CAT or SOD reducedpartly the activity of PMA-stimulated eosinophils [38].

GPX also has a protective role against oxidative stress and a regulatoryfunction in arachidonic acid metabolism, which leads to prostaglandins synthesis[39]. Reduced GPX activity contributes to an allergic inflammation and it isassociated with intolerance to some food and aspirin (Table 1). It seems likelythat the reduced activity of this enzyme in platelets and blood may reflectmechanisms associated with the pathogenesis and severity of allergic disorders[47]. The lowest levels of GPX activity were found during the acute attack,which were significantly less than the control, even in patients with mildsymptomatology [48].

SOD is constitutively expressed in leukocytes and other tissues. Significantinduction of SOD activity occurs in peripheral blood leukocytes incubated invitro with paraquat, an agent known to cause intracellular superoxide production[49]. Cu,Zn-SOD activities in platelets from the asthmatics were significantlyhigher than those from normal healthy subjects. Platelet Cu,Zn-SOD activitieswere significantly higher in atopic than in non-atopic asthmatics [50]. Theseresults suggest that an oxidant-to-antioxidant imbalance may play a role in theinflammatory situations in the airways of asthmatics.

In fact, an imbalance between oxidants and antioxidants is proposed in

Table 1Allergy and main antioxidant enzymes involved in the allergic response

Clinical manifestations Allergens Enzymes Reference

Hypersensitivity reactions Skin tests SOD [21]Hypersensitivity reactions Olive pollen SOD [40]Hypersensitivity reactions Pollens and house dust mite SOD/CAT [41]Hypersensitivity reactions Latex SOD [42]Acute respiratory syndrome Ragweed SOD [43]Asthma Anti-asthma drugs SOD/GPX [28]

aAsthma Anti-asthma drugs EPO [22]Asthma Oxidants SOD [44]Asthma Mercury GPX [45]Asthma Foods GPX [21]Asthma Aspirin GPX [22]

bAsthma Non aspirin, non NSAID GPX [46]cAllergic encephalomyelitis Myelin protein NOS [21]

a EPO: Eosinophil peroxidase.b NSAID: non-steroidal anti-inflammatory drugs.c NOS: nitric oxide synthase.


smokers and in patients with airways diseases. This hypothesis has been testedby measuring the Trolox equivalent antioxidant capacity (TEAC) of plasma andthe concentrations of lipid peroxidation products as indices of overall oxidativestress. The plasma TEAC was markedly reduced, with increased levels of lipidperoxidation products in healthy chronic smokers as compared with healthynonsmokers. Plasma TEAC was also low in patients presenting with acuteexacerbations of chronic obstructive pulmonary disease (COPD) or asthma [51].

IgE-mediated systemic anaphylaxis can also follow parenteral SOD adminis-tration [52]. In addition, olive pollen extracts have a heterogeneous composition,with several important allergens, one of which showed a high degree ofhomology with a SOD. Otherwise, characterization and identification of latexallergens show that some of the IgE-reactive protein spots have high homologywith SOD (Table 1).

Cytokines are implicated in allergic diseases and can modulate effectorfunctions of eosinophils stimulated by another agonist, inducing eosinophildegranulation and superoxide production in vitro. Therefore these cytokines maybe important in the release of toxic granule proteins from eosinophils in allergicdiseases [53].

Indeed, asthma is characterized by an accumulation of activated eosinophils inthe airway. Bronchial epithelial cells have been shown to release cytokinesincluding granulocyte-macrophage colony-stimulating factor (GM-CSF). Eosin-ophil peroxidase (EPO) stimulates epithelial cells to release GM-CSF and formsa self-stimulatory cycle [54]. On the other hand, in bronchial asthma, in-flammatory cells, infiltrating the airway mucosa, release oxygen radicals thatcause tissue damage and amplify the airway inflammation. Therefore, anti-oxidant enzymes may have a protective effect on the airways, and a beneficialeffect on bronchial asthma [43]. In addition, oxidative stress can be measuredrather easily and non invasively by hydrogen peroxide, pentane, CO and NO inexhaled air [55–59].

5. Antioxidant enzymes also against cytotoxicity?

Cell-mediated cytotoxicity is a kind of immune response mainly due to T andNK cells. Examples of such reactions are the T cell infiltration of tumor bedsand the T cell infiltration of blood vessels and alveoli [60]. Oxygen radicals havebeen detected in a variety of stimulated blood cells (Fig. 2) [61]. For instance,during various biological processes as inflammation or septic shock, free radicaldamages are not only caused by a direct generation of oxygen radicals byphagocytes, but also by a TNF-a-mediated generation in target cells. Theoxidative effect of TNF-a is beneficial in physiological conditions as it candestroy cancerous or virus infested cells. But this effect can be deleterious in a


situation of deficiency in some antioxidants. TNF-a-induced free radicals canincrease the replication of virus as HIV-1 and destroy immunocompetent cellssuch as T cells. This last action explains the defect in cellular immunityobserved in oxidative stress and the immunostimulatory effect of manyantioxidants. In this event, catalase has the better protecting effect whereasCu,Zn-SOD has little effect [62]. So, antioxidants have been demonstrated asprotective against TNF-a cytotoxicity.

On the other hand, addition of IFN-a or IFN-g enhanced the monocyte-mediated cytotoxicity of a colon carcinoma cell line. However, inhibitors ofH O -myeloperoxidase system suppressed both IFN-a- and IFN-g-induced2 2

cytotoxicity of these cells [63].

6. Summary and prospects

There is considerable interest in the therapeutic use of antioxidants. This mayinvolve the use of naturally occurring antioxidants or completely syntheticmolecules. In addition, there is evidence that some drugs already used clinicallymay exert part or all their effect by antioxidant mechanisms. Infusions of SODin liposomes (usually with catalase) have been reported to protect animalsagainst O toxicity. Cu,Zn-SOD has an anti-inflammatory effect in animal2

models of acute inflammation, in part because it can decrease the number ofneutrophils entering sites of inflammation. A wide variety of Cu,Zn-SODconjugates are available, including polyethylene glycol (PEG)-SOD, Ficoll-SOD, lecithinized SOD, polyamine conjugated SOD, cationized SOD, ge-netically engineered SOD polymers, pyran-SOD and albumin-SOD complexes.All have longer circulating half-lives than the unconjugated SOD molecules[25]. In addition, several low-molecular-mass compounds that react withsuperoxide anion have been described. Most contain transition-metal ions.Examples include iron porphyrins, a complex of manganese ions with thechelatins agents desferrioxamine and copper ions chelated to amino acids or toanti-inflammatory drugs [25,64].

It is well established that immunotherapy can prevent or reduce allergy bothincreasing IFN-g production and decreasing IgE production. Nevertheless,sometimes immunotherapy is not the best indicated treatment. Drugs, traditional-ly used against clinical manifestations of allergy, include coumarins, glucocor-ticoids, anti-leukotrienes and anti-histaminics (Fig. 3).

We know today that immune cell response to allergens induces an accumula-tion of ROS that brings about mast cell in order to release histamine, the mainchemical mediator of inflammation in allergy. Additionally, active oxygenbecomes toxic when an imbalance arises between antioxidant enzymes and freeradical production during an allergic reaction. Consequently, could the in-


Fig. 3. ROS involvement in allergic response and alternative treatments. Alternative treatment topatients suffering from an allergic process, includes allergen avoidance, immunotherapy, glucocor-ticoids, coumarins, anti-histaminics and anti-leukotriens. Antioxidant defence system (antioxidantenzymes and non enzymatic antioxidant substrates) may provide a valuable help for immuno-therapy and traditional drug. Mast cell (chemical mediators) and eosinophil (granule proteins)degranulation are also shown. Transformations with dotted arrows represent ROS generation.

vestigation in antioxidant enzymes open a new and complementary pathway inthe treatment of allergic diseases?

We believe that the established connections between antioxidant enzymes andseveral allergic diseases (Table 1) may be a sign of their functional importancein the mechanism of the immunopathologic reaction named allergy. In fact,oxidative stress and antioxidant enzymes have been widely studied in manyother pathologies and they have also been determined separately as an indicatorof oxidative damage in many patients suffering from an allergic reaction. Forinstance, unsaturated lipid components of membrane are essential for a correctimmune function, and represent one of the main targets of free radical damage.However, a complete study in this field has not been described to date forallergic patients.

This work provides further clues to the interaction between oxidative stressand allergic diseases. Therefore, in spite of considering potential negativeconsequences of antioxidant therapy, efforts are necessary to fully understandthe relevance of ROS and free radical scavengers in the immune system and


allergy: without any doubt one of the most important human diseases at thebeginning of this new century.

Acknowledgements

˜´We wish to thank Prof. I. Nunez de Castro, Dr. J.A. Segura and Dr. J.C.Aledo for critically reading the manuscript, to Ms. M. Asenjo, M.D. for herhelpful suggestions, and to Miss C. Segura and Mr. N. McVeigh for the revisionof the spelling and the grammar. This work was supported by projects SAF98-0150 and SAF98-0153.

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