170

OCCASIONAL REVIEW

Oxidants and asthma
G Caramori, A Papi
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Thorax 2004;59:170–173. doi: 10.1136/thorax.2002.002477

Many decades of research have produced a significant hydrogen peroxide (H2O2), either spontaneously
or under the influence of superoxide dismutases
amount of data showing increased oxidative stress in (SODs). Although O22 and H2O2 themselves are
asthma and indicating a potential role for oxidants in the moderate oxidants, both species are critical for
pathogenesis of the disease, particularly during the formation of potent cytotoxic radicals in
biological systems through their interaction with
exacerbations. Putatively relevant pro-oxidative other molecules. For instance, the lysosomal
mechanisms have also been identified. Currently available enzymes myeloperoxidase (MPO) from neutro-
asthma drugs are generally effective for the treatment of phils and monocytes/macrophages and the eosi-
nophil peroxidase (EPO) catalyse the oxidation
the disease, but their effects on oxidative stress have still not of halides (Cl2, Br2, and I2) by H2O2 to form
been completely elucidated. From the data available in the hypohalous acids (HOCl or HOBr). MPO pro-
literature one can conclude that antioxidant compounds duces predominantly hypochlorous acid (HOCl)
whereas EPO produces more hypobromous acid
may have a potential role in the treatment of asthma, (HOBr). Hypohalous acid production is impor-
especially of asthma exacerbations. More convincing tant in the host defence against infectious
evidence from controlled clinical trials is required. agents, but during this reaction the hydroxyl
radical (OH2) is also produced, which is a
...........................................................................
powerful and indiscriminate oxidant.
Eosinophils possess several times greater

O
xidant generation is part of the normal capacity for generating oxidants than neutro-
metabolism of many types of cells and is phils, and the EPO content of eosinophils is
critical for cell homeostasis. To protect several times higher than that of MPO in
itself against exposure to noxious oxidants, the neutrophils.3–9 MPO and EPO derived reactive
lung has a well developed antioxidant system.1 2 oxygen species can also interact with nitrite
When an imbalance occurs between oxidants (NO22) and H2O2 leading to the formation of
and antioxidants in favour of oxidants, oxidative reactive nitrogen species (RNS; nitrosants). A
stress is said to occur. Many experimental and powerful oxidant, the radical peroxynitrite
clinical data suggest that oxidants play a role in (ONOO2), is produced from the reaction
the pathogenesis of several respiratory disorders, between O22 and nitric oxide (NO) which is
including bronchial asthma. increased in the asthmatic airways.3–8 10
In particular, there is increasing evidence that As in many other inflammatory conditions, the
the chronic airway inflammation typical of oxidative ‘‘burst’’ in asthma is a non-specific
asthma results in an increased oxidative stress process initiated by the concurrent action of
to the airways. Also, many of the triggers for numerous inflammatory pathways. Indeed, sev-
asthma exacerbations, including viral infections eral asthma mediators including lipid mediators,
and air pollutants, may activate the production chemokines, adhesion molecules, and eosinophil
of oxidants, triggering increased inflammation granule proteins are potential promoters of
which produces asthmatic symptoms. oxidant production.4

OXIDANTS AND INFLAMMATION IN Effects of oxidants in experimental settings
ASTHMA In experimental models, oxidants can produce
Sources many of the features typical of asthma. They
The inflammatory cells recruited to the asthmatic induce bronchoconstriction and increase airway
airways have an exceptional capacity for produ- responsiveness to several agonists.3–8 The release
cing oxidants. Once recruited in the airspaces, into the airways of tachykinins and neurokinins
inflammatory cells may become activated and and the decrease of b2 adrenergic receptor,
generate reactive oxidants in response to various cholinesterase, and neutral endopeptidase activ-
stimuli. Activated eosinophils, neutrophils, ities have been documented in these experimen-
See end of article for monocytes, and macrophages, and also resident tal conditions.3–8 Oxidants can also lead to
authors’ affiliations cells such as bronchial epithelial cells, can increased permeability of the airways in these
....................... generate oxidants.3–8 The univalent reaction of models.3–8 Conversely, reducing agents exert a
Correspondence to: oxygen to superoxide anion (O22) is an impor- relaxing effect on airway smooth muscle and can
Dr A Papi, Research tant step in the formation of oxidants. Sources of inhibit bronchial smooth muscle contraction and
Centre on Asthma and superoxide anion include primarily the mem- prevent airway hyperresponsiveness in several
COPD, University of brane associated NADPH oxidase dependent experimental models.3–8
Ferrara, Via Savonarola 9,
44100 Ferrara, Italy; complex, the cytosolic xanthine oxidase system, Experimental exposure to oxidants induces
ppa@unife.it and the mitochondrial respiration chain many degrees of injury to bronchial epithelial
....................... (fig 1).3–8 Superoxide anion is then converted to cells until cell death. EPO can induce lysis of

www.thoraxjnl.com

is reduced in the sputum of have been found in the urine. whether peroxidases simply reflect gran- inflamatory mediators found in the airways of asthmatic ulocytic inflammation or whether they actively contribute to patients. and in eosinophils of bronchial airways and lung inflammatory cell recruitment in asthma.23 A significant increase in 3-bromotyrosine 1 (AP-1).11 12 non-invasive markers on oxidative stress and in their possible In vitro exposure of structural and inflammatory cells of clinical application17–19 as their concentrations are signifi- the lungs to oxidants induces the release of pro-inflammatory cantly increased in asthma. plasma. Taken together. Many studies suggest that levels of oxidative stress are increased in children and in adults with asthma. EPO.14 Such activation can the level of 3-bromotyrosine is strongly related to levels of potentially explain the increased expression of many pro. patients with stable asthma and its level is positively related and lung tissues of patients with asthma. induced sputum. in smooth muscle and adhesion molecules (and their ligands) involved in cells.13 has also been described in the proteins of sputum of Both these transcription factors are activated in the bronchial asthmatic subjects. This finding is of particular interest as epithelial cells of asthmatic subjects.3–8 15 and bronchoalveolar lavage (BAL) fluid from patients with For instance. not only in their lungs but also in the circulation. ANTIOXIDANT DEFENCES IN ASTHMA Excessive production of oxidants occurs spontaneously or Many controlled studies suggest that there is a deficiency after stimulation in blood leucocytes of stable asthmatics of antioxidants with few studies indicating an activation of compared with normal subjects. bronchial and bronchiolar epithelial cells.17 18 There is a lot of interest in the effect of these new subjects. sputum.25 Similarly. an antioxidant system. two pivotal regulators of inflammatory processes. including those samples. in vitro oxidative stress can induce stress.3–8 parenchyma of patients with stable asthma. peroxynitrite inhibitory thiobarbituric acid reactive products (TBARs). analysis of sputum eosinophilia. another marker of oxidative expression.20–22 Excessive Within the nucleus. and that such redox imbalance is not confined within the lungs.17 18 The latter are footprints of oxidation on glutathione.26 exhaled breath and exhaled condensate has recently allowed Free NO levels are generally low in the respiratory system direct assessment of H2O2 and nitric oxide (NO) and as the NO produced by endogenous NO synthases (NOSs) is measurement of several indirect byproducts of oxidation in complexed with reducing agents like thiols.thoraxjnl. mediators including cytokines.com . and DNA (hydroxydeoxyguano- apoptosis of bronchial epithelial cells from asthmatic sine).8 In stable conditions. a marked reduction in plasma antioxidant stable asthma. these data indicate that oxidative stress is OXIDANTS IN ASTHMA enhanced in asthma. Recently. in normal subjects.3–8 Their level is to airway responsiveness and negatively related to forced often related to the severity of the disease and is inversely expiratory volume in 1 second (FEV1) and the degree of related to the degree of stability. growth factors. bronchial epithelial cells at concentrations that have been different substrates such as proteins (nitrotyrosine). and H2O2) activity. BAL fluid.9 24 However.3–8 Furthermore.3–9 16 capacity occurs during exacerbations.Oxidants and asthma 171 Figure 1 Main cell sources of oxidants. oxidants induce changes in gene production of 3-bromotyrosine. arachidonic acid metabolites.3–8 Oxidants induce increased (isoprostanes and ethane).3–8 15 Levels of EPO and/or the pathways protecting lung cells from oxidant mediated MPO are increased in the peripheral blood. Interestingly. to form a major reservoir of NO related www. chemokines (and their The expression of nitrotyrosine is increased also in receptors). lipids found in the asthmatic airways. damage in the lungs or circulation of asthmatic subjects. has been reported in the airways of patients with activation of nuclear factor kB (NF-kB) and activator protein severe asthma. increased levels of many direct and indirect CuZn-SOD activity is lower in steroid naı¨ve asthmatics than markers of oxidative stress (including malondialdehyde.14 tissue damage in asthma remains to be determined.

35 36 production and release. particularly in those with genetically induced oxidant generation and inflammatory mediator determined increased susceptibility to oxidant stress. However.40 Treatment with 1 Comhair SA. Erzurum SC. Aminophylline reduces the generation of oxidants in an 9 Aldridge RE. et al.. Puddicombe SM.. possibly recommend a specific role for vitamin C in the treatment of recruited via cytokines or chemokines released by bronchial asthma.172 Caramori. In: Barnes PJ..46 Rhinovirus infection of respiratory allergic stimuli in animals and dietary vitamin E levels are epithelial cells causes intracellular oxidant generation which inversely related to the incidence of asthma. Eosinophil peroxidase produces hypobromous acid in the airways of stable asthmatics. 3 Barnes PJ. both in children and in adults. University of Ferrara. Italy asthmatics. Drazen J.thoraxjnl.61:29–43. Viruses in asthma. is somehow linked to their influence on oxidant/antioxidant Volume 105.17 18 Similarly. Pharmacol Rev 1998. 8 Rahman I.. Increased oxidative stress and stable asthma.9:235–43.29 30 A link between asthma and selenium deficiency Respiratory viruses represent the most important causes of (glutathione peroxidase is one of many selenium dependent asthma exacerbations.. gene whether the efficacy of glucocorticoid treatment in asthma expression. EFFECT OF ASTHMA DRUGS ON THE OXIDANT/ ANTIOXIDANT BALANCE . 15 Nadeem A. Reactive oxygen species as mediators in asthma..8 17 18 patients.12 term selenium supplementation in patients with intrinsic Experimental rhinovirus infection of asthmatic patients can asthma. et al. Asthma and COPD. Although glucocorticoids do not inhibit in vitro oxidant production from eosinophils. London: Academic Press. Oxidant stress in asthma. In: Most of the studies on oxidative stress in asthma have Barnes PJ. a protein that protects against oxidative stress such as H2O2 and isoprostanes are increased oxidative stress. airway levels airway inflammation.34 Recent studies is a crucial step in the activation of NF-kB and in the found that supplementation with vitamin C and vitamin E following production of proinflammatory adhesion molecules reduced ozone related decrement in lung function in and cytokines.8 In this context.27 It locally. hypothesised that the antioxidant activity of b2 agonists is Pulm Pharmacol Ther 2001. have a significant antioxidant effect.com . Lordan JL. Nijkamp FP.29:345–50. 2002:315–21. siveness. Free Radic Biol Med animal model of endotoxin induced bronchial hyperrespon.31 However. and cellular function. several indirect markers of inhibitor p21CIP1/WAF1.50:515–96.58:175–82. Page CP.47 48 Many promising new antioxidants such as nitrones (spin Taken together.283:L246–55. J Allergy Clin Immunol 2002. Massaro DJ. Reactive oxygen species and airway inflammation. sputum. Lung Biology in Health and Disease Series. a direct correlation between increased has been hypothesised that GSNO could be broken down by oxidative burden and changes in pulmonary function and/ oxidants in the asthmatic lung and that its catabolism could or airway inflammation described during exacerbations have an inhibitory effect on airway smooth muscle relaxa.. a hypothesis that links tion. Crapo JD..32 induce an inflammatory response in the airways associated Vitamin C has also been studied for its possible inverse with variable airflow obstruction and increased airway relationship with increased risk of asthma33 but.8 32 Furthermore. Thorax 2000. et al. Chhabra SK.47 Reducing agents inhibit both rhinovirus asthmatic subjects. In vitro. hyperresponsiveness. until now.10 Interestingly. Neill SJ. Asthmatic bronchial epithelium is more susceptible to oxidant-induced apoptosis. have an antioxidant effect on neutrophils and eosinophils. Papi bioactivity in the form of S-nitrosothiols (SNOs) which are Episodic worsening of asthma is associated with increased relatively resistant to oxidants. and BAL fluid during exacerbations are increased in bronchial epithelial cells of asthmatic and after allergen exposure.110:349–56.. relevance of such an effect is unclear. It has been 7 Henricks PA. short acting and long acting inhaled b2 agonists 4 Barnes PJ.43 44 12 Message SD. Drazen J. 2003.12 Rhinovirus induced airway inflamma- evidence from randomised controlled trials is insufficient to tory responses involve eosinophils and neutrophils. www. release from blood eosinophils in a dose dependent manner. 2002. Rhinoviruses are the virus type most antioxidant enzymes) has also been hypothesised. cyclin dependent kinase been proposed. Department of Clinical and Experimental Medicine. 1997:367–98.. frequently identified in respiratory tract specimens during a controlled trial did not show any significant benefit of short exacerbations of asthma. van Dalen CJ. within their molecular structure.. eds.. Reactive oxygen species. Theophylline also inhibits platelet activating factor 10 Ricciardolo FL. Thorax (PAF) induced and interleukin (IL)-5 induced oxidant 2003.28 exacerbations of asthma to dietary antioxidant deficiency has Among antioxidant systems.. to achieve their antioxidant effect. Chan T. Multiple roles of nitric oxide in the airways.14:409–20. eds.. 13 Hancock JT. et al. Am J Physiol Lung Cell Mol Physiol 2002. and the pathogenetic mechanisms putatively involved have been investigated mostly in vitro. In: Clerch LB. related to the number of hydroxyl groups on the phenol rings Rennard S..25 It is unknown in respiratory tract lining fluids. 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