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Annals of Clinical & Laboratory Science 37:96-101 (2007)
© 2007 Association of Clinical Scientists

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Antioxidant Vitamin Supplementation in Asthma

Graziano Riccioni1, Mancini Barbara1, Tonino Bucciarelli2, Carmine di Ilio2 and Nicolantonio D’Orazio1
1 Human Nutrition, Department of Biomedical Sciences, G. D’Annunzio University, and 2 Biochemical Clinic, Department of Biomedical Sciences, University of Chieti, Chieti, Italy

Address correspondence to Graziano Riccioni, M.D., PhD., Via G. De Rogatis 12, CP 188, San Severo (FG) 71016, Italy; tel 39 333 636 6661; fax 39 088 222 7022; e-mail griccioni{at}hotmail.com.


   Abstract
Top
 Abstract
Introduction
 Oxidative Processes
 Antioxidant Vitamins
 Conclusions
 References
 
The influence of nutrition on chronic bronchial asthma has an important place in the management of this disease. Evidence suggests that specific inflammatory abnormalities exist in the airways of subjects suffering from mild-to-moderate persistent asthma, in whom an inflammatory state is often associated with increased generation of reactive oxygen species and the damaging effects of free radicals. For this reason oxidant stress may be an important pathogenic factor in the progress of the disease. The role of nutrition in bronchial asthma is related to antioxidant vitamins A, C, and E. By counteracting oxidants and reducing external attacks (bacteria, virus, toxins, xenobiotics) in the lung, antioxidant vitamins modulate the development of asthma and the impairment of pulmonary function. Dietary studies suggest relations between oxidative stress, bronchial inflammation, development of asthmatic symptoms, and reduction of cellular functions. Dietary interventions may reduce oxidant stress and prevent or minimize asthmatic symptoms. Such interventions may provide a cost-effective approach to asthma management that may supplement current pharmacological strategies, although this conclusion is not supported by many randomized, placebo-controlled studies. The aim of this short review is to summarize current knowledge regarding the relations between antioxidant vitamins and the treatment of bronchial asthma.

Keywords: asthma, vitamins A, C, and E, antioxidants, free radicals


   Introduction
Top
 Abstract
 Introduction
Oxidative Processes
 Antioxidant Vitamins
 Conclusions
 References
 
Studies have evaluated the relations between asthma prevalence in youths and serum levels of antioxidant vitamins A, C, and E [1], as well as the relations between diminished pulmonary function in children and inadequate dietary intake of anti-oxidant vitamins [2]. The experimental evidence on these topics is controversial; some studies have failed to show a positive correlation between regular dietary supplements of antioxidants and clinical benefits in asthma [3]. Many reports suggest that oxidant stress causes inflammation and tissue damage in the respiratory system and derangements of the immune system; lowered cellular reducing capacity represents a risk factor for the development of bronchial asthma [4]. Dietary, environmental, and genetic factors that diminish the cellular reducing capacity can increase tissue vulnerability to oxidant stress and are likely to enhance asthma risk. Dietary selenium (Se) deficiency lowers erythrocyte glutathione peroxidase (GSH-Px) activity and is associated with increased risk of asthma; low dietary intake of vitamins C and E also appears to increase the risk of asthma [5].


   Oxidative Processes
Top
 Abstract
 Introduction
 Oxidative Processes
Antioxidant Vitamins
 Conclusions
 References
 
Many studies have shown that cells involved in an asthmatic inflammatory process have a capacity for producing reactive oxygen species (ROS). Activated eosinophils, neutrophils, monocytes, and macrophages generate superoxides (O2–) via a membrane-associated NADPH-dependent complex. The subsequent dismutation of O2– can result in the formation of hydrogen peroxide (H2O2). O2– and H2O2 are moderate oxidants and both are critical in the formation of potent cytotoxic free radicals in biological systems through their interactions with other molecules [6]. This process is involved in asthmatic inflammation; moreover, the concentration of nitric oxide (NO) is increased in airways of asthmatic subjects [7]. In addition to the recruited inflammatory cells, epithelial airway cells are potential sources of ROS production [8].

Several asthma mediators (eg, platelet activating factor [9], chemokines [10,11], adhesion molecules [12], and eosinophilic granule proteins [13]) are potential promoters of ROS production. In addition to these endogenous sources, environmental factors linked to asthma, such as air pollutants, are important [14]. Increased production of ROS is deleterious because free radical-induced oxidation of proteins, DNA, and lipids can cause direct tissue damage and evoke cellular responses through the generation of secondary reactive species [15].


   Antioxidant Vitamins
Top
 Abstract
 Introduction
 Oxidative Processes
 Antioxidant Vitamins
Conclusions
 References
 
Many studies have reported increased indices of oxidative stress in the blood and airways of asthmatic subjects [16]. Gilliland et al [2] investigated the relation between pulmonary function and the intake of fruit, vegetables, juices, and vitamins A, C, and E by examining cross-sectional data from a Children’s Health Study that involved 2,566 children. Low total intake of vitamins A, C, and E was associated with deficits in spirometric parameters (forced vital capacity [FVC], forced expiratory flow at 1 sec [FEV1], and forced expiratory flow (25–75%) [FEF]) [2]. Other studies have likewise demonstrated lower lung function levels in children with inadequate dietary intake of antioxidant vitamins [17,18].

Vitamin A.  Vitamin A is a fat-soluble vitamin with 3 active forms: retinol, retinal, and retinoic acid, which collectively are called retinoids. In addition, there are provitamin A compounds, defined as carotenoids, the most important being ß-carotene, which prevent DNA damage secondary to lipid peroxidation [19]. Studies have shown effects of vitamin A and carotenoids in human diseases such as diarrhea, acute respiratory infections, ischemic heart disease, immunological disorders, and asthma [20–22]. Some authors have reported an association between low levels of serum vitamin A and chronic airway obstruction in adults, even if patients with asthma were not included in these studies [23,24]. Arora et al [25] observed that vitamin A deficiency was 4 times more common in children with asthma compared to controls [25].

Many hypotheses have been proposed to explain the altered vitamin A status in asthma. Children with asthma have frequent exacerbations of asthmatic symptoms in association with airway inflammation, infection, exertion, or stress. These factors have been shown to decrease serum retinol levels by increasing cellular demand for retinol and increasing its urinary elimination [26,27]. Airway inflammation in asthmatic patients is associated with increased production of ROS (superoxide anion, hydrogen peroxide, and hydroxyl radicals) by peripheral blood eosinophils, neutrophils, and alveolar macrophages [28]. ß-Carotene, by quenching singlet oxygen (an antioxidant effect), may reduce airway inflammation in asthma [29]. The utilization of vitamin A as an antioxidant may contribute to reducing serum vitamin A levels. Hypovitaminosis A induces respiratory epithelial changes, such as metaplasia [30], and may predispose to respiratory infections [31,32], which may exacerbate acute asthmatic attacks in children. These findings suggest that vitamin A supplementation might help to control the disease; therapeutic trials are needed to test this hypothesis.

Vitamin C.  Vitamin C is an important water-soluble vitamin that is present in 2 biologically active forms: ascorbic acid and its oxidized derivative, dehydroascorbic acid. Vitamin C can act as a hydrogen donor to reverse oxidation and therefore functions as an antioxidant that reacts with free radicals (FRs) and deactivates them before they cause damage to proteins or lipids [19]. Oxygen metabolites may play direct and indirect roles in the modulation of airway inflammation. Many studies suggest that SOD and other FR scavengers in blood are significantly lower in patients with asthma. There is correlation between asthmatic severity and ROS products in asthmatic subjects [33,34].

Epidemiological studies indicate that elevated dietary intake of vitamin C may be associated with a reduced risk of asthma [35–37]. Furtheremore, vitamin C levels are diminished in mild asthma [38]. A study of 7,505 youths (age 4–16 yr) in the National Health And Nutrition Examination Survey-III (NHANES III) showed an association between antioxidants and the prevalence of asthma; this association was stronger among children exposed to cigarette smoke [2,39]. A study of 4,300 healthy Norwegians (20–44 yr) reported that dietary vitamin C intake reduced coughing and wheezing in smokers having high oxidant stress [40]. Romieu et al [41] studied the effects of vitamin C supplementation on the disturbances of pulmonary function caused by ozone, nitrogen dioxide, and particulates. This double-blind, placebo-controlled trial included 158 Mexican asthmatic children randomized to receive vitamin C (250 mg/day) for 19 mo. The authors observed no association between ozone and lung functions in the vitamin C-supplemented group, but they did observe significant lowering of lung functions between the supplemented and control groups for FEF 25–75 and peak expiratory flow (PEF). They concluded that supplementation with antioxidants might modulate the impact of ozone exposure on small airways of children suffering from moderate-to-severe asthma.

Similar results were found in a double-blind crossover study of adults with asthma, which evaluated the effects of dietary antioxidant vitamins (C and E) on ozone-induced bronchial hyper-responsiveness (BHR), suggesting that such supplementation benefits asthmatic adults exposed to air pollutants [42]. The Nutritional and Health Survey in Taiwan (NAHSIT) study examined the relationships of nutrient intake and physician-diagnosed asthma and allergic rhinitis in 1,166 adolescents (13–17 yr). The study showed a marginally significant association between vitamin C intake in the lowest quartile and an elevated risk for asthma [43]. Kongerud et al [44] found decreased levels of ascorbic acid in induced sputum collected from the airways of 16 mild-asthmatic subjects compared to 18 healthy controls.

On the other hand, many studies do not indicate any relation between asthma and vitamin C [45]. A randomized, placebo-controlled trial including 300 asthmatic patients (18–60 yr) tested the association between vitamin C supplementation and clinical control of asthma. The results demonstrated that regular vitamin C dietary supplementation did not add any clinical benefit to the current standard therapy of asthma [3]. Kalayci et al [46] did not observe in 14 asthmatic children any correlation between the serum levels of antioxidant vitamins and lipid peroxidation products. The serum antioxidant vitamins levels were decreased in asthmatic patients even during asymptomatic periods, and the decreases were not associated with increased oxidative stress as reflected by serum levels of lipid peroxidation products.

In conclusion, the role of vitamin C in the prevention or treatment of asthma remains controversial [47] and the effectiveness of dietary supplementation in open-population samples has not been clearly demonstrated. Several authors have raised unresolved questions on the relationship between diet and respiratory disease [48–51].

Vitamin E.  Vitamin E is an important antioxidant vitamin in the body, playing an essential protective role against FR damage [52–54]. Vitamin E consists of a group of substances belonging to two closely related groups: tocopherols and tocotrienols, each existing in 4 isomeric forms, ß, ß, {gamma}, and {delta}, making a total of 8 different group members. The most important member, with the greatest biological potency and accounting for 90% of the vitamin activity in tissues, is {alpha}-tocopherol [55,56]. The chemical structure of tocopherols and tocotrienols, with an -OH group on the ring structure, makes them effective hydrogen donors. In donating hydrogen, vitamin E becomes oxidized itself, while preventing the oxidation of other factors more metabolically important, for example polyunsaturated fatty acids (PUFA) in cell membranes. This is important when FRs are present, as these highly reactive substances can attack double bonds, setting up chain reactions, with more FRs produced.

In the case of damage to fatty acids, the lipid peroxides produced alter the functions of the cell membrane and may cause irreversible damage to metabolic pathways [19,57,58]. Vitamin C is involved in the regeneration of vitamin E [59] and this process is particularly important in those parts of the body where large amounts of oxygen are present, including airways. The lungs are exposed to environmental pollutants containing FRs, and therefore protection is essential [51–54]. Pulmonary tissue can be damaged in various ways. The ROS induce bronchoconstriction, elevate mucus secretion, cause microvascular leakage, and produce autonomic imbalance between muscarinic receptor-mediated contraction and ß-adrenergic relaxation of the pulmonary smooth muscle. Vitamin E and Se have regulatory roles in this balance [60]. Normal plasma levels of tocopherol may enhance the lipoxygenation of arachidonic acid, whereas higher tocopherol levels exert a suppressive effect as a hydroperoxide scavenger. Receptor-mediated activation of neutrophils in individuals with asthma results in the synthesis of leukotrienes. Their activation is inhibited by tocopherol in a concentration-dependent manner [61].

A study of 2,633 adults indicated that vitamin E intake was associated with low serum IgE concentrations and low frequency of allergen sensitization [62]. This study suggested a beneficial effect that vitamin E could have on asthma incidence [62]. In patients with bronchial asthma, vitamin E supplements may induce immunological effects that increase the functional activity of T-lymphocytes and enhance the phagocytic activity of peripheral granulocytes [63].

In a case-controlled study of 118 asthmatic patients, no association was found between bronchial asthma and the intake or the circulating levels of micronutrients or antioxidants [64]. However, reduction of platelet GSH-Px activity was noted in patients with severe asthma, suggesting that such patients have diminished capacity to restore their antioxidant defenses [64].


   Conclusions
Top
 Abstract
 Introduction
 Oxidative Processes
 Antioxidant Vitamins
 Conclusions
References
 
Oxidant stress is evident in patients with bronchial asthma. However, little is known about the role of ROS and oxidant substances in the inflammatory and immunological cascades that are characteristic of asthma. Most investigations of the role of antioxidant substances in asthma have been inconclusive because they were short-term and only assessed immediate effects. Long-term placebo-controlled studies of supplementation with vitamins A, C, and E are needed to clarify the effects of antioxidants on the inflammatory process in asthmatic subjects. The authors speculate that antioxidant agents may, in the future, prove to be beneficial in the treatment of asthma, as adjuncts to current pharmacological strategies.


   References
Top
 Abstract
 Introduction
 Oxidative Processes
 Antioxidant Vitamins
 Conclusions
 References
 

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