Oxidative stress plays an important role in the development of age-related diseases [
120].Evidence increasingly suggests that poor diet, including clinical malnutrition may increase the risk for oxidative stress and chronic diseases [
92‐
97,
120]. Nutrition is known to play a significant role in the prevention and management of these same chronic diseases and has been shown to modulate the toxicity of PCBs [
93‐
97]. One study has suggested that there may be increased susceptibility to NO
2 when someone is in a fasting state [
121] but it is not known if it is the same for other pollutants.
Oxidative stress, resulting from an imbalance between reactive oxidant species and antioxidants, can lead to tissue damage, airway inflammation with increased asthma severity and abnormal immune responses [
122‐
124]. Serum concentrations of antioxidants have been positively associated with FEV
1 in people with and without asthma [
125,
126]. Vitamin, mineral and botanical compounds, with and without antioxidant properties will be discussed.
Vitamin A and carotenoids
Vitamin A contributes to key biological processes including growth, vision, epithelial differentiation, reproduction, and immune responses [
127]. The two dietary sources of this vitamin are pre-formed vitamin A (retinol) and pro-vitamin A (carotenoids) [
128]. Dietary intake of retinol comes from animal sources (eg, whole milk, liver, and eggs) and fortified foods. Orange and yellow fruits and vegetables (eg, carrots) are the main dietary sources of carotenoids, including α-carotene, β-carotene, lycopene and β-cryptoxanthins and they are known antioxidants [
129]. Oxidative stress might exacerbate asthma by increasing the release of pro-inflammatory cytokines, which may lead to increased airway inflammation, and airway responsiveness [
122,
123,
130]. Vitamin A might improve prevention or treatment of asthma by downregulation of oxidative stress [
131], or via direct effects on the immune system [
132] for example downregulation of T-helper (Th)2 (pro-allergic) immune responses [
133,
134]. However, vitamin A also enhances protective Th2 immune responses (eg, interleukin (IL) 4 expression) [
135]. Lycopene, (a carotenoid) supplementation was shown to reduce allergic airway inflammation, [
136]. Self-reported dietary intake of vitamin A or its components (retinol and carotenoids) was inversely associated with asthma and asthma severity. However, dietary intake of vitamin A was not significantly associated with wheeze or airway responsiveness [
137].
No primary randomised controlled trial (RCT) of vitamin A for the prevention or treatment of asthma has yet been performed. There are a number of studies of vitamin A supplementation, but such studies were difficult to control for dietary intake, and gave variable results [
138‐
140]. However, higher intake of tomatoes, carrots, and leafy vegetables (which are rich in carotenoids such as α-carotene, β-carotene, lutein, and zeaxanthin) has been associated with lower prevalence of asthma in women [
141]. Of the pro-vitamin A carotenoids, β-carotene has been most intensely studied because of its protective properties against the effects of free radicals and oxidative damage. A meta-analysis of five observational studies showed that high dietary intake of β-carotene was not significantly associated with asthma or FEV
1 [
142]. However, this meta-analysis was limited by sample size and residual confounding. Results of two RCTs showed that modification of dietary intake of carotenoids through a diet rich in fruits and vegetables [
143] or lycopene-rich tomato extract and tomato juice [
144] improved indicators of asthma control, including lung function measures and time to disease exacerbations, in adults with asthma. Larger RCTs (including both children and adults) with longer follow-up are needed to further validate these findings.
According to World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Second Expert Report from 2007, foods rich in carotenoids may protect against lung cancer (strength graded as ‘probable’) [
145]. However, in contrast, two large randomized double-blind placebo-controlled trials, the alpha-tocopherol-
β-carotene (ATBC) and the
β-carotene and Retinol Efficacy Trial (CARET) showed an increased risk of lung cancer among high-risk people supplemented with high doses of
β-carotene and/or
α-tocopherol [
146‐
149]. The latest meta-analysis showed higher blood concentrations of total carotenoids,
α-carotene,
β-carotene, lycopene, and retinol were inversely associated with lung cancer risk [
150]. However, because of the lack of data in people who never smoked, further large scale studies stratified by smoking status are needed to rule out residual confounding by smoking.
Vitamin C and E
Observational studies have reported that low vitamin C and vitamin E intakes are associated with a higher prevalence of asthma. [
151]. In the 2004 Cochrane database review, supplementation of vitamin C was not believed to have clinical benefits in people with asthma [
152] although this, and later reviews were withdrawn as there were serious data errors.
Exposure to O
3 results in dose dependent depletion of antioxidants vitamin C and E in the skin [
153]. Antioxidant supplementation with vitamin C and E above the minimum dietary requirement led to attenuated nasal inflammation and partially restored antioxidant levels in asthmatic patients exposed to high levels of O
3 [
154]. A meta-analysis of 24 observational studies in children and adults found lower dietary intake (but not serum level) of vitamin E was also significantly associated with increased asthma severity [
155]. A review of 15 observational studies (including 3 birth cohorts), suggested that the evidence linking low vitamin E to asthma development was methodologically weak but sufficiently supportive of a potential effect warranting follow-up in clinical trials [
156].
A RCT found no effect of vitamin E supplementation (500 mg/day) for six weeks on airway responsiveness in 72 British adults with asthma [
157]. A second RCT found no effect of an antioxidant supplement (containing β-carotene, vitamin C and vitamin E) on plasma F2-isoprostanes, exhaled nitric oxide (NO) or peripheral blood mononuclear cell (PBMC) immune responses in 54 allergic adults [
158]. In contrast to these negative results, four RCTs reported that vitamin E-containing antioxidants reduce O
3-induced bronchoconstriction in subjects with [
159,
160] and without [
161,
162] asthma, suggesting potential protective effects of vitamin E against the detrimental effects of O
3. A study in children looked at total antioxidant intake and asthma rates, and there appeared to be a link between higher antioxidant intake (total antioxidant capacity) and diminished sensitivity to inhaled allergens. Children in areas of low traffic pollution displayed a stronger association between sensitivity to allergens and antioxidant capacity [
163]. In people with exercise induced asthma, vitamin C and Vitamin E supplement aided recovery by improving flow rates [
164]. A London based bidirectional case cross-over study looked at whether individual plasma antioxidant concentrations (uric acid and vitamins C, A, and E) and 10 antioxidant genes could modify the response to PM with respect to hospital admissions for COPD or asthma. Two hundred and thirty four admissions were recorded and the level of PM10 was noted 14 days before and after each event. Combined admission rates were related to a 10 μg/m increase in PM10. Serum vitamin C modified the effect of PM10 on asthma/COPD exacerbations. A similar (although weaker) influence was observed for low levels of uric acid and vitamin E, whereas vitamin A showed no effect modification [
165].
In terms of cancer, one team demonstrated that vitamin E intake is a protective factor against lung cancer [
166] whereas other studies suggested vitamin E intake has no effect on lung cancer [
167‐
169]. Moreover, a different study showed that vitamin E intake increased the risk of lung cancer [
170]. In a meta-analysis of 9 prospective cohort studies of vitamin E and lung cancer from 1955-2015 found that for every 2 mg/d increase in dietary vitamin E intake, the risk of lung cancer decreased by 5% [
171]. A later single prospective cohort study in Japan found that vitamin C and E intake had no effect on lung cancer risk [
172].
Vitamin D
Vitamin D is key to the metabolism of calcium and phosphorus. In adults with Asthma, normal vitamin D levels correlated with improved asthma control and therefore supplementation may play a role in uncontrolled asthmatics with vitamin D deficiency [
173].
Irrespective of the threshold used, in a US cohort, reduced serum or plasma vitamin D concentrations are commonly detected in children and adults particularly in subgroups at high risk for asthma or asthma morbidity [
174,
175].
Three population-based studies (two cross-sectional [
174,
176] and one longitudinal [
177] showed an association between reduced serum vitamin D concentrations and severe disease exacerbations or core measures (eg, hospitalisations) of severe exacerbations in Costa Rican, North American, and Puerto Rican children with asthma. In the most recent of these studies, [
174] vitamin D insufficiency or deficiency (a serum 25[OH] D concentration <30 ng/mL) was associated with increased odds of one or more severe asthma exacerbations in the previous year even in non-atopic children. This suggests that vitamin D affects the risk of severe asthma exacerbations through mechanisms other than regulation of allergic immune responses. Reduced vitamin D concentrations are also associated with increased airway smooth muscle mass, decreased lung function, and worse disease control in children with severe, therapy-resistant asthma [
178]. A Cochrane database systematic review was undertaken on vitamin D and asthma. Meta-analysis of a modest number of trials in people with predominantly mild to moderate asthma suggests that vitamin D is likely to reduce both the risk of severe asthma exacerbation and healthcare use [
179].
The latest dose –response meta-analysis of 17 prospective cohort studies found the highest circulating 25-hydroxyvitamin D was associated with decreased lung cancer risk [
180]. Another meta-analysis of 22 studies found that high vitamin D (or calcium) intake and serum 25(OH)D levels correlate with lower lung cancer risk and better prognosis [
181].
Curcumin
The phytochemical curcumin, from turmeric, has been found to be a potent anti-inflammatory agent, and has been studied in regards to its anti-tumour, antifungal and antioxidant properties [
182]. Animal models have demonstrated that curcumin is a potent anti-inflammatory agent in the lungs [
183] and that it may also protect against pulmonary fibrosis [
184]. A number of studies have suggested that curcumin may have some protective role against the DNA damage caused by arsenic [
185,
186]. In a pre-clinical renal cancer study, addition of curcumin to cancer cells exhibited a strong potential for protection against diesel exhaust and cisplatin-induced cytotoxicity [
187]. Preclinical trials have also shown that curcumin inhibited POP associated cellular and DNA damage [
188,
189]. It has also reversed nicotine induced liver toxicity in an animal study [
190].
Pre-clinical studies have shown that curcumin can prevent cadmium-induced IL-6 and IL-8 inflammatory secretion by human airway epithelial cells. Cadmium (Cd) is a toxic metal present in the environment and its inhalation can lead to pulmonary disease including lung cancer and COPD. Curcumin could therefore potentially be used to prevent airway inflammation due to cadmium inhalation [
191]. An animal model investigated the effect of Cadmium (CdCl
2)-polluted drinking water (40 mg CdCl
2/L) on the level of tumour necrosis factor- alpha (TNF-α) and IL-6 and found a preventative action of curcumin against Cd toxicity [
192].
Specifically in COPD, curcumin has been shown in animal models to have a beneficial effect in smooth muscle cells and improve the mean pulmonary artery pressure and right ventricular myocardial infarction (RVMI) through stimulating the suppressor of cytokine signalling (SOCS) -3/JAK2/STAT signalling pathways [
193]. In another model, curcumin was shown to suppress chemokines and affect corticosteroid sensitivity in COPD through modulating Histone deacetylase 2 (HDAC2) expression and its effect on histone modification [
194]. Another animal model showed that curcumin attenuates alveolar epithelial injury in COPD, which may be partially due to the down-regulation of Protein 66 homologous- collagen homologue (p66Shc) [
195]. In a randomised, double blinded, parallel group study in patients with mild COPD and raised LDL cholesterol, 90mg curcumin was found to reduce the α1-antitrypsin–low-density lipoprotein (AT-LDL) complex, thus reducing risk of future cardiovascular events [
196].
In other patients, a population based study of 2478 people found that people taking dietary curcumin through eating curry had better pulmonary function. The mean adjusted FEV
1 associated with curry intake was 9.2% higher among current smokers, 10.3% higher among past smokers, and 1.5% higher among non-smokers [
197]. In 89 patients who had poor pulmonary function due to sulphur mustard, curcumin (1500 mg/day) + piperine (15 mg/day) or a placebo were given for 4 weeks. The active supplement reduced systemic oxidative stress and clinical symptoms, and also improved health related quality of life [
198].
The anti-cancer effects of curcumin against lung cancer have been investigated in vitro and in vivo xenograft mouse models. The key pathways appear to be downregulation of NF-ĸB, modulation of miRNA pathways with inhibition of caspase-3 as well as inhibition of PI3K/AKT pathways. In addition curcumin can act both as a chemo- and radio-sensitizing agent in lung cancer [
199].
N-acetylcysteine
N-acetylcysteine (NAC) supplementation has been shown to attenuate airway responsiveness by 42% in individuals with airway hyper-responsiveness following inhalation of diesel exhaust compared with filtered air [
200] and a pre-clinical study demonstrated N-acetyl-L-cysteine supplementation in smoke exposed rats showed antioxidant protective effects [
201]. A meta-analysis and systematic review found long-term NAC therapy may reduce risk of patients COPD exacerbation [
202]. An ex-vivo study found that NAC reduced COPD exacerbation induced by lipopolysaccharide (LPS) [
203]. Supplementation of NAC, 600mg once a day and a 20 minute daily walk in addition to regular treatment improved quality of life in stable COPD patients [
204]. However in another trial, treatment with NAC elevated plasma glutathione but did not modulate central or peripheral components of the O
2 transport pathway and did not therefore improve exercise tolerance in patients with mild COPD [
205]. There is little evidence of any benefits such as reducing lung cancer risk.
Fats
Omega-3 oils (or n-3 polyunsaturated fats-PUFAs) have received much attention due to their ability to reduce inflammation, and for its anti-coagulant properties, thus reducing risk of cardiovascular diseases. Two randomised controlled studies have investigated early life fish oil dietary supplementation in relation to asthma outcomes in children at high risk of atopic disease (at least one parent or sibling had atopy with or without asthma). In a study, powered only to detect differences in cord blood, maternal dietary fish oil supplementation during pregnancy was associated with reduced cytokine release from allergen stimulated cord blood mononuclear cells. However, effects on clinical outcomes at one year, in relation to atopic eczema, wheeze and cough, were marginal [
206] In a second study, fish oil supplementation started in early infancy with or without additional house dust mite avoidance, was associated with a significant reduction in wheeze at 18 months of age. By five years of age fish oil supplementation was not associated with effects on asthma or other atopic diseases [
207]. In the absence of any evidence of benefit from the use of fish oil supplementation in pregnancy, the British Thoracic Society SIGN 2016 guidelines do not recommend it as a strategy for primary prevention of childhood asthma [
208].
There are recent studies which use omega-3 oils to combat the effects of pollution. Animal models of fine particle matter pollution, demonstrated that omega-3 oils prevented and improve inflammation caused by these fine particles [
209] with a further pre-clinical study showing that omega-3 oils reduced the oxidative damage in the intestines after heavy metals ingestion [
210].
For the early and milder forms of allergic asthma, dietary supplementation with long-chain polyunsaturated fatty acids (LCPUFA), predominantly fish oil-associated eicosapentaenoic (C20:5 ω-3) and docosahexaenoic acid (C22:6 ω-3), and distinct crop oil-derived fatty acids have been proposed to provide a sustainable treatment strategy [
211,
212]. C20:5 and C22:6 ω-3 fatty acids inhibit cyclooxygenase (COX) activity and decrease eicosanoid synthesis from amino acids. [
213]. They also suppress immunoglobulin (Ig) E production and thereby reduce airway inflammation and bronchoconstriction in asthma [
214]. In 2002 a Cochrane database review concluded that there was insufficient evidence to recommend fish oil supplementation for the treatment of asthma [
215].
In addition to immune-controlling prostaglandins, leukotrienes, and thromboxanes, specialised mediators, such as lipoxins, resolvins, protectins, and maresins are metabolised from different LCPUFA, which actively resolve inflammation. Where people with asthma are allergic to pollutants and other allergens, omega-3 and some omega 6 oils also act to reduce inflammation, rebuilding fatty acid homeostasis in cellular membranes, modifying eicosanoid metabolic pathways, thus reducing clinical symptoms [
216,
217]. Most recently, an animal study compared the effects of olive oil, coconut oil and fish oil. Although fish oil protected against O3 induced vascular damage, it increased pulmonary injury/inflammation and impaired lipid transport mechanisms [
218].
A Mediterranean diet has long been suggested as the most ‘healthy’ diet to follow and its health benefits are largely attributed to the content of fibre, antioxidants, protein, and moderate amounts of fat-predominantly from mono-unsaturated (MUFA) and omega-3 PUFA. Airway inflammation during asthma may be modulated by dietary intake [
144,
219‐
221]. Fruit, vegetables and their antioxidants may lower airway inflammation [
144,
220]. Fruit and vegetable intake was inversely associated with IL-8 protein in nasal lavage of asthmatic children [
220]. The Mediterranean diet does offer some protection against the effects of tobacco smoke in smokers and passive smokers [
222].
In contrast, high fat intake comprising of a low intake of n-3PUFAs with a corresponding increase in intake of n-6PUFAs is characteristic of the Western diet, can cause an increase in airway inflammation. This change has been linked to increasing rates of allergic disease and asthma [
151]. Consumption of a high-fat mixed meal has been shown to increase sputum neutrophils 4 h post-meal in patients with asthma [
223], as well as activation of a number of genes in sputum involved in “immune system processes”, such as TLR4, indicating an increase in airway inflammation [
221]. Reduction of dietary saturated fat intake was associated with a reduction in neutrophilic airway inflammation in asthmatics [
222]. In adults with severe asthma, higher fat and lower fibre intakes have been associated with increased eosinophilic airway inflammation [
219].
In a COPD randomised placebo controlled trial of 86 patients, an omega-3, vitamin D and leucine supplement drink was given to half the group for 4 months alongside high intensity training, whilst the other half undertook the exercise alone. The population had moderate airflow limitation, low diffusion capacity, normal protein intake, low plasma vitamin D, and docosahexaenoic acid. There were significant differences after 4 months favouring the supplement group for body mass, plasma vitamin D, eicosapentaenoic acid, docosahexaenoic acid and number of steps [
224].In a meta-analysis of 8 prospective cohort studies looking at PUFA and lung cancer risk, the team concluded that PUFA intake had little or no effect on lung cancer risk. PUFA intake might play a small role in lung cancer prevention in women, but this is unclear [
225].
Choline
Choline is a lipotropic agent involved in several biological functions (eg, neurotransmitter production, signalling lipids, and components of structural membranes), and as a methyl group donor [
226]. Dietary sources of choline include meat, liver, eggs, poultry, fish and shellfish, peanuts, and cauliflower. Choline deficiency is associated with neurological disorders, cardiovascular diseases, and inflammation [
227].
Intranasal or oral administration of choline has been shown to reduce the number of eosinophils and reactive oxidant species in bronchoalveolar lavage fluid in a murine model of allergic airway disease [
228]. In human studies, 76 asthma patients were recruited and treated with a choline supplement (1500 mg twice) or standard pharmacotherapy for 6 months in two groups. The patients were evaluated by clinical, immunologic and biochemical parameters. The treatment with choline showed significant reduction in symptom/drug score and improvement in FEV
1 compared to baseline or standard pharmacotherapy. Choline therapy significantly reduced IL-4, IL-5 and TNF-alpha level as compared to baseline or standard pharmacotherapy after 6 months (
p<0.01). Blood eosinophil count and total IgE levels were reduced in both of the treatment groups. [
229]. In a cross-sectional survey that enrolled 1514 men and 1528 women with no history of cardiovascular disease (the ATTICA Study), fasting blood samples were collected and inflammatory markers were measured. Compared with the lowest tertile of choline intake (<250 mg/d), participants who consumed >310 mg/d had, on average, 22% lower concentrations of C-reactive protein (
P < 0.05), 26% lower concentrations of IL-6 (
P < 0.05), and 6% lower concentrations of tumour necrosis factor-alpha (
P < 0.01). These findings were independent of various sociodemographic, lifestyle, and clinical characteristics of the participants [
230]. This suggests that choline might attenuate allergic inflammation in general and airway inflammation in particular.