Encyclopedia
Please note this is a comparison between Version 1 by Naser Alsharairi and Version 2 by Dean Liu.
Asthma is considered a chronic inflammatory disorder associated with airway hyperresponsiveness (AHR). Increased oxidative stress (OS) is a clinical feature of asthma, which promotes the inflammatory responses in bronchial/airway epithelial cells. Smokers and nonsmokers with asthma have been shown to have increases in several OS and inflammatory biomarkers.
- asthma
- antioxidant
- vitamins
- minerals
- supplements
- biomarkers
- oxidative stress
1. Introduction
Smoking is regarded as a significant risk factor for asthma progression [1]. The number of asthma deaths due to smoking in 2019 was higher in men than in women [1][2][1,2]. Asthma is characterized by airway hyperresponsiveness (AHR) and reversible airflow obstruction, which is attributed to increased airway smooth muscle (ASM) contraction [3][4][5][3,4,5]. Asthma is associated predominantly with mast/CD4+ cells, T lymphocytes and eosinophils. Mucous hypersecretion, luminal obstruction, goblet cell hyperplasia, and thickening of bronchial walls are commonly observed features in asthma [3].
Tobacco smoke is associated with reduced lung function measured as forced expiratory volume in 1 s (FEV1) and increased bronchial hyperresponsiveness in smokers with asthma [6]. Asthmatic patients who smoked ≥10 pack/year had a rapid decline in FEV1 and forced vital capacity (FVC) compared with those who smoked <10 pack/year after 12-year follow-up [7]. Secondhand smoke (SHS) exposure has been linked to asthma risk in active and/or former smokers [8]. Exposure to SHS in public places was associated with a marked decrease in peak expiratory flow rate (PEFR) and FVC in asthmatic smokers [9]. The risk of asthma among nonsmokers who were exposed to SHS has increased in a large adult-onset asthma population with 16 years of follow-up [10].
Tobacco smoke consists of a range of toxic chemicals (e.g., benzopyrene, acrolein, crotonaldehyde, phenols, ammonia, nitrosamines, hydrocarbons, aromatic amines), which are potentially harmful to human bronchial epithelial cells (HBECs), causing airway inflammation by increasing mitochondrial reactive oxygen species (ROS) and pro-inflammatory interleukin (IL)-8 cytokine production [11][12][11,12]. Downregulation of microRNAs in lung fibroblasts of smokers may affect its function due to aberrant DNA methylation at specific sites [13]. Moderate asthma was associated with lung inflammation, and this response is related to reduced expression of microRNA target genes such as I-miR-146a [14]. Cigarette smoke extract (CSE) exposure in HBECs results in increased oxidative stress (OS) and pro-inflammatory cytokines IL-6, IL-8, and tumor necrosis factor α (TNF-α) by the activation of several inflammatory signaling pathways, including the transcription factor-kappaB (NF-κB), extracellular signal-regulated kinases (ERK 1/2), c-Jun N-terminal kinase (JNK), and mitogen-activated protein kinases (MAPKs) [15]. Tobacco smoke alters immune responses in the lung, triggering asthma by activating Toll-like receptors (e.g., TLR-2 and TLR-4)-stimulated pro-inflammatory cytokine production and increasing total serum immunoglobulin E (IgE) levels in airway epithelial cells [16]. In asthmatic patients, exposure to environmental tobacco smoke (ETS) results in oxidant/antioxidant imbalance, which leads to increased pro-inflammatory biomarkers as assessed by increased TNFα, IL-6, and IL-8 [16]. Evidence suggests that nicotine is not carcinogenic, but it may affect the airway epithelial cells of asthmatic smokers by activating nitrosamine 4(methylnitrosamino)-1-(3–pyridyl)-1-butanone (NNK), which binds to the α7 nicotinic acetylcholine receptor (α7nAChR), leading to AHR and inflammation by upregulating the α7nAChR-mediated signaling pathways [17].
The genetic variants–tobacco smoke exposure interaction has been shown to increase asthma risk in smokers and nonsmokers. Evidence of the interaction between variants of rs9969775 on chromosome 9, rs5011804 on chromosome 12, and active tobacco smoking was reported in asthmatic adults [18]. Genetic variants of NLR Family CARD Domain Containing 4 (NLRP4) inflammasome are implicated in asthma exacerbation in current and former adult smokers as evidenced by high genotype-specific expression of rs16986718G [19]. The presence of mutant AG/GG genotype for CD14 rs2569190 and rs13150331 (TLR) polymorphism in asthmatic adult smokers increases the risk of the disease [20]. Asthmatic nonsmokers carrying allele homozygotes of rs1384006 C > T of the OS responsive kinase 1 (OXSR1) gene are at higher asthma exacerbation risk than asthmatic smokers [21].
Few studies have evaluated evidence-based treatment for asthma in smokers. Pycnogenol®, a herbal dietary supplement-based extract manufactured by Horphag Research (Geneva, Switzerland) and derived from French Pinus pinaster bark, is regarded as an option for the treatment of asthma when used in combination with the inhalation corticosteroid (ICS) therapy, resulting in improvement of asthma symptoms [22]. Asthmatic smokers have ICS insensitivity as compared to asthmatic nonsmokers and are less responsive to the benefits of ICS treatment alone. Alterations of inflammatory phenotypes and glucocorticoid receptors and the reduction of histone deacetylase (HDAC) activity are considered potential mechanisms of corticosteroid insensitivity in asthmatic smokers [23][24][23,24]. The combination of ICS therapy and a long-acting β2 adrenergic (LABA) displays a better clinical improvement for smoking and nonsmoking asthmatics than using ICS alone [25][26][25,26]. The use of nicotine replacement therapy, varenicline or bupropion, may significantly improve lung function and AHR in asthmatic smokers [25].
There is still a significant amount of uncertainty in the safety and efficacy of dietary supplements for the treatment of lung diseases among smokers and/or nonsmokers due to the limited number randomized controlled trials (RCTs) [27][28][27,28]. Thus, there is a need to focus on the role of antioxidants in smoking-related asthma risk. A recent review investigating the effects of dietary antioxidant intake on lung cancer (LC) risk among smokers and nonsmokers suggests that dietary vitamins (C, D, E, and carotenoids) and minerals (zinc and copper) may exert protective effects against cigarette smoke (CS)-induced OS and/or inflammation. However, dietary retinol and iron intake did not provide any protection, and research suggests caution in recommending these for LC treatment [29]. There is a direct association between LC and asthma in smokers [30][31][30,31]. Given that smoking is considered a risk factor for asthma through increased levels of OS and inflammatory cytokine production [17], targeting dietary/supplement-derived antioxidants might help theour understanding of their role in protecting bronchial epithelial cells against CS-induced-OS/inflammatory biomarkers in smokers and nonsmokers.
2. Antioxidant Intake and Asthma in Relation to Smoking Status
Studies investigating the associations between antioxidant intake and asthma according to smoking status are limited. Smokers with low dietary vitamin C (VC) intake had chronic bronchitis symptoms associated with asthma compared with those who had higher intake [32]. According to quartiles of carotenoid dietary/supplement intake (carotene, lycopene, and lutein with zeaxanthin), the risk of asthma was reported to be lower in the fourth quartile (≥165.59 μg/kg per day) than the first quartile (<41.43 (μg/kg per day) among current smokers, ex-smokers, and nonsmokers with asthma [33]. One trial revealed no effects of 6 weeks of supplemental vitamin E (VE) on AHR in nonsmokers with asthma [34]. Supplementation with selenium (Se) had no significant improvement in asthma-related quality of life (QoL) and lung function regardless of smoking status [35]. These findings suggest that dietary VC and carotenoids intake may reduce asthma in smokers and/or nonsmokers. Supplementation with VE and Se had no effect on asthma in smokers and nonsmokers. The associations between antioxidant intake and asthma risk according to smoking status are summarized in Table 1.Table 1. Antioxidants and asthma risk in relation to smoking status.
| Design | Study Population | Antioxidants | Main Findings | Ref. | ||||
|---|---|---|---|---|---|---|---|---|
| Cross-sectional | Total subjects = 2112 | 1 | 2th grade US students | VC, VE (diet) | Low dietary VC intake (<110 mg/day) was associated with FEV | 1 | decline and respiratory symptoms in smokers with asthma | [32] |
| Smokers = 515 | VE intake was not associated with asthma | |||||||
| Cross-sectional | Total subjects = 13,039 US adults (20–80 yrs) | Total carotenoids (diet and supplement) | High intake of carotenoids (≥165.59 μg/kg/day) was associated with reduced asthma risk in nonsmokers (OR = 0.63, 95% CI = 0.42 to 0.93), current smokers (OR = 0.54, 95% CI = 0.36 to 0.83), and ex-smokers (OR = 0.64, 95% CI = 0.42 to 0.97) | [33] | ||||
| Current asthma = 1784; non-current asthma = 11,255 | ||||||||
| Nonsmokers= 7106; current smokers= 3304; ex-smokers= 2624 | ||||||||
| RDBPC | Total subjects = 72 UK nonsmoking asthmatics (18–60 yrs) | VE (supplement) | VE had no beneficial effects on asthma | [34] | ||||
| 500 mg VE capsules (D-α-tocopherol) in soya bean oil or matched placebo (capsules, gelatine base) for 6 weeks | ||||||||
| RDBPC | Total subjects = 197 UK smoking and nonsmoking asthmatics (18–54 yrs) | Se (supplement) | Plasma Se was increased by 48% in the Se group. However, no significant improvement in QoL score was observed in the Se group compared with placebo | [35] | ||||
| 100 μg/day high-Se yeast preparation or matched placebo (yeast only) for 24 weeks |
Abbreviations: RDBPC, randomized double blind placebo control; VC, vitamin C; VE, vitamin E; Se, selenium; QoL, quality of life; OR, odds ratio.
3. Biomarkers of OS and Inflammation in Relation to Smoking Status
OS is regarded as the major contributor to CS-induced airway inflammation [36]. Evidence from many studies, mostly derived from case-control design, has shown that CS activates OS by augmenting airway inflammation in smoking and nonsmoking asthmatics.3.1. Biomarkers of OS
Case-Control Studies
Asthmatic current smokers showed increased serum levels of malondialdehyde (MDA) and decreased levels of the ferric-reducing ability of plasma (FRAP) [37]. Higher MDA levels in exhaled breath condensate (EBC) have been reported in active smoking asthmatics than in their ex-smoking and nonsmoking counterparts [38]. The levels of protein carbonyls and peroxynitrite in plasma were reported to be higher in current smoking asthmatics than in their ex-smoking and nonsmoking counterparts [39]. Smoking asthmatics with a lower FEV1 have higher erythrocyte antioxidant enzyme activity, including superoxide dismutase (SOD) and disulfide/oxidized glutathione (GSH) activity, than nonsmoking patients with asthma and healthy controls. Increased SOD and GSH in smoking asthmatics may not protect airway epithelial cells against the harmful effects of free radicals. SOD and GSH activities were found to be higher in nonsmoking asthmatics than healthy controls [40]. Nonsmoking asthmatics demonstrated increased levels of nitrite (NO2−), protein carbonyls, lipid peroxide, SOD activity, and decreased protein sulfhydrils and glutathione peroxidase (GPx) activity in leukocytes and red blood cells [41]. High sputum GSH and NO2− levels were reported in nonsmokers with stable and acute asthma [42]. Overall findings suggest that the oxidant/antioxidant imbalance derived by CS is likely to exist in smoking and nonsmoking asthmatics. OS biomarkers are increased in current and nonsmokers, but the increase in the enzymatic antioxidants in smokers may be insufficient to protect bronchial/airway epithelial cells against oxidative damage. Table 2 shows the OS biomarkers in smoking and nonsmoking asthmatics.Table 2. OS biomarkers in smoking and nonsmoking asthmatics.
| Design | Study Population | OS Biomarkers | Ref. | ||
|---|---|---|---|---|---|
| Case-control study | Total subjects = 210 Indian (13–80 yrs) Smokers/nonsmokers (asthmatics = 19/101; healthy controls = 29/61) | Asthmatic smokers = MDA ↑, FRAP ↓ | [37] | ||
| Case-control study | Total subjects = 194 Italian patients with different pulmonary diseases (average 45.8 yrs) | Asthmatic current smokers = MDA ↑ | [38] | ||
| Asthmatics (current and ex-smokers) = 64; healthy controls (nonsmokers) = 14 | |||||
| Case-control study | Total subjects = 329 Tunisian adults (average 43.6 yrs) | Asthmatic current smokers = Protein carbonyls, peroxynitrite ↑ | [39] | ||
| Asthmatic current smokers/healthy controls = 14/73; Asthmatic ex- smokers/healthy controls = 17/13 | |||||
| Asthmatic nonsmokers/healthy controls = 120/92 | |||||
| Case-control study | Total subjects = 266 Chinese adults (39–47 yrs) | Asthmatic smokers and nonsmokers = SOD, GSH ↑ | [40] | ||
| Asthmatic smokers/nonsmokers = 25/106; healthy controls (nonsmokers) = 135 | |||||
| Case-control study | Total subjects = 61 Indian (15–40 yrs) Asthmatic nonsmokers/healthy controls= 38/23 | Asthmatic nonsmokers = SOD, NO | 2− | , protein carbonyls, lipid peroxide ↑ | [41] |
| GPx, protein sulfhydrils ↓ | |||||
| Case-control study | Total subjects = 32 Turkish adults (average 41 yrs) | Asthmatic nonsmokers = GSH, NO | 2− | ↑ | [42] |
| Stable asthmatic nonsmokers = 11; Severe asthmatic nonsmokers = 10; Healthy nonsmokers = 11 |
(↓) decrease, (↑) increase.
