Coenzyme Q in Asthma

To the Editor: Asthma is a chronic inflammatory disease characterized by an increase of reactive oxygen and nitrogen species production in the airways (1–3). Oxidative stress has been proportionately linked to the severity of the disease (2, 3). The lung has effective, well-integrated antioxidant systems to combat oxidative and nitrative injury, including superoxide dismutase (SOD), a primary antioxidant enzyme. SOD activity is lower in patients with asthma than in control subjects and decreases further during acute asthma attacks (1, 2, 4–6). Loss of SOD activity is a result of changes in the reducing–oxidizing environment in asthma, which increases the susceptibility of SOD enzymes to oxidative inactivation (2). It has been suggested that corticosteroids have a beneficial effect on antioxidants (7). A previous report has shown that treatment with inhaled or oral corticosteroids does not affect serum SOD activity measures in patients with asthma (1). Oxidative stress causes damage to a variety of biomolecules, including lipid membranes, proteins, and DNA, all of which mechanistically contribute to injury of the asthmatic airways. Increased oxidant production in asthma has been attributed to the activation of leukocytes (7, 8), but accumulating evidence from murine models of asthma and human studies points to a mitochondrial source of oxidant production by airway epithelium and smooth muscle (9). Coenzyme Q10 (CoQ), an integral part of the mitochondrial electron transport chain, also serves as an important mitochondrial antioxidant by scavenging free radicals and inhibiting lipid and protein peroxidation (10). There is evidence that CoQ has beneficial properties as an antioxidant molecule with antiinflammatory properties (10). For example, CoQ increases antioxidant enzyme activities in the liver of diabetic rats (11) and in patients with coronary artery disease (12). CoQ supplementation prevents mitochondrial-mediated oxidative damage in rodent models of sepsis and reperfusion injury of the heart (13). CoQ decreases oxidative and nitrative inflammatory biomarkers in a rodent model of metabolic syndrome and improves endothelial dysfunction (9). A possible beneficial role of CoQ in asthma was found in a study in which CoQ supplementation was associated with corticosteroid dose reduction (14). Here, we hypothesized that CoQ supplementation will restore the reducing–oxidizing balance and antioxidant capacity of patients with asthma to normal levels. To test this, 10 control subjects and 10 patients with asthma were supplemented with oral CoQ (H2Q Advanced Bioavailability CoQ10, H2Q; Health Thru Nutrition, Westbury, NY) for 4 weeks. Informed consent was obtained, and subjects had baseline characterization (visit 1, baseline) (Table 1). Subsequently, CoQ (100 mg) was taken orally with a meal daily for 4 weeks and then evaluated at a second visit (visit 2, end of CoQ). Six weeks after the end of CoQ, subjects were evaluated at a third visit (visit 3, follow-up). At each visit, serum SOD activity, urine oxidation products of DNA damage, and the redox ratio of dihydrobiopterin (BH2) to biopterin were tested. During the study, all patients with asthma were maintained on their standard antiasthma therapy. Spirometry and fractional exhaled nitric oxide were measured according to published guidelines (6). SOD activity and CoQ levels were measured as described previously (6, 15). The urinary pterin metabolites (biopterin, 7,8-BH2, and neopterin) and urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) were determined by HPLC Online Tandem Mass Spectrometry (see the online supplement). Table 1. Clinical Baseline Characteristics of Study Population Control subjects and patients with asthma had similar amounts of endogenous CoQ at baseline. CoQ supplementation increased plasma CoQ levels in control subjects and patients with asthma (Figure 1A). The average increase in plasma CoQ was significantly higher in control subjects than in patients with asthma (Figure 1A). As previously reported (1, 2, 5), patients with asthma had lower SOD activity than control subjects at baseline (P = 0.02; Figure 1B). CoQ corrected SOD activity in asthma, leading to SOD activities similar to those of control subjects (P = 0.2). SOD activity increased significantly in patients with asthma with CoQ (Figure 1B). Urinary 8-OHdG was not significantly different between the groups and was not affected by CoQ supplementation (urinary 8-OHdG [ng/mg Cr], mean ± SE: patients with asthma: visit 1, 1.41 ± 0.18; visit 2, 1.69 ± 0.22; visit 3, 1.77 ± 0.19; control subjects: visit 1, 2.11 ± 0.42; visit 2, 1.71 ± 0.21; visit 3: 2.10 ± 0.31). However, patients with asthma had a lower ratio of the reduced to oxidized forms of biopterin (BH2/[biopterin + BH2]) than control subjects at baseline (P = 0.04), which increased significantly with CoQ (paired t test, P = 0.03) (Figure 1C). The effect of CoQ on reduced/oxidized biopterin ratio was sustained even after stopping CoQ. A potential beneficial effect of CoQ on airflow was made evident by a significant increase in FEV1/FVC ratio, which continued to increase even 6 weeks after stopping CoQ (Figure 1D) (P = 0.008). Figure 1. Coenzyme Q10 (CoQ) supplementation in asthma and healthy control subjects. (A) Supplementation of CoQ at 100 mg/d for 4 weeks increases plasma CoQ in patients with asthma and in control subjects. Levels are higher in control subjects than in patients ... Oxidative mechanisms participate in the pathogenesis of asthma, either by direct oxidative damage to basic cellular components or through the activation of redox-sensitive signaling pathways that control apoptosis and inflammation. Here, we show that CoQ supplementation (100 mg daily for 4 wk) in asthma is associated with recovery of normal levels of SOD activity and redox state, as well as improvement in airflow. The study has limitations. First, the numbers of subjects were small. Second, the study was designed using 100 mg CoQ/day, without a placebo control group, for 4 weeks. Larger and longer intervention studies that are randomized and placebo-controlled are needed to investigate the clinical benefits of CoQ or other strategies targeting mitochondrial redox mechanisms in asthma.