Coenzyme Q10 in COPD: An Unexplored Opportunity?

Abstract

COPD represents a major cause of mortality and morbidity worldwide, is linked to systemic inflammation and tends to coexist with a variety of comorbidities. Inflammation, oxidative stress and protease-antiprotease imbalance represent the pathogenic triad of COPD. Even though oxidative stress and mitochondrial dysfunction is a well-studied phenomenon in COPD and there is a variety of studies that aim to counteract its effect, there is limited data available on the use of coenzyme Q10 in COPD. The aim of the current review is to analyze the current data on the use of coenzyme Q10 in the management of COPD and frequently encountered comorbidities.

Keywords:

• COPD
• oxidative stress
• CoQ10
• comorbidities

Introduction

COPD represents a major cause of mortality and morbidity worldwide. It is defined in GOLD strategic document as “common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases” [1]. There is also a significant increase in the prevalence and global disability-adjusted life years of COPD from 1990 to 2015 [2]. Therefore, every year COPD becomes an increasing healthcare problem. Furthermore, COPD is linked to systemic inflammation and tends to coexist with a variety of comorbidities like cardiovascular, endocrine, musculoskeletal, renal, gastrointestinal and other [3]. Inflammation, oxidative stress and protease-antiprotease imbalance are the pathogenic triad of COPD, where oxidative stress may very well be the prime component [4].

Coenzyme Q10 (CoQ10) is known for its key role in bioenergetics processes and has anti-inflammatory, membrane stabilizing, regenerative processes. These functions are the basis for supporting the use of CoQ10 in clinical practice. Low CoQ10 levels can be found in case of mitochondrial diseases, aging, cancer, drugs, neurodegenerative disorders, diabetes, muscular and cardiovascular diseases [5].

Even though oxidative stress and mitochondrial dysfunction is a well-studied phenomenon in COPD and there is a variety of studies that aim to counteract its effect, there is limited data available on the use of CoQ10 in COPD [6]. Nevertheless, CoQ10 has positive effects in other conditions, which are also linked to profound disturbances of metabolism [7]. For instance, CoQ10 has demonstrated its effect in lung injury and diseases [8]. The aim of the current review is to analyze the current data on the use of CoQ10 in the management of COPD and frequently encountered comorbidities.

Oxidative stress in COPD

The balance between oxidative stress and antioxidants plays a major role in the pathogenesis of COPD [9]. Internal factors such as neutrophils and macrophages from the lungs that continuously release large amounts of superoxide and hydrogen peroxide promote cell damage. Both alveolar macrophages and blood neutrophils are more active in COPD, releasing greater amounts reactive oxygen species (ROS) amount in the form of hydrogen peroxide and superoxide radical [10–12]. This leads to imbalance between ROS production and antioxidant defenses the term for which is oxidative stress [13,14]. Oxidative stress is prevalent in patients with COPD, especially during acute exacerbations.

Oxidative stress in COPD includes elevated concentrations of lipid peroxidation products such as malondialdehyde (MDA), 8-isoprostane and increased levels of nitrotyrosine [15]. On the contrary, the level of the endogenous antioxidants such as glutathione is lowered, especially in patients with frequent exacerbations [16].

It is worth mentioning that because of its anatomic structure, lungs are especially susceptible to environmental oxidative stress. They are continuously in contact with air oxygen, industry related nanoparticles, oxidant gases and vehicle exhaust emissions. Moreover, there are multiple endogenous processes caused by autoimmune, infectious and other factors. Nevertheless, the most widely accepted opinion is that the crucial etiologic factor in COPD is cigarette smoking [17].

The inflammatory processes also cause excessive ROS generation. It was found that around fifty cytokines and chemokines correlate with COPD. The intercellular signaling pathways are dependent on oxidative stress because of redox-sensitive molecular targets incorporation, for example Ras/Rac signaling molecules, p38 mitogen-activated protein kinase and others [18].

Finally, there is a relation between directly measured free radicals lung dysfunction and respiratory muscle performance [19,20]. Although oxidative stress is a constantly studied phenomenon in COPD, its pharmacological management in clinical practice is rare. This is to some degree explained by the absence of effective medication that has demonstrated its’ effects in preclinical and clinical studies.

CoQ10 functions

CoQ10 (ubiquinone) is a compound which is present in almost every aerobic organism [21]. The scheme of CoQ10 synthesis is represented in Figure 1. It is considered to be electron transport chain’s crucial component in mitochondria [22]. CoQ10 transfers electrons from Complex I and Complex II to Complex III of mitochondria respiratory chain, in such a way contributing to ATP generation [23]. It should be mentioned that CoQ10 exists in a reduced form (ubiquinol) and the oxidized one (ubiquinone). Therefore, while transferring electrons to Complex III, ubiquinol is turned to ubiquinone. After that ubiquinone turns back to ubiquinol by obtaining electrons from acyl-Co-A-dehydrogenases or glycerol-3-phosphate dehydrogenase or dihydroorotate dehydrogenase [24].

Figure 1. The scheme of ubiquinone synthesis.

Moreover, CoQ10 participates in a variety of redox reactions and is involved in bioenergetic and antioxidant mechanisms [25]. CoQ10 is the only lipid-soluble antioxidant that is generated endogenously. It helps to prevent oxidation of lipids, proteins and DNA [26]. Due to its property of preventing LDL from oxidation, it also has antiatherogenic properties. Furthermore, CoQ10 diminishes lipid peroxides levels, which are associated with lipoproteins in atherosclerotic lesions [27,28]. CoQ10 has a better effect in LDL-oxidation prevention than β-carotene, α–tocopherol and lipid antioxidants [29]. Mashima et al. demonstrated that CoQ-enriched LDL are more resistant to oxidation than native LDL [30]. Likewise, CoQ10 has an anti-inflammatory effect by affecting the NFjB1-dependent genes expression [31].

The quantity of CoQ10 in tissues is 6–10 times higher than vitamin’s E, which is considered to be one of the main antioxidants. Nevertheless, its’ blood level is significantly lower in comparison with vitamin E. CoQ10 participates in vitamin E regeneration from α-tocoperoxyl and can even prevent vitamin E prooxidant activity [27].

Thus, several significant functions of CoQ10 are particularly relevant in COPD, namely, antioxidant, anti-inflammatory, bioenergetic and antiaterogenic functions.

CoQ10 and smoking

External factors as cigarette smoke and noxious gases, which are the major cause of COPD, contain very high concentrations of gaseous and soluble oxidants that cause cell injury and death. COPD is a condition that is most commonly associated with smoking [32]. Smoking causes oxidative stress with the decrease of major antioxidant components in the blood regardless of their daily antioxidant intake [33]. Cigarette smoke contains free radicals, which can injure proteins, lipids and DNA. The increased time of smoking habit is associated with increased levels of LDL-adjusted serum CoQ10 concentration and of the reduced form of CoQ10 [34]. Smokers have significantly lower vitamin A, C, E levels and CoQ10 [35,36]. Nevertheless, the link between smoking and CoQ10 plasma concentration is controversial. Some researchers find positive association [37], while others find either none [38], or a negative one [39].

Cigarette smoke contributes to high oxidant propagation and decrease of antioxidant activity. This fact explains oxidant α₁-proteinase inhibitor inactivation and loss of binding substrates ability (neutrophils elastase inactivation). Elastase, which destroys elastic fibers in the lung, is excessively released by neutrophils, but in healthy people it is usually inactivated by lung antiproteases. This contributes to elastic fiber degradation in a continuous process which results in emphysema. Moreover, it is known that inflammatory cells (neutrophils and macrophages) migrate in lungs of smokers where they release ROS [40]. Furthermore, free iron content in the air enhances generation of oxidants in epithelial lining fluid in smokers [41]. This also results in the increase of intracellular iron content of alveolar macrophages in cigarette smokers [42]. Besides, macrophages in smokers release a greater amount of free iron in comparison with nonsmokers [43]. Free iron participates in the Fenton and Haber-Weiss reactions with hydroxyl radical generation, which produces lipid peroxidation and damage the cell membranes [44]. Thus, the increase of exogenous and endogenous oxidants leads to disturbance in redox status. Consequently, oxidant particles prevalence over antioxidants contributes to lung matrix damage and disorders in elastin repair and its synthesis [45].

Finally, smoking is associated with pulmonary, cardiovascular, metabolic oncological and other comorbidities [46]. Some of these conditions are associated with oxidative state and lower CoQ10 levels. For instance, the severity of cardiovascular and metabolic conditions increases in patients who continue to smoke and can be both improved with the administration of CoQ10 [7].

CoQ10 in COPD

Animal models have demonstrated that CoQ10 has anti-inflammatory properties, it is involved in DNA replication and repair, regulates the physiochemical properties of cellular membranes, and modulates gene expression [47,48]. Multiple organ and system dysfunction is an important feature of COPD [3,49]. These effects are beneficial in COPD patients. Nevertheless, there is a limited number of human studies on CoQ10 in COPD or in other respiratory diseases.

Compared to the healthy controls COPD patients have significantly higher levels of malondialdehyde (MDA) and CoQ10 that indicated lipid peroxidation [50]. The percentage of oxidized CoQ10 in total coenzyme Q10 indicates the degree of systemic oxidative stress and can be a valuable marker [51]. However, there seems to be no correlation between CoQ10 and ventilator function in COPD patients [52].

CoQ10 is lower in exacerbation of COPD than in control, although MDA, Cu, and Zn levels are significantly higher (p < 0.05). There is also a negative correlation between MDA, Cu, Zn, FEV1, and FVC values in exacerbation and control subjects (p < 0.05). The decrease in CoQ10 level and Cu/Zn ratio and elevation in Cu and Zn levels probably result from the defense response of the organism and are mediated by the pro-inflammatory state [53].

The level of plasma CoQ10 can also be elevated in hypothyroid subjects, a subclinical condition which can be often found in COPD patients. This index may be useful in assessing metabolic status in COPD [54].

COPD is a condition characterized by its frequent overlaps with other diseases as asthma, OSAS and other. The levels of CoQ10 are different in asthma and OSAS than in healthy controls contributes to their antioxidant imbalance and oxidative stress [50,55–57].

COPD treatment and CoQ10

Several animal studies demonstrated beneficial effect of CoQ10 on lung function. CoQ10 decreases histamine, slow-reacting substance of anaphylaxis and tumor necrosis factor-alpha in animal models [58,59]. Similarly in animal models CoQ10 pretreatment one hour before harvesting, the lungs showed significantly better preservation in pulmonary artery pressure, airway pressure, gas exchange function and the wet/dry weight ratio than those of the control group [60]. This underlines its' protective effect in the settings of lung damage. CoQ10 also alters the pharmacokinetic parameters of theophylline in rats. After five consecutive days of pretreatment with CoQ10 the time to reach maximum plasma concentration of theophylline was delayed, maximum plasma concentration and area under the curve of theophylline were about two-fold increased and other pharmacokinetic parameters such as half-life and volume of distribution were also changed significantly [61]. Moreover, as a recent advantage CoQ10 can be delivered in a nebulizer [62]. These animal studies demonstrate several important CoQ10 protective functions such as protection in case of lung injury, gas exchange, vascular function and enhancement of bronchodilator drugs.

The plasma CoQ10 of COPD patients without oxygen treatment is significantly higher than that of controls, indicating an increased oxidative stress. It was also noted that COPD patients who received an oxygen supplementation had CoQ10 levels lower than those who didn’t receive oxygen therapy [51]. Several human studies demonstrated CoQ10 efficiency in patients with obstructive lung diseases. In a double-blind randomized study, patients with COPD and chronic respiratory failure with long term O2 therapy, in stable phase of the disease and without severe comorbidities were assigned to receive either daily dietary supplementation with creatine 340 and 320 mg CoQ10 for 2 months or placebo. After 2 months of therapy there was a statistically significant 3.7% fat free mass index increase in the daily dietary supplementation group and 0.6% decrease in the placebo group. Statistically significant treatment differences, favoring daily dietary supplementation group, were also seen for the 6MWT comparison. The treatment group had shown a significant improvement of dyspnea, independence level in activities of daily living, improvement in quality of life in activity and in total score, exacerbation number decrease [63]. Oral administration of CoQ10 at 90 mg/day for eight weeks is associated with an improvement in hypoxemia at rest. In these patients during exercise, PaO2 was significantly improved, and heart rate was significantly decreased compared with the results obtained at an identical workload at baseline. Furthermore, lactate production was suppressed and exercise performance tended to increase [52]. In a double-blinded randomized placebo-controlled clinical study 108 patients with COPD from nine Italian hospitals received CoQ10 and creatinine or placebo. After 2 months of therapy, the patients underwent spirometry, 6MWT, bioelectrical impedance analysis, and activities of daily living questionnaire, as well as calculation of dyspnea scores and BODE index. Ninety patients, who randomly received supplementation with CoQ10 and creatine or placebo, completed the study. Compared with placebo, patients who received supplements showed improvements in 6MWT (51 ± 69 vs. 15 ± 91 m, p < 0.05), body mass and phase angle, sodium/potassium ratio, dyspnea indices and activities of daily living score [64].

Several studies have demonstrated the efficiency of CoQ10 in asthma. Although asthma differs from COPD, these two conditions have a common pathophysiology, especially in case of their overlap. In an open, cross-over, randomized clinical study with 41 asthma patients where all patients suffered from persistent mild to moderate asthma received 120 mg CoQ10, 400 mg alpha-tocopherol and 250 mg vitamin C daily and resulted in a reduction in the dosage of required corticosteroids [56]. Another study demonstrated an improved pulmonary function, which continued to increase 6 weeks after the treatment [65]. An overview of the use of CoQ10 for asthma and COPD can be seen in Table 1.

Table 1. The use of CoQ10 in obstructive lung diseases.

Number of patients	Treatment and dose	Duration of treatment	Outcomes	Reference
Prospective observational study
21 COPD patients and 3 with idiopathic pulmonary fibrosis	CoQ10 at 90 mg/day	8 weeks	Improvement in hypoxemia at rest, improved PaO2, decreased heart rate, decreased lactate production and increased exercise performance.	[52]
10 asthma patients and 10 healthy control	CoQ10 at 100 mg/day	4 weeks	Significant increase in FEV1/FVC ratio, which continued to increase even 6 weeks after stopping CoQ10	[65]
Randomized clinical studies
41 bronchial asthma patients	One group received standard antiasthmatic therapy. The second group received, in addition, antioxidants consisting of CoQ10 120 mg, 400 mg alpha-tocopherol, 250 mg vitamin C a day.	Crossed over at 16 weeks. Total duration of 32 weeks.	Reduction in the required dosage of corticosteroids.	[56]
55 COPD patients	Group A (30 patients) with daily dietary supplementation with Creatine 340 mg, 320 mg CoQ10 whereas Group B (25 patients) received placebo.	2 months	Increased lean body mass and exercise tolerance, reduced dyspnea, improved quality of life, decreased frequency of exacerbations.	[63]
108 COPD patients	Two groups (each 45 patients) CoQ10 160 mg and Creatine 170 mg, or placebo twice daily.	2 months	Improvements in 6MWT, body cell mass and phase angle, sodium/potassium ratio, dyspnea indices and activities of daily living questionnaire score.	[64]

Although there are several studies which demonstrate potential for the use of CoQ10 in management of COPD and asthma there are several limitations which should also be discussed. These studies have a low number of patients (typically not more than 100). The dose of administered CoQ10 differs from 90 to 320 mg/day. Also some of the studies combined the use of CoQ10 with other supplements like creatine or vitamins.

Finally, patients with COPD are particularly at risk for pneumonia and it was demonstrated in a randomized trial that patients on CoQ10 had faster recovery and shorter hospital stay compared with the placebo group. The subgroup analysis of the patients with severe pneumonia showed differences in clinical cure at day 14 and treatment failure was less in CoQ10 group than in the placebo group (10% vs. 22.5% and p = 0.0440) [66]. There have also been reports that seasonal and pandemic influenza patients have significantly lower levels of CoQ10 although this was demonstrated in children [67].

COPD comorbidities and CoQ10

The list of diseases that are associated with COPD is enormous and includes cardiovascular, endocrine, musculoskeletal, renal, gastrointestinal and other pathologies [3]. In addition, at least one comorbidity of clinical relevance is present in 78.6% of patients, two in 68.8%, and three or more are found in 47.9% of subjects. The overall prevalence of comorbidities in COPD patients is 2.6 comorbidities [68]. According to Divo et al. research there are 79 comorbidities that can be associated COPD. From all these comorbidities 12 presented a major risk for patient’s life, such as lung, esophageal and breast cancers, pulmonary fibrosis, atrial fibrillation/flutter, congestive heart failure, coronary artery disease, gastric/duodenal ulcers, liver cirrhosis, diabetes with neuropathy and anxiety [69]. Cluster analysis is an important method to group patients. In a prospective research, which included 213 patients with COPD all comorbidities were classified into five clusters: less comorbidity (included patients with fewer comorbidities and administered drugs), cardiovascular (atherosclerosis and hypertension), cachectic (renal function deterioration, osteoporosis), metabolic (atherosclerosis, obesity) and psychological one which included anxiety and depression. A total of 97.7% of all patients had one or more comorbidities and 53.5% had four or more comorbidities [49].

Over the years, it has been demonstrated that CoQ10 has been a useful supplement in a variety of acute and chronic conditions.

CoQ10 has beneficial effects in several cardiovascular conditions [7]. In a 10-year follow-up of a group of healthy elderly participants who received selenium and CoQ10, significantly reduced cardiovascular mortality was observed [70]. CoQ10 supplementation enhances antioxidant enzymes activities, vitamin E level, and lowers inflammation (TNF-α, IL-6, hs-CRP) in patients who have coronary artery disease during statins therapy [71–73]. The Q-SYMBIO trial found that CoQ10 supplementation in patients with heart failure improved functional capacity and significantly reduced cardiovascular events and mortality [74]. A meta-analysis that included a total of 14 randomized clinical trials with 2149 patients demonstrated that patients with heart failure who received CoQ10 had lower mortality and a higher exercise capacity improvement than the placebo-treated patients with heart failure [75].

Muscular diseases are particularly important in case of COPD especially respiratory muscle function. CoQ10 may improve sarcopenia particularly in elderly. Spearman's correlation revealed a significant positive association between CoQ10/cholesterol level and hand grip. There was also a negative correlation with the CoQ10 redox state in subjects who exhibit a lower muscular strength. Moreover, the level of CoQ10 was negatively associated to upper body muscle strength, peak flow and muscle mass. [76].

Lipid metabolism is one of the key pathophysiological mechanism for both cardiovascular and metabolic diseases. A meta-analysis of seven randomized controlled trials with a total of 409 subjects demonstrated that overall, CoQ10 supplementation was associated with a slight but significant reduction of plasma lipoproteins, particularly in patients with lipoprotein a more than 30 mg/dL, although, other lipid indices were not altered by CoQ10 supplementation [77]. In another meta-analysis that included 514 patients and 525 controls with metabolic diseases CoQ10 significantly reduce serum triglycerides levels, and help to improve lipid profile [78].

The analysis of CoQ10 use in diabetes, which included seven trials, involving 356 patients, demonstrated that CoQ10 alone nor CoQ10 plus fenofibrate improved glycemic control. On the other hand, triglycerides levels were significantly reduced with CoQ10 and CoQ10 plus fenofibrate. Moreover, CoQ10 plus fenofibrate also effectively reduced total cholesterol [79]. Therefore, the current data on diabetes is controversial. Patients with prediabetes who were administered coenzyme Q10 showed a significant reduction in homeostatic model assessment for insulin resistance values [80]. However, coenzyme Q10 was reported to reduce fasting blood glucose levels in another study, particularly involving patients with coronary artery disease [81]. Other studies demonstrate no relationship between CoQ10, glucose metabolism and insulin resistance [82,83].

Several animal studies proved that CoQ10 prevents fibrosis and organ remodeling [84–86]. This is particularly important in case of liver diseases [87]. In a recent double-blind randomized placebo clinical study, 100 mg/day of Coenzyme Q10 for 3 weeks resulted in a significant reduction of transaminases, gamma-GT, hsCRP, degrees of nonalcoholic fatty liver disease, and improvement of the adiponectin/leptin ratio [88].

It was found that the level of CoQ10 in cancer-affected tissues is much lower than in normal tissues. In a Chinese prospective study 340 patients and 653 controls were screened to determine a link between circulation levels of CoQ10 and cancer incidence. It was discovered that in women with breast cancer the CoQ10 level is significantly lower [89]. There are studies that demonstrate CoQ10 can decrease of MMP-2, MMP-9 activities with consequent inhibition of tumor invasion and metastasis [90,91]. CoQ10 levels can also be useful as a biomarker for lung cancer risk assessment, as they are significantly lower in patients with lung cancer [92]. Moreover, the median survival rate for patients with end-stage lung, esophageal, breast and other cancers is longer for patients receiving CoQ10 [93].

CoQ10 significantly improves quality of life in elderly patients in a double blind, placebo-controlled prospective study that included 443 participants who were evaluated after 48 months. The group who received supplement with selenium and CoQ10 declined significantly less in the health-related quality of life (HR-QoL) domains of physical role performance (p = 0.001), vitality (p = 0.001), physical component score (p = 0.001), overall QoL (p = 0.001), somatic dimension (p = 0.001), conative dimension (p = 0.001) and global function (p = 0.001) [94]. Age seems to be a significant factor for lower quality of life in COPD [95]. Aging is associated with the development of comorbidities. The HR-QoL in patients with cardiovascular diseases, metabolic, musculoskeletal diseases receiving CoQ10 improves [96,97]. There is evidence that supplementation positively affects the symptoms related to aging due to improvements in bioenergetics and in aging-related disorders, particularly in cardiovascular and metabolic diseases [22,98].

Future directions

There are limited studies on the effects of CoQ10 and lung diseases. Still, there are also multiple studies that combine administration of CoQ10 with other medications, which make it difficult to assess whether the effect is due to CoQ10, other supplements or their combination. Another limitation is the poor oral bioavailability of CoQ10. Taking into account that CoQ10 is a relatively accessible and very high safety profile more randomized studies are required to assess its’ role in COPD. The development of inhalatory CoQ10 is a promising approach and may prove useful in the future. The importance of these studies are motivated by the fact that CoQ10 has demonstrated its effects in similar conditions such as cardiovascular and metabolic which are also associated with antioxidant imbalance and pro-inflammatory state.

Conclusions

Oxidative stress is a well demonstrated and important phenomenon in COPD. There are multiple studies that aim to counteract the effect of oxidative stress in COPD. Nevertheless, there is limited data available on the use of CoQ10 as a possible supplement in the treatment of COPD patients. The current review was aimed to demonstrate multiple effects of CoQ10 on lung function and lung injury in animal models as well as its’ positive effects as a supplement in patients with COPD and associated comorbidities. There are several limitations that should be assessed to better understand the role of CoQ10 in COPD, particularly the effects of sole administration of CoQ10 without other medications, and improvement of oral bioavailability. Taking into account that CoQ10 is a relatively accessible and very high safety profile it may be considered as a supplement in COPD.

Declaration of interest

All authors have nothing to declare