Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by persistent airflow obstruction and lung inflammation primarily caused by inhalation of cigarette smoke . The pulmonary inflammation involves macrophages, epithelial cells, dendritic cells, neutrophils, eosinophils and T and B-lymphocytes which release many inflammatory mediators that contribute to the pathophysiology of COPD . Furthermore, antioxidant capacity is reduced in COPD, whereas oxidant release from increased activated inflammatory cells is increased . The resulting oxidative stress is even further increased during exacerbations and may be associated with increased inflammation, airway remodeling and corticosteroid resistance .
Next to the respiratory impairment, extrapulmonary manifestations and comorbidities contribute to disease burden and mortality . Cardiovascular disease is a common comorbidity in patients with COPD and is even the leading cause of mortality in patients with mild-to-moderate COPD . Furthermore, skeletal muscle wasting is highly prevalent in COPD, in particular in patients with emphysema , and is associated with intrinsic muscular abnormalities . A shift from less oxidative type-I toward more glycolytic type-II muscle fibers has been consistently reported in lower limb muscles of patients with COPD  and markedly decreased phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) protein levels were observed in muscle biopsies of COPD patients [8–10]. In addition, these patients rely more on the metabolically less-efficient complex-II driven mitochondrial respiration [11▪]. Moreover, increased reactive oxygen species production has been observed in skeletal muscle mitochondria of patients with COPD compared with controls . The respiratory muscles are also affected in patients with COPD, mainly due to lung hyperinflation and increased airway resistance and obstruction but also by systemic factors such as inflammation and oxidative stress . In contrast to lower limb muscle, the diaphragm has an increased proportion of type-I fibers and increased mitochondrial and capillary content . Boosting muscle oxidative metabolism could be beneficial for patients with COPD by stimulating adaptive changes in respiratory muscles and/or reversing altered cellular energy metabolism in limb muscle.
The natural polyphenol resveratrol (3,5,4′-trihydroxystilbene) might be an interesting therapeutic candidate for COPD by simultaneously targeting both pulmonary as well as extrapulmonary pathology. Interest in resveratrol started when cardioprotective effects of red wine were identified . Nowadays, resveratrol is receiving increasing interest because of its potential to improve metabolic health and its anti-inflammatory and antioxidant properties [15▪,16,17], which might also benefit the lungs and muscles. Beneficial effects of resveratrol have been reviewed in relation to aging, obesity or diabetes [15▪,18,19], but not in relation to COPD. Here we will therefore evaluate available evidence regarding the effects of resveratrol on lung injury, muscle metabolism and cardiovascular risk profile and discuss if resveratrol supplementation is just a hype or could give hope to patients with COPD.
THE MECHANISMS OF ACTION OF RESVERATROL
Resveratrol exerts its beneficial health effects through several signaling pathways which have been reviewed elsewhere [15▪,18,20–22]. Here we will briefly summarize the processes and molecular pathways affected by resveratrol and relevant for COPD, focusing on molecular targets to decrease lung and muscle impairment. The most relevant target for the downstream effects of resveratrol is Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent histone deacetylase that promotes cell survival, which is activated by resveratrol directly or indirectly via the activation of AMPK [15▪]. Activation of SIRT1 has been proposed to be involved in a number of beneficial health effects of resveratrol. First of all, SIRT1 activates PGC-1α, a master regulator of mitochondrial metabolism and biogenesis [15▪]. This beneficial effect of resveratrol may improve mitochondrial function which is known to be compromised in muscles and lungs of patients with COPD [10,23▪]. Second, SIRT1 activation can modulate several stress response transcription factors such as forkhead box O (FOXO)3 which regulates autophagy [18,21]. Autophagy is the process of eliminating organelles and proteins through the lysosomal degradation pathway; it is increased in both lungs and skeletal muscle of patients with COPD [24,25]. Third, SIRT1 downregulates the transcription factor nuclear factor kappa B (NF-κB) which is involved in the anti-inflammatory properties of resveratrol . Activation of SIRT1 inhibits degradation of the inhibitor of κB, inhibiting the translocation of NF-κB to the nucleus and reducing the expression of inflammatory and immune genes including proinflammatory cytokines, chemokines, inflammatory enzymes and adhesion molecules . Other putative pathways responsible for the anti-inflammatory properties of resveratrol have been described elsewhere , but as most inflammatory proteins upregulated in COPD macrophages are regulated by NF-κB pathway , this pathway would be most interesting for resveratrol in COPD.
In addition, resveratrol exerts its antioxidant effects mainly through regulation of nuclear factor erythroid-2-related factor-2 (Nrf2). By inhibiting proinflammatory cytokines and oxidative stress Nrf2 plays a protective role against inflammation in cells . Normally Nrf2 is activated by oxidative stress; however, in COPD, activation is not appropriate despite high levels of oxidative stress in the lungs . Activation of Nrf2 leads to the induction of many antioxidant enzymes including heme-oxigenase-1, superoxide dismutase, glutathione peroxidase, and catalase and can be protective against damage, inflammation and oxidative cell death . The activation of Nrf2 is also suggested to be mediated by SIRT1 . The described anti-inflammatory and antioxidant properties of resveratrol can also contribute to cardiovascular protective effects as reviewed elsewhere [27▪].
EFFECTS OF RESVERATROL ON LUNG DAMAGE
Anti-inflammatory and antioxidant properties of resveratrol in the lungs have been demonstrated in preclinical models. Resveratrol causes a reduction in lung tissue neutrophilia and proinflammatory cytokines in a rodent model of acute lipopolysaccharide (LPS)-induced airway inflammation . Furthermore, in-vitro treatment with resveratrol inhibited the release of inflammatory cytokines from bronchoalveolar lavage fluid macrophages and human bronchial smooth muscle cells isolated from COPD patients [29–32]. These anti-inflammatory effects of resveratrol were ascribed to the inhibition of NF-κB activation . Resveratrol has also been shown to inhibit autophagy in vitro in human bronchial epithelial cells and in vivo in a LPS and cigarette smoke-induced COPD mice model by reversing the decrease in SIRT1 and FoxO3a expression and by decreasing the production of Beclin1 protein [33▪▪,34,35].
Long-term cigarette smoke exposure caused persistent oxidative stress-induced impairments in mitochondrial structure and function in human bronchial epithelial cells . This mitochondrial dysfunction is also involved in the pathogenesis of COPD and may be related to a reduction in PGC-1α [23▪]. Resveratrol has been shown to attenuate cigarette smoke-induced oxidative stress in human lung epithelial cells via nuclear translocation of Nrf2 [37,38], possibly mediated by SIRT1 . Moreover, intratracheal instillation of resveratrol in mice caused increased SIRT1 levels and maintained PGC-1α in alveolar epithelial cells [39▪▪]. These mitochondrial effects were correlated with maintenance of lung structure and function.
Corticosteroids are able to suppress the release of inflammatory mediators in macrophages, but fail to sufficiently suppress airway inflammation in stable COPD . Furthermore, long-term treatments with oral corticosteroids bear high risks of significant adverse effects such as increasing blood glucose levels, muscle atrophy and abdominal obesity . Resveratrol could be an alternative treatment for corticosteroids in COPD. Indeed, in cultured human airway, smooth muscle cells exposed to TNF-α resveratrol reduced the release of inflammatory mediators more efficiently than dexamethasone . Furthermore, resveratrol was superior to dexamethasone in reducing COPD-associated cytokines and matrix-metalloprotease-9 in human airway smooth muscle cells and alveolar macrophages [30,42]. These potential effects of resveratrol have led to the development of a spray-dried resveratrol powder [43,44▪], which showed anti-inflammatory activities in vitro[44▪].
The various reported experimental models consistently show beneficial effects of resveratrol on inflammatory processes and oxidative stress markers in the lungs. However, up till now no clinical proof-of-concept studies are available to confirm these results in a clinical setting.
EFFECTS OF RESVERATROL ON SKELETAL MUSCLE MASS AND MITOCHONDRIAL HEALTH
The described mechanisms of action suggest that resveratrol can both improve skeletal muscle oxidative metabolism and maintain skeletal muscle mass. Timmers et al. were the first to confirm improved mitochondrial metabolism in a clinical proof-of-concept study, as increased muscle protein expression of AMPK, SIRT1, PGC-1α and citrate synthase were observed after 30 days of 150 mg/day resveratrol supplementation in healthy obese men. Although another study including 10 patients with type 2 diabetes mellitus (T2DM) also found increased SIRT1 after 12 weeks of resveratrol (3 g/day) , three other studies including T2DM, obese and nonobese patients did not find increased mitochondrial biogenesis markers after resveratrol treatment, despite comparable dosage and duration [45,47,48]. In addition, improved muscle mitochondrial respiration on the electron input of both complexes I and II and increased maximal capacity of the electron transport chain was found after resveratrol supplementation in overweight and obese patients [45,49▪▪] and in T2DM patients [50▪▪]. In these studies, no differences in mitochondrial content were found, suggesting that mitochondria became more efficient. Contradictory, another study found an increased mitochondrial number after 6 weeks of resveratrol in older adults, despite no changes in mitochondrial size and morphology [51▪]. However, a higher dose of resveratrol (2–3 g/day) was used compared with the studies that did find an improvement in mitochondrial respiration (80–150 mg/day) [45,49▪▪,50▪▪]. In addition, an increment in the oxidative type-I myosin heavy chain protein in primate soleus muscle was found after long-term resveratrol treatment [52▪]. To our knowledge, only one study investigated the effect of resveratrol on skeletal muscle mRNA and protein expression levels in a model of COPD . In rats exposed to cigarette smoke and LPS, supplementation with resveratrol lowered serum and muscle TNF-α accompanied by an increase in AMPK. Altogether, these results show promising results of resveratrol on skeletal muscle oxidative metabolism.
Preliminary data also suggest several beneficial effects of resveratrol on skeletal muscle mass maintenance. In C2C12 myotubes and in mice, muscle atrophy, induced by TNF-α or glucocorticoids, was inhibited by resveratrol through inhibition of the atrogenes downstream of the Akt/mTOR/FOXO1 signaling pathway [54–56]. In addition, resveratrol reduced the expression of palmitate-induced inflammation in C2C12 myoblasts by mechanisms involving the inhibition of oxidative stress and decreasing the activity of NF-κB [57▪]. Moreover, loss of oxidative capacity is postulated to accelerate the process of muscle loss . Therefore, improving the skeletal muscle oxidative capacity might maintain skeletal muscle mass. These preclinical effects of resveratrol on skeletal muscle maintenance have not been observed in human clinical studies yet [48,49▪▪,59▪], possibly because the studied populations (i.e. healthy obese or nonobese individuals with metabolic syndrome) were not characterized with muscle wasting.
EFFECTS OF RESVERATROL ON THE CARDIOVASCULAR RISK PROFILE
Preclinical animal studies have suggested beneficial effects of resveratrol for the treatment of cardiovascular diseases as was recently reviewed [27▪,60,61]. However, these reviews also revealed that clinical studies produced inconsistent results and were not as promising as preclinical data. Nevertheless, a recent meta-analysis including overweight and obese participants showed that SBP, fasting glucose and total cholesterol were significantly lower after resveratrol supplementation, whereas other cardiovascular risk parameters remained unaltered [62▪▪]. More specifically, a subgroup analysis showed that beneficial effects of resveratrol were found at a high dose of resveratrol (≥300 mg/day). The variability in dosage (8–3000 mg/day) and duration (2 weeks to 6 months) between studies and the low bioavailability of resveratrol  can contribute to the variation in results between studies. The fact that some cardiovascular risk parameters were lowered in a group of individuals at risk for cardiovascular disease still implicates that there is potential for resveratrol to decrease the cardiovascular risk. In COPD, not only obese patients but even normal weight patients are already at an increased cardiovascular risk [64▪,65].
RESVERATROL IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Resveratrol could be an interesting intervention for COPD as it targets both lung and muscle via overlapping mechanisms (Fig. 1). First of all, the anti-inflammatory properties of resveratrol can reduce both lung and muscle impairment and may potentially even reduce the need for anti-inflammatory drugs with their negative side-effects. Systemic inflammation, measured by NF-κB, TNF-α and matrix-metalloprotease-9 protein expression in lymphocytes, was increased in COPD patients compared with healthy controls and was reduced after resveratrol treatment [66▪]. This increased systemic inflammation may affect both the lungs and muscles . Moreover, increased macrophage numbers in the lungs play a key role in the pathophysiology of COPD and most inflammatory proteins upregulated in these macrophages are regulated by NF-κB . Inflammatory modulation in the lungs would therefore be beneficial for COPD. As systemic inflammation has been implicated in skeletal muscle wasting, loss of lower limb mitochondrial capacity and deterioration of respiratory muscles [13,67], the anti-inflammatory effects of resveratrol would also benefit the muscular impairments in COPD.
Resveratrol not only improves mitochondrial oxidative capacity indirectly via its anti-inflammatory properties, but also directly via the AMPK-SIRT1-PGC-1α axis. Again this beneficial effect of resveratrol can affect both the muscle and the lung as SIRT1 levels and PGC-1α are decreased in both lung and muscle tissue of patients with COPD [9,10,23▪,68]. Preclinical findings suggest that inhaled resveratrol can improve mitochondrial function in the lungs and subsequently maintain lung structure and function in COPD [39▪▪]. In muscle, nutritional supplementation with resveratrol showed improved mitochondrial function accompanied by improved mitochondrial respiration in obese men .
Finally, the antioxidant properties of resveratrol may affect both the lungs and the skeletal muscle as well. In COPD patients, high levels of oxidative stress have been observed in the lungs and have been associated with increased inflammation, airway remodeling, autoimmunity and corticosteroid resistance . Reducing oxidative stress would therefore be beneficial to decrease lung injury in COPD. Moreover, many studies indicate an important role of oxidative stress, in skeletal and respiratory muscle dysfunction and loss of skeletal muscle mass in patients with COPD [6,13,69].
Because of the overlapping mechanisms in lungs and skeletal muscle that can be improved by resveratrol, treatment with resveratrol would be even more interesting for specific phenotypes of patients with COPD. For example, the cachectic COPD phenotype, characterized by high prevalence of emphysema and muscle wasting , display more severe abnormalities in muscle oxidative phenotype which could be improved by resveratrol . Furthermore, patients with COPD who often experience exacerbations would be another interesting population for resveratrol treatment, as exacerbations are often accompanied by pulmonary and systemic inflammation and are associated with increased susceptibility to muscle wasting .
On top of the beneficial effects of resveratrol on the lungs and muscle, preclinical studies suggest cardioprotective effects of resveratrol. Cardiovascular risk modification is currently underappreciated in COPD management and should receive more attention. Early assessment of the cardiovascular risk profile is expected to result in the initiation of risk-lowering therapies. Despite overwhelming attention to resveratrol in the cardiovascular risk context, we conclude that clinical evidence for resveratrol is inconclusive due to the large variability in dosage and duration. Therefore, it is still unclear whether resveratrol can be used as adjunct or alternative for proven lifestyle interventions including smoking cessation, physical activity and nutritional and dietary modulation, to improve the cardiovascular risk in COPD.
Resveratrol seems a promising candidate to decrease lung injury and to improve skeletal muscle mitochondrial function which is known to be compromised in COPD. However, there is no convincing evidence that resveratrol will significantly decrease the cardiovascular risk in patients with COPD.
Financial support and sponsorship
R.J.H.C.G.B. was funded by the Lung Foundation Netherlands grant 3.4.12.023.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. Gold executive summary. Am J Respir Crit Care Med 2017; 195:557–582.
2. Barnes PJ. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease
. J Allergy Clin Immunol 2016; 138:16–27.
3. Kirkham PA, Barnes PJ. Oxidative stress in COPD. Chest 2013; 144:266–273.
4. Patel AR, Hurst JR. Extrapulmonary comorbidities in chronic obstructive pulmonary disease
: state of the art. Expert Rev Respir Med 2011; 5:647–662.
5. Vanfleteren LE, Spruit MA, Groenen M, et al. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease
. Am J Respir Crit Care Med 2013; 187:728–735.
6. Maltais F, Decramer M, Casaburi R, et al. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease
. Am J Respir Crit Care Med 2014; 189:e15–e62.
7. Gosker HR, Zeegers MP, Wouters EF, Schols AM. Muscle fibre type shifting in the vastus lateralis of patients with COPD is associated with disease severity: a systematic review and meta-analysis. Thorax 2007; 62:944–949.
8. Natanek SA, Gosker HR, Slot IG, et al. Pathways associated with reduced quadriceps oxidative fibres and endurance in COPD. Eur Respir J 2013; 41:1275–1283.
9. Remels AH, Schrauwen P, Broekhuizen R, et al. Peroxisome proliferator-activated receptor expression is reduced in skeletal muscle in COPD. Eur Respir J 2007; 30:245–252.
10. van den Borst B, Slot IG, Hellwig VA, et al. Loss of quadriceps muscle oxidative phenotype and decreased endurance in patients with mild-to-moderate COPD. J Appl Physiol 2013; 114:1319–1328.
11▪. Gifford JR, Trinity JD, Layec G, et al. Quadriceps exercise intolerance in patients with chronic obstructive pulmonary disease
: the potential role of altered skeletal muscle mitochondrial respiration. J Appl Physiol 2015; 119:882–888.
The study showed that patients with chronic obstructive pulmonary disease (COPD) rely less on complex I driven mitochondrial respiration and more on the metabolically less-efficient complex II driven respiration. These qualitative alterations in skeletal muscle mitochondrial potentially contribute to exercise intolerance associated with COPD.
12. Puente-Maestu L, Tejedor A, Lazaro A, et al. Site of mitochondrial reactive oxygen species production in skeletal muscle of chronic obstructive pulmonary disease
and its relationship with exercise oxidative stress. Am J Respir Cell Mol Biol 2012; 47:358–362.
13. Gea J, Pascual S, Casadevall C, et al. Muscle dysfunction in chronic obstructive pulmonary disease
: Update on causes and biological findings. J Thorac Dis 2015; 7:E418–E438.
14. Siemann EH, Creasy LL. Concentration of the phytoalexin resveratrol
in wine. Am J Enol Viticult 1992; 43:49–52.
15▪. de Ligt M, Timmers S, Schrauwen P. Resveratrol
and obesity: can resveratrol
relieve metabolic disturbances? Biochim Biophys Acta 2015; 1852:1137–1144.
The review gives a detailed description of the preclinical and clinical studies investigating the effect of resveratrol on obesity-induced negative health outcomes.
16. Schrauwen P, Timmers S. Can resveratrol
help to maintain metabolic health? Proc Nutr Soc 2014; 73:271–277.
17. Baur JA, Sinclair DA. Therapeutic potential of resveratrol
: the in vivo evidence. Nat Rev Drug Discov 2006; 5:493–506.
18. Bitterman JL, Chung JH. Metabolic effects of resveratrol
: addressing the controversies. Cell Mol Life Sci 2015; 72:1473–1488.
19. Timmers S, Hesselink MK, Schrauwen P. Therapeutic potential of resveratrol
in obesity and type 2 diabetes: new avenues for health benefits? Ann N Y Acad Sci 2013; 1290:83–89.
20. Cardozo LF, Pedruzzi LM, Stenvinkel P, et al. Nutritional strategies to modulate inflammation and oxidative stress pathways via activation of the master antioxidant switch nrf2. Biochimie 2013; 95:1525–1533.
21. Hwang JW, Yao H, Caito S, et al. Redox regulation of SIRT1 in inflammation and cellular senescence. Free Radic Biol Med 2013; 61:95–110.
22. Svajger U, Jeras M. Anti-inflammatory effects of resveratrol
and its potential use in therapy of immune-mediated diseases. Int Rev Immunol 2012; 31:202–222.
23▪. Yue L, Yao H. Mitochondrial dysfunction in inflammatory responses and cellular senescence: Pathogenesis and pharmacological targets for chronic lung diseases. Br J Pharmacol 2016; 173:2305–2318.
The review discusses how mitochondrial dysfunction affects inflammatory responses and discusses the mechanisms of mitochondrial dysfunction underlying the pathogenesis of chronic lung diseases including COPD.
24. Barnes PJ. Cellular and molecular mechanisms of chronic obstructive pulmonary disease
. Clin Chest Med 2014; 35:71–86.
25. Kneppers AEM, Langen RCJ, Gosker HR, et al. Increased myogenic and protein turnover signaling in skeletal muscle of chronic obstructive pulmonary disease
patients with sarcopenia. J Am Med Dir Assoc 2017; 18:637.e1–637.e11.
26. Kawai Y, Garduno L, Theodore M, et al. Acetylation-deacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic localization. J Biol Chem 2011; 286:7629–7640.
27▪. Cho S, Namkoong K, Shin M, et al. Cardiovascular protective effects and clinical applications of resveratrol
. J Med Food 2017; 20:323–334.
The review described the effect of resveratrol on cardiovascular diseases in preclinical and clinical studies.
28. Birrell MA, McCluskie K, Wong S, et al. Resveratrol
, an extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators through an Nf-kappaB-independent mechanism. FASEB J 2005; 19:840–841.
29. Culpitt SV, Rogers DF, Fenwick PS, et al. Inhibition by red wine extract, resveratrol
, of cytokine release by alveolar macrophages in COPD. Thorax 2003; 58:942–946.
30. Knobloch J, Sibbing B, Jungck D, et al. Resveratrol
impairs the release of steroid-resistant inflammatory cytokines from human airway smooth muscle cells in chronic obstructive pulmonary disease
. J Pharmacol Exp Ther 2010; 335:788–798.
31. Knobloch J, Wahl C, Feldmann M, et al. Resveratrol
attenuates the release of inflammatory cytokines from human bronchial smooth muscle cells exposed to lipoteichoic acid in chronic obstructive pulmonary disease
. Basic Clin Pharmacol Toxicol 2014; 114:202–209.
32. Liu H, Ren J, Chen H, et al. Resveratrol
protects against cigarette smoke-induced oxidative damage and pulmonary inflammation. J Biochem Mol Toxicol 2014; 28:465–471.
33▪▪. Chen J, Yang X, Zhang W, et al. Therapeutic effects of resveratrol
in a mouse model of LPS and cigarette smoke-induced COPD. Inflammation 2016; 39:1949–1959.
The study showed that resveratrol inhibited autophagy in vivo by inhibiting the expression of the Beclin1 protein in a lipopolysaccharide (LPS) and cigarette-smoke-induced COPD mice model.
34. Hwang JW, Chung S, Sundar IK, et al. Cigarette smoke-induced autophagy is regulated by SIRT1-PARP-1-dependent mechanism: implication in pathogenesis of COPD. Arch Biochem Biophys 2010; 500:203–209.
35. Shi J, Yin N, Xuan LL, et al. Vam3, a derivative of resveratrol
, attenuates cigarette smoke-induced autophagy. Acta Pharmacol Sin 2012; 33:888–896.
36. Hoffmann RF, Zarrintan S, Brandenburg SM, et al. Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells. Respir Res 2013; 14:97.
37. Kode A, Rajendrasozhan S, Caito S, et al. Resveratrol
induces glutathione synthesis by activation of nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 2008; 294:L478–488.
38. Li S, Zhao G, Chen L, et al. Resveratrol
protects mice from paraquat-induced lung injury: the important role of sirt1 and nrf2 antioxidant pathways. Mol Med Rep 2016; 13:1833–1838.
39▪▪. Navarro S, Reddy R, Lee J, et al. Inhaled resveratrol
treatments slow ageing-related degenerative changes in mouse lung. Thorax 2017; 72:451–459.
The study showed that intratracheal instillation of resveratrol in mice caused increased Sirtuin 1 levels and maintained peroxisome proliferator-activated receptor gamma coactivator 1-alpha in alveolar epithelial cells which was correlated with maintenance of lung structure and function.
40. Barnes PJ. Corticosteroid resistance in airway disease. Proc Am Thorac Soc 2004; 1:264–268.
42. Knobloch J, Hag H, Jungck D, et al. Resveratrol
impairs the release of steroid-resistant cytokines from bacterial endotoxin-exposed alveolar macrophages in chronic obstructive pulmonary disease
. Basic Clin Pharmacol Toxicol 2011; 109:138–143.
43. Trotta V, Lee WH, Loo CY, et al. In vitro biological activity of resveratrol
using a novel inhalable resveratrol
spray-dried formulation. Int J Pharm 2015; 491:190–197.
44▪. Trotta V, Lee WH, Loo CY, et al. Co-spray dried resveratrol
and budesonide inhalation formulation for reducing inflammation and oxidative stress in rat alveolar macrophages. Eur J Pharm Sci 2016; 86:20–28.
In this study, a novel cospray-dried resveratrol was produced which had anti-inflammatory activities in vitro due to its ability to reduce the levels of TNF-α and IL-6 in LPS-stimulated alveolar macrophages.
45. Timmers S, Konings E, Bilet L, et al. Calorie restriction-like effects of 30 days of resveratrol
supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 2011; 14:612–622.
46. Goh KP, Lee HY, Lau DP, et al. Effects of resveratrol
in patients with type 2 diabetes mellitus on skeletal muscle sirt1 expression and energy expenditure. Int J Sport Nutr Exerc Metab 2014; 24:2–13.
47. Poulsen MM, Vestergaard PF, Clasen BF, et al. High-dose resveratrol
supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes 2013; 62:1186–1195.
48. Yoshino J, Conte C, Fontana L, et al. Resveratrol
supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. Cell Metab 2012; 16:658–664.
49▪▪. Most J, Timmers S, Warnke I, et al. Combined epigallocatechin-3-gallate and resveratrol
supplementation for 12 wk increases mitochondrial capacity and fat oxidation, but not insulin sensitivity, in obese humans: a randomized controlled trial. Am J Clin Nutr 2016; 104:215–227.
The randomized controlled trial showed increased mitochondrial capacity after 12-week resveratrol supplementation in obese patients.
50▪▪. Timmers S, de Ligt M, Phielix E, et al. Resveratrol
as add-on therapy in subjects with well controlled type 2 diabetes: a randomized controlled trial. Diabetes Care 2016; 39:2211–2217.
The randomized controlled trial investigated the effect of 30 days resveratrol supplementation on insulin sensitivity in patients with type 2 diabetes and found improved ex-vivo mitochondrial function after resveratrol.
51▪. Pollack RM, Barzilai N, Anghel V, et al. Resveratrol
improves vascular function and mitochondrial number but not glucose metabolism in older adults. J Gerontol A Biol Sci Med Sci 2017; 72:1703–1709.
The randomized controlled trial investigated the effect of 6-week resveratrol supplementation on glucose metabolism and vascular function in older adults and found an increased mitochondrial number after resveratrol supplementation, despite no changes in mitochondrial size and morphology.
52▪. Hyatt JP, Nguyen L, Hall AE, et al. Muscle-specific myosin heavy chain shifts in response to a long-term high fat/high sugar diet and resveratrol
treatment in nonhuman primates. Front Physiol 2016; 7:77.
The study showed that long-term resveratrol treatment caused an increment in type I myosin heavy chain protein in the soleus muscle of primates.
53. Qi Y, Shang JY, Ma LJ, et al. Inhibition of AMPK expression in skeletal muscle by systemic inflammation in COPD rats. Respir Res 2014; 15:156.
54. Alamdari N, Aversa Z, Castillero E, et al. Resveratrol
prevents dexamethasone-induced expression of the muscle atrophy-related ubiquitin ligases atrogin-1 and murf1 in cultured myotubes through a SIRT1-dependent mechanism. Biochem Biophys Res Commun 2012; 417:528–533.
55. Liu J, Peng Y, Wang X, et al. Mitochondrial dysfunction launches dexamethasone-induced skeletal muscle atrophy via AMPK/FOXO3 signaling. Mol Pharm 2016; 13:73–84.
56. Wang DT, Yin Y, Yang YJ, et al. Resveratrol
prevents TNF-alpha-induced muscle atrophy via regulation of Akt/mTOR/FoxO1 signaling in c2c12 myotubes. Int Immunopharmacol 2014; 19:206–213.
57▪. Sadeghi A, Seyyed Ebrahimi SS, Golestani A, Meshkani R. Resveratrol
ameliorates palmitate-induced inflammation in skeletal muscle cells by attenuating oxidative stress and JNK/NF-kB pathway in a SIRT1-independent mechanism. J Cell Biochem 2017; 118:2654–2663.
The study showed that resveratrol ameliorates the expression of palmitate-induced inflammation in C2C12 myoblasts by mechanisms involving the inhibition of oxidative stress and decreasing the activity of nuclear factor kappa B (NF-κB) pathway.
58. Remels AH, Gosker HR, Langen RC, Schols AM. The mechanisms of cachexia underlying muscle dysfunction in COPD. J Appl Physiol 2013; 114:1253–1262.
59▪. Kjaer TN, Ornstrup MJ, Poulsen MM, et al. No beneficial effects of resveratrol
on the metabolic syndrome: a randomized placebo-controlled clinical trial. J Clin Endocrinol Metab 2017; 102:1642–1651.
The randomized controlled trial showed no improve in inflammatory status, glucose homeostasis, blood pressure or hepatic lipid content after resveratrol supplementation for 16 weeks in men with metabolic syndrome.
60. Bonnefont-Rousselot D. Resveratrol
and cardiovascular diseases. Nutrients 2016; 8:250.
61. Zordoky BN, Robertson IM, Dyck JR. Preclinical and clinical evidence for the role of resveratrol
in the treatment of cardiovascular diseases. Biochim Biophys Acta 2015; 1852:1155–1177.
62▪▪. Huang H, Chen G, Liao D, et al. The effects of resveratrol
intervention on risk markers of cardiovascular health in overweight and obese subjects: a pooled analysis of randomized controlled trials. Obes Rev 2016; 17:1329–1340.
The meta-analysis provides clinical evidence that resveratrol can lower SBP, fasting glucose and total cholesterol in overweight and obese patients.
63. Walle T. Bioavailability of resveratrol
. Ann N Y Acad Sci 2011; 1215:9–15.
64▪. Beijers R, van de Bool C, van den Borst B, et al. Normal weight but low muscle mass and abdominally obese: implications for the cardiometabolic risk profile in chronic obstructive pulmonary disease
. J Am Med Dir Assoc 2017; 18:533–538.
The study shows that normal weight patients with low muscle mass and abdominal obesity have an increased cardiometabolic risk compared with those without abdominal obesity.
65. Cebron Lipovec N, Schols AM, van den Borst B, et al. Sarcopenia in advanced COPD affects cardiometabolic risk reduction by short-term high-intensity pulmonary rehabilitation. J Am Med Dir Assoc 2016; 17:814–820.
66▪. Liu XJ, Bao HR, Zeng XL, Wei JM. Effects of resveratrol
and genistein on nuclear factor kappaB, tumor necrosis factor alpha and matrix metalloproteinase9 in patients with chronic obstructive pulmonary disease
. Mol Med Rep 2016; 13:4266–4272.
The study showed that resveratrol can reduce systemic inflammation in COPD, indicated by inhibition of NF-κB protein expression and reduced protein levels of TNF-α and matrix metallopeptidase 9 in lymphocytes of patients with COPD.
67. Remels AH, Gosker HR, Langen RC, et al. Classical Nf-kappaB activation impairs skeletal muscle oxidative phenotype by reducing IKK-alpha expression. Biochim Biophys Acta 2014; 1842:175–185.
68. Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease
. Am J Respir Crit Care Med 2008; 177:861–870.
69. Passey SL, Hansen MJ, Bozinovski S, et al. Emerging therapies for the treatment of skeletal muscle wasting in chronic obstructive pulmonary disease
. Pharmacol Ther 2016; 166:56–70.
70. Ceelen JJ, Langen RC, Schols AM. Systemic inflammation in chronic obstructive pulmonary disease
and lung cancer: Common driver of pulmonary cachexia? Curr Opin Support Palliat Care 2014; 8:339–345.