Oxidative stress, respiratory muscle dysfunction, and potential therapeutics in chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a highly relevant disorder that induces respiratory muscle dysfunction. One prevalent symptom of COPD is resistive breathing which causes respiratory muscle to significantly increase the magnitude of contractions, resulting in reactive oxygen species (ROS) formation and oxidative stress. Through cellular signaling cascades, ROS activate molecules such as mitogen-activated protein kinases and nuclear factor-κB. These signaling molecules stimulate the release of cytokines which in turn cause damage to the diaphragm, involving sarcomeric disruptions. In response to COPD induced fatigue, the diaphragm undergoes a beneficial fiber-type shift to type I muscle fibers, which are more resistant to hypoxia than type II fibers. The lung hyperinflation that occurs in COPD also causes intercostal muscle dysfunction, thereby exacerbating COPD symptoms. In addition, COPD is known to have a connection with heart failure, diabetes, and aging, further decreasing respiratory function. Currently, there is no cure for this disorder. Nevertheless, various potential therapeutic strategies focusing on respiratory muscle have been identified including respiratory muscle training, β₂-agonist therapy, and lung volume reduction surgery. In this review, we will outline the role of COPD, oxidative stress, and related complications in respiratory muscle dysfunction.

Keywords

COPD / diaphragm / ROS / cytokine / respiratory therapy

References

[1] ACCP/AACVPR evidence-based guidelines (1997). Pulmonary rehabilitation: joint ACCP/AACVPR evidence-based guidelines. ACCP/AACVPR pulmonary rehabilitation guidelines panel. American College of Chest Physicians. American Association of Cardiovascular and Pulmonary Rehabilitation. Chest, 112: 1363–1396

[2] Allen R G, Tresini M (2000). Oxidative stress and gene regulation. Free Radic Biol Med, 28(3): 463–499

[3] Anthonisen N R, Connett J E, Kiley J P, Altose M D, Bailey W C, Buist A S, Conway W A Jr, Enright P L, Kanner R E, O’Hara P, Owens G R, Scanlon P D, Tashkin D P, Wise R A, Altose M D, Connors A F, Redline S, Deitz C, Rakos R F, Conway W A, DeHorn A, Ward J C, Hoppe-Ryan C S, Jentons R L, Reddick J A, Sawicki C, Wise R A, Permutt S, Rand C S, Scanlon P D, Davis L J, Hurt R D, Miller R D, Williams D E, Caron G M, Lauger G G, Toogood S M, Buist A S, Bjornson W M, Johnson L R, Bailey W C, Brooks C M, Dolce J J, Higgins D M, Johnson M A, Lorish C D, Martin B A, Tashkin D P, Coulson A H, Gong H, Harber P I, Li V C, Roth M, Nides M A, Simmons M S, Zuniga I, Anthonisen N R, Manfreda J, Murray R P, Rempel-Rossum S C, Stoyko J M, Connett J E, Kjelsberg M O, Cowles M K, Durkin D A, Enright P L, Kurnow K J, Lee W W, Lindgren P G, Mongin S J, O’Hara P, Voelker H T, Waller L A, Owens G R, Rogers R M, Johnston J J, Pope F P, Vitale F M, Kanner R E, Rigdon M A, Benton K C, Grant P M, Becklake M, Burrows B, Cleary P, Kimbel P, Nett L, Ockene J K, Senior R M, Snider G L, Spitzer W, Williams O D, Hurd S S, Kiley J P, Wu M C, Ayres S M, Hyatt R E, Mason B A (1994). Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV₁. The Lung Health Study. JAMA, 272(19): 1497–1505

[4] Armstrong R B (1990). Initial events in exercise-induced muscular injury. Med Sci Sports Exerc, 22(4): 429–435

[5] Barreiro E, de la Puente B, Minguella J, Corominas J M, Serrano S, Hussain S N, Gea J (2005). Oxidative stress and respiratory muscle dysfunction in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 171(10): 1116–1124

[6] Barreiro E, Peinado V I, Galdiz J B, Ferrer E, Marin-Corral J, Sánchez F, Gea J, Barberà J A, the ENIGMA in COPD Project (2010). Cigarette smoke-induced oxidative stress: A role in chronic obstructive pulmonary disease skeletal muscle dysfunction. Am J Respir Crit Care Med, 182(4): 477–488

[7] Begin P, Grassino A (1991). Inspiratory muscle dysfunction and chronic hypercapnia in chronic obstructive pulmonary disease. Am Rev Respir Dis, 143(5 Pt 1): 905–912

[8] Brochard L, Mancebo J, Wysocki M, Lofaso F, Conti G, Rauss A, Simonneau G, Benito S, Gasparetto A, Lemaire F, Isabey D, Harf A (1995). Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med, 333(13): 817–822

[9] Burge P S, Calverley P M, Jones P W, Spencer S, Anderson J A, Maslen T K (2000). Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ, 320(7245): 1297–1303

[10] Cannon J G, St Pierre B A (1998). Cytokines in exertion-induced skeletal muscle injury. Mol Cell Biochem, 179(1-2): 159–167

[11] Cavalcante A G, de Bruin P F (2009). The role of oxidative stress in COPD: current concepts and perspectives. J Bras Pneumol, 35(12): 1227–1237

[12] Cooper J D, Trulock E P, Triantafillou A N, Patterson G A, Pohl M S, Deloney P A, Sundaresan R S, Roper C L (1995). Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg, 109: 106–116; discussion 116–119

[13] Covey M K, Larson J L, Wirtz S E, Berry J K, Pogue N J, Alex C G, Patel M (2001). High-intensity inspiratory muscle training in patients with chronic obstructive pulmonary disease and severely reduced function. J Cardiopulm Rehabil, 21(4): 231–240

[14] Crisafulli E, Costi S, Fabbri L M, Clini E M (2007). Respiratory muscles training in COPD patients. Int J Chron Obstruct Pulmon Dis, 2(1): 19–25

[15] Curkendall S M, DeLuise C, Jones J K, Lanes S, Stang M R, Goehring E Jr, She D (2006). Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Ann Epidemiol, 16(1): 63–70

[16] Cutler R G (2005). Oxidative stress and aging: catalase is a longevity determinant enzyme. Rejuvenation Res, 8(3): 138–140

[17] Dal Vecchio L, Polese G, Poggi R, Rossi A (1990). “Intrinsic” positive end-expiratory pressure in stable patients with chronic obstructive pulmonary disease. Eur Respir J, 3(1): 74–80

[18] De Troyer A, Kirkwood P A, Wilson T A (2005). Respiratory action of the intercostal muscles. Physiol Rev, 85(2): 717–756

[19] De Troyer A, Wilson T A (2009). Effect of acute inflation on the mechanics of the inspiratory muscles. J Appl Physiol, 107(1): 315–323

[20] Doucet M, Debigaré R, Joanisse D R, Côté C, Leblanc P, Grégoire J, Deslauriers J, Vaillancourt R, Maltais F (2004). Adaptation of the diaphragm and the vastus lateralis in mild-to-moderate COPD. Eur Respir J, 24(6): 971–979

[21] Eid A A, Ionescu A A, Nixon L S, Lewis-Jenkins V, Matthews S B, Griffiths T L, Shale D J (2001). Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 164(8 Pt 1): 1414–1418

[22] Ferguson G T (2006). Why does the lung hyperinflate? Proc Am Thorac Soc, 3(2): 176–179

[23] Fessler H E, Permutt S (1998). Lung volume reduction surgery and airflow limitation. Am J Respir Crit Care Med, 157(3 Pt 1): 715–722

[24] Friden J, Sjöström M, Ekblom B (1983). Myofibrillar damage following intense eccentric exercise in man. Int J Sports Med, 4(3): 170–176

[25] Gea J, Barreiro E (2008). Update on the mechanisms of muscle dysfunction in COPD. Arch Bronconeumol, 44(6): 328–337

[26] Groneberg D A, Chung K F (2004). Models of chronic obstructive pulmonary disease. Respir Res, 5(1): 18

[27] Guerri R, Gayete A, Balcells E, Ramirez-Sarmiento A, Vollmer I, Garcia-Aymerich J, Gea J, Orozco-Levi M (2010). Mass of intercostal muscles associates with risk of multiple exacerbations in COPD. Respir Med, 104(3): 378–388

[28] Haluszka J, Chartrand D A, Grassino A E, Milic-Emili J (1990). Intrinsic PEEP and arterial PCO2 in stable patients with chronic obstructive pulmonary disease. Am Rev Respir Dis, 141(5 Pt 1): 1194–1197

[29] Ito K, Barnes P J (2009). COPD as a disease of accelerated lung aging. Chest, 135(1): 173–180

[30] Janssens J P, Pache J C, Nicod L P (1999). Physiological changes in respiratory function associated with ageing. Eur Respir J, 13(1): 197–205

[31] Kang M J, Lee C G, Lee J Y, Dela Cruz C S, Chen Z J, Enelow R, Elias J A (2008). Cigarette smoke selectively enhances viral PAMP- and virus-induced pulmonary innate immune and remodeling responses in mice. J Clin Invest, 118(8): 2771–2784

[32] Klimathianaki M, Vaporidi K, Georgopoulos D (2011). Respiratory muscle dysfunction in COPD: from muscles to cell. Curr Drug Targets, 12(4): 478–488

[33] Kosmidou I, Vassilakopoulos T, Xagorari A, Zakynthinos S, Papapetropoulos A, Roussos C (2002). Production of interleukin-6 by skeletal myotubes: role of reactive oxygen species. Am J Respir Cell Mol Biol, 26(5): 587–593

[34] Lando Y, Boiselle P M, Shade D, Furukawa S, Kuzma A M, Travaline J M, Criner G J (1999). Effect of lung volume reduction surgery on diaphragm length in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 159(3): 796–805

[35] Laoutaris I D, Adamopoulos S, Manginas A, Panagiotakos D B, Kallistratos M S, Doulaptsis C, Kouloubinis A, Voudris V, Pavlides G, Cokkinos D V, Dritsas A (2012). Benefits of combined aerobic/resistance/inspiratory training in patients with chronic heart failure. A complete exercise model? A prospective randomised study. Int J Cardiol, doi: 10.1016/j.ijcard.2012.05.019

[36] Laude E A, Duffy N C, Baveystock C, Dougill B, Campbell M J, Lawson R, Jones P W, Calverley P M (2006). The effect of helium and oxygen on exercise performance in chronic obstructive pulmonary disease: a randomized crossover trial. Am J Respir Crit Care Med, 173: 865–870

[37] Levine S, Gregory C, Nguyen T, Shrager J, Kaiser L, Rubinstein N, Dudley G (2002). Bioenergetic adaptation of individual human diaphragmatic myofibers to severe COPD. J Appl Physiol, 92(3): 1205–1213

[38] Levine S, Kaiser L, Leferovich J, Tikunov B (1997). Cellular adaptations in the diaphragm in chronic obstructive pulmonary disease. N Engl J Med, 337(25): 1799–1806

[39] Loring S H, Garcia-Jacques M, Malhotra A (2009). Pulmonary characteristics in COPD and mechanisms of increased work of breathing. J Appl Physiol, 107(1): 309–314

[40] Lotters F, van Tol B, Kwakkel G, Gosselink R (2002). Effects of controlled inspiratory muscle training in patients with COPD: a meta-analysis. Eur Respir J, 20(3): 570–576

[41] Louvaris Z, Zakynthinos S, Aliverti A, Habazettl H, Vasilopoulou M, Andrianopoulos V, Wagner H, Wagner P, Vogiatzis I (2012). Heliox increases quadriceps muscle oxygen delivery during exercise in COPD patients with and without dynamic hyperinflation. J Appl Physiol, 113(7): 1012–1023

[42] Mador M J (2002). Muscle mass, not body weight, predicts outcome in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 166(6): 787–789

[43] Mannino D M, Ford E S, Redd S C (2003). Obstructive and restrictive lung disease and markers of inflammation: data from the Third National Health and Nutrition Examination. Am J Med, 114(9): 758–762

[44] Mascarenhas J, Azevedo A, Bettencourt P (2010). Coexisting chronic obstructive pulmonary disease and heart failure: implications for treatment, course and mortality. Curr Opin Pulm Med, 16(2): 106–111

[45] McCullough P A, Hollander J E, Nowak R M, Storrow A B, Duc P, Omland T, McCord J, Herrmann H C, Steg P G, Westheim A, Knudsen C W, Abraham W T, Lamba S, Wu A H, Perez A, Clopton P, Krishnaswamy P, Kazanegra R, Maisel A S, Investigators B N P M S, the BNP Multinational Study Investigators (2003). Uncovering heart failure in patients with a history of pulmonary disease: rationale for the early use of B-type natriuretic peptide in the emergency department. Acad Emerg Med, 10(3): 198–204

[46] Meecham Jones D J, Paul E A, Jones P W, Wedzicha J A (1995). Nasal pressure support ventilation plus oxygen compared with oxygen therapy alone in hypercapnic COPD. Am J Respir Crit Care Med, 152(2): 538–544

[47] Mercadier J J, Schwartz K, Schiaffino S, Wisnewsky C, Ausoni S, Heimburger M, Marrash R, Pariente R, Aubier M (1998). Myosin heavy chain gene expression changes in the diaphragm of patients with chronic lung hyperinflation. Am J Physiol, 274(4 Pt 1): L527–L534

[48] Meyer T J, Hill N S (1994). Noninvasive positive pressure ventilation to treat respiratory failure. Ann Intern Med, 120(9): 760–770

[49] Mizuno M (1991). Human respiratory muscles: fibre morphology and capillary supply. Eur Respir J, 4(5): 587–601

[50] Mohanraj P, Merola A J, Wright V P, Clanton T L (1998). Antioxidants protect rat diaphragmatic muscle function under hypoxic conditions. J Appl Physiol, 84(6): 1960–1966

[51] Moon C, Lee Y J, Park H J, Chong Y H, Kang J L (2010). N-acetylcysteine inhibits RhoA and promotes apoptotic cell clearance during intense lung inflammation. Am J Respir Crit Care Med, 181(4): 374–387

[52] Mroz R M, Szulakowski P, Pierzchala W, Chyczewska E, MacNee W (2006). Pathogenesis of chronic obstructive pulmonary disease. Cellular mechanisms (part I). Wiad Lek, 59(1–2): 92–96

[53] Naunheim K S, Wood D E, Mohsenifar Z, Sternberg A L, Criner G J, DeCamp M M, Deschamps C C, Martinez F J, Sciurba F C, Tonascia J, Fishman A P, the National Emphysema Treatment Trial Research Group (2006). Long-term follow-up of patients receiving lung-volume-reduction surgery versus medical therapy for severe emphysema by the National Emphysema Treatment Trial Research Group. Ann Thorac Surg, 82(2): 431–443

[54] Nava S, Crotti P, Gurrieri G, Fracchia C, Rampulla C (1992). Effect of a beta 2-agonist (broxaterol) on respiratory muscle strength and endurance in patients with COPD with irreversible airway obstruction. Chest, 101(1): 133–140

[55] Orozco-Levi M, Lloreta J, Minguella J, Serrano S, Broquetas J M, Gea J (2001). Injury of the human diaphragm associated with exertion and chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 164(9): 1734–1739

[56] Ottenheijm C A, Heunks L M, Dekhuijzen P N (2007). Diaphragm muscle fiber dysfunction in chronic obstructive pulmonary disease: toward a pathophysiological concept. Am J Respir Crit Care Med, 175(12): 1233–1240

[57] Ottenheijm C A, Heunks L M, Dekhuijzen R P (2008). Diaphragm adaptations in patients with COPD. Respir Res, 9(1): 12

[58] Ottenheijm C A, Heunks L M, Sieck G C, Zhan W Z, Jansen S M, Degens H, de Boo T, Dekhuijzen P N (2005). Diaphragm dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 172(2): 200–205

[59] Pauwels R A, Löfdahl C G, Laitinen L A, Schouten J P, Postma D S, Pride N B, Ohlsson S V, the European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (1999). Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med, 340(25): 1948–1953

[60] Pitsiou G, Kyriazis G, Hatzizisi O, Argyropoulou P, Mavrofridis E, Patakas D (2002). Tumor necrosis factor-alpha serum levels, weight loss and tissue oxygenation in chronic obstructive pulmonary disease. Respir Med, 96(8): 594–598

[61] Puente-Maestu L, Pérez-Parra J, Godoy R, Moreno N, Tejedor A, González-Aragoneses F, Bravo J L, Alvarez F V, Camaño S, Agustí A (2009). Abnormal mitochondrial function in locomotor and respiratory muscles of COPD patients. Eur Respir J, 33(5): 1045–1052

[62] Ramirez-Sarmiento A, Orozco-Levi M, Guell R, Barreiro E, Hernandez N, Mota S, Sangenis M, Broquetas J M, Casan P, Gea J (2002). Inspiratory muscle training in patients with chronic obstructive pulmonary disease: structural adaptation and physiologic outcomes. Am J Respir Crit Care Med, 166(11): 1491–1497

[63] Rana J S, Mittleman M A, Sheikh J, Hu F B, Manson J E, Colditz G A, Speizer F E, Barr R G, Camargo C A Jr (2004). Chronic obstructive pulmonary disease, asthma, and risk of type 2 diabetes in women. Diabetes Care, 27(10): 2478–2484

[64] Reid M B (2001). Invited Review: redox modulation of skeletal muscle contraction: what we know and what we don’t. J Appl Physiol, 90(2): 724–731

[65] Reid M B, Haack K E, Franchek K M, Valberg P A, Kobzik L, West M S (1992). Reactive oxygen in skeletal muscle. I. Intracellular oxidant kinetics and fatigue in vitro. J Appl Physiol, 73(5): 1797–1804

[66] Rennard S I, Vestbo J (2008). Natural histories of chronic obstructive pulmonary disease. Proc Am Thorac Soc, 5(9): 878–883

[67] Ribera F, N’Guessan B, Zoll J, Fortin D, Serrurier B, Mettauer B, Bigard X, Ventura-Clapier R, Lampert E (2003). Mitochondrial electron transport chain function is enhanced in inspiratory muscles of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 167(6): 873–879

[68] Roisin R R, Vestbo J (2011). Global initiative for chronic obstructive lung disease. GOLD: 1–74

[69] Rutten F H, Cramer M J, Grobbee D E, Sachs A P, Kirkels J H, Lammers J W, Hoes A W (2005). Unrecognized heart failure in elderly patients with stable chronic obstructive pulmonary disease. Eur Heart J, 26(18): 1887–1894

[70] Sanchez J, Bastien C, Medrano G, Riquet M, Derenne J P (1984). Metabolic enzymatic activities in the diaphragm of normal men and patients with moderate chronic obstructive pulmonary disease. Bull Eur Physiopathol Respir, 20(6): 535–540

[71] Schols A M (2003). Nutritional and metabolic modulation in chronic obstructive pulmonary disease management. Eur Respir J Suppl, 46: 81s–86s

[72] Scott A, Wang X, Road J D, Reid W D (2006). Increased injury and intramuscular collagen of the diaphragm in COPD: autopsy observations. Eur Respir J, 27(1): 51–59

[73] Shindoh C, DiMarco A, Thomas A, Manubay P, Supinski G (1990). Effect of N-acetylcysteine on diaphragm fatigue. J Appl Physiol, 68(5): 2107–2113

[74] Sidney S, Sorel M, Quesenberry C P Jr, DeLuise C, Lanes S, Eisner M D (2005). COPD and incident cardiovascular disease hospitalizations and mortality: Kaiser Permanente Medical Care Program. Chest, 128(4): 2068–2075

[75] Sigala I, Zacharatos P, Toumpanakis D, Michailidou T, Noussia O, Theocharis S, Roussos C, Papapetropoulos A, Vassilakopoulos T (2011). MAPKs and NF-κB differentially regulate cytokine expression in the diaphragm in response to resistive breathing: the role of oxidative stress. Am J Physiol Regul Integr Comp Physiol, 300(5): R1152–R1162

[76] Smith W N, Dirks A, Sugiura T, Muller S, Scarpace P, Powers S K (2002). Alteration of contractile force and mass in the senescent diaphragm with beta(2)-agonist treatment. J Appl Physiol, 92(3): 941–948

[77] Son Y O, Wang L, Poyil P, Budhraja A, Hitron J A, Zhang Z, Lee J C, Shi X (2012). Cadmium induces carcinogenesis in BEAS-2b cells through ROS-dependent activation of PI3K/AKT/GSK-3beta/beta-catenin signaling. Toxicol Appl Pharmacol, doi: S0041–008X(12)00329–8 [pii] 10.1016/j.taap.2012.07.028

[78] Stauber W T, Smith C A, Miller G R, Stauber F D (2000). Recovery from 6 weeks of repeated strain injury to rat soleus muscles. Muscle Nerve, 23(12): 1819–1825

[79] Stubbings A K, Moore A J, Dusmet M, Goldstraw P, West T G, Polkey M I, Ferenczi M A (2008). Physiological properties of human diaphragm muscle fibres and the effect of chronic obstructive pulmonary disease. J Physiol, 586(10): 2637–2650

[80] Testelmans D, Crul T, Maes K, Agten A, Crombach M, Decramer M, Gayan-Ramirez G (2010). Atrophy and hypertrophy signalling in the diaphragm of patients with COPD. Eur Respir J, 35(3): 549–556

[81] Tidball J G (2005). Inflammatory processes in muscle injury and repair. Am J Physiol Regul Integr Comp Physiol, 288(2): R345–R353

[82] Van Der Heijden H F, Dekhuijzen P N, Folgering H, Ginsel L A, Van Herwaarden C L (1998). Long-term effects of clenbuterol on diaphragm morphology and contractile properties in emphysematous hamsters. J Appl Physiol, 85(1): 215–222

[83] Vestbo J, Sørensen T, Lange P, Brix A, Torre P, Viskum K (1999). Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet, 353(9167): 1819–1823

[84] Watz H, Waschki B, Meyer T, Kretschmar G, Kirsten A, Claussen M, Magnussen H (2010). Decreasing cardiac chamber sizes and associated heart dysfunction in COPD: role of hyperinflation. Chest, 138(1): 32–38

[85] Wijnhoven H J, Heunks L M, Geraedts M C, Hafmans T, Viña J R, Dekhuijzen P N (2006). Oxidative and nitrosative stress in the diaphragm of patients with COPD. Int J Chron Obstruct Pulmon Dis, 1(2): 173–179

[86] Willems M E, Stauber W T (2001). Force deficits after repeated stretches of activated skeletal muscles in female and male rats. Acta Physiol Scand, 172(1): 63–67

[87] Wouters E F (2000). Nutrition and metabolism in COPD. Chest, 117(5 Suppl 1): 274S–280S

[88] Zuo L, Nogueira L, Hogan M C (2011a). Reactive oxygen species formation during tetanic contractions in single isolated Xenopus myofibers. J Appl Physiol, 111(3): 898–904

[89] Zuo L, Roberts W J, Tolomello R C, Goins A T (2011b). Ischemic and hypoxic preconditioning protect cardiac muscles via intracellular ROS signaling. Front Biol, doi: 10.1007/s11515-012-1225-z

Acknowledgments

This work is supported by grants of OU General Fund G110 and Research Excellence Fund of Biomedical Research. We thank the assistance from Dr. Arik Dvir, William Roberts, and Juliana Kishek.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg