Inflammatory cytokine response to exercise in alpha-1-antitrypsin deficient COPD patients ‘on’ or ‘off’ augmentation therapy

BMC Pulmonary Medicine

Peter D Wagner¹  Harrieth Wagner¹  Tomas ML Eagan²  Moh H Malek¹  I Mark Olfert³ 

[1]Department of Medicine, Division of Physiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0623, USA

[2]Department of Thoracic Medicine, Haukeland University Hospital, Jonas Lies vei 65, N-5021 Bergen, Norway

[3]Center for Cardiovascular and Respiratory Sciences, Division of Exercise Physiology, One Medical Center Dr, West Virginia University School of Medicine, Morgantown, WV 26506-9105, USA

关键词: Inflammation;    Emphysema;    Skeletal muscle;    C-reactive protein;    Tumor necrosis factor-α;   

Others  :  862753
DOI  :  10.1186/1471-2466-14-106

 received in 2013-12-30, accepted in 2014-06-19,  发布年份 2014

【 摘 要 】

Background

There is still limited information on systemic inflammation in alpha-1-antitrypsin-deficient (AATD) COPD patients and what effect alpha-1-antitrypsin augmentation therapy and/or exercise might have on circulating inflammatory cytokines. We hypothesized that AATD COPD patients on augmentation therapy (AATD + AUG) would have lower circulating and skeletal muscle inflammatory cytokines compared to AATD COPD patients not receiving augmentation therapy (AATD-AUG) and/or the typical non-AATD (COPD) patient. We also hypothesized that cytokine response to exercise would be lower in AATD + AUG compared to AATD-AUG or COPD subjects.

Methods

Arterial and femoral venous concentration and skeletal muscle expression of TNFα, IL-6, IL-1β and CRP were measured at rest, during and up to 4-hours after 50% maximal 1-hour knee extensor exercise in all COPD patient groups, including 2 additional groups (i.e. AATD with normal lung function, and healthy age-/activity-matched controls).

Results

Circulating CRP was higher in AATD + AUG (4.7 ± 1.6 mg/dL) and AATD-AUG (3.3 ± 1.2 mg/dL) compared to healthy controls (1.5 ± 0.3 mg/dL, p < 0.05), but lower in AATD compared to non-AATD-COPD patients (6.1 ± 2.6 mg/dL, p < 0.05). TNFα, IL-6 and IL-1β were significantly increased by 1.7-, 1.7-, and 4.7-fold, respectively, in non-AATD COPD compared to AATD COPD (p < 0.05), and 1.3-, 1.7-, and 2.2-fold, respectively, compared to healthy subjects (p < 0.05). Skeletal muscle TNFα was on average 3–4 fold greater in AATD-AUG compared to the other groups (p < 0.05). Exercise showed no effect on these cytokines in any of our patient groups.

Conclusion

These data show that AATD COPD patients do not experience the same chronic systemic inflammation and exhibit reduced inflammation compared to non-AATD COPD patients. Augmentation therapy may help to improve muscle efflux of TNFα and reduce muscle TNFα concentration, but showed no effect on IL-6, IL-1β or CRP.

【 授权许可】

   
2014 Olfert et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Laurell CB, Eriksson S: The electrophoretic alpha-1-globulin pattern of serum in alpha-1-antitrypsin deficiency. Scand J Clin Lab Invest 1963, 15:132-140.
• [2]Tobin MJ, Cook PJ, Hutchison DC: Alpha 1 antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z. A survey by the British Thoracic Association. Br J Dis Chest 1983, 77(1):14-27.
• [3]Wood AM, Harrison RM, Semple S, Ayres JG, Stockley RA: Outdoor air pollution is associated with rapid decline of lung function in alpha-1-antitrypsin deficiency. Occup Environ Med 2010, 67(8):556-561.
• [4]Wood AM, De Pablo P, Buckley CD, Ahmad A, Stockley RA: Smoke exposure as a determinant of autoantibody titre in alpha(1)-antitrypsin deficiency and COPD. Eur Respir J 2011, 37(1):32-38.
• [5]Di Stefano A, Capelli A, Lusuardi M, Balbo P, Vecchio C, Maestrelli P, Mapp CE, Fabbri LM, Donner CF, Saetta M: Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 1998, 158(4):1277-1285.
• [6]De Godoy I, Donahoe M, Calhoun WJ, Mancino J, Rogers RM: Elevated TNF-alpha production by peripheral blood monocytes of weight-losing COPD patients. Am J Respir Crit Care Med 1996, 153(2):633-637.
• [7]Fabbri LM, Rabe KF: From COPD to chronic systemic inflammatory syndrome? Lancet 2007, 370(9589):797-799.
• [8]Sinden NJ, Stockley RA: Systemic inflammation and comorbidity in COPD: a result of ‘overspill’ of inflammatory mediators from the lungs? Review of the evidence. Thorax 2010, 65(10):930-936.
• [9]Aldonyte R, Jansson L, Piitulainen E, Janciauskiene S: Circulating monocytes from healthy individuals and COPD patients. Respir Res 2003, 4:11.
• [10]Agusti AG, Noguera A, Sauleda J, Sala E, Pons J, Busquets X: Systemic effects of chronic obstructive pulmonary disease. Eur Respir J 2003, 21(2):347-360.
• [11]Schols AM, Buurman WA, van den Brekel AJ S, Dentener MA, Wouters EF: Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax 1996, 51(8):819-824.
• [12]Elliott PR, Bilton D, Lomas DA: Lung polymers in Z alpha1-antitrypsin deficiency-related emphysema. Am J Respir Cell Mol Biol 1998, 18(5):670-674.
• [13]Mulgrew AT, Taggart CC, Lawless MW, Greene CM, Brantly ML, O’Neill SJ, McElvaney NG: Z alpha1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant. Chest 2004, 125(5):1952-1957.
• [14]Wang Y, He Y, Abraham B, Rouhani FN, Brantly ML, Scott DE, Reed JL: Cytosolic, autocrine alpha-1 proteinase inhibitor (A1PI) inhibits caspase-1 and blocks IL-1beta dependent cytokine release in monocytes. PLoS One 2012, 7(11):e51078.
• [15]Malerba M, Ricciardolo F, Radaeli A, Torregiani C, Ceriani L, Mori E, Bontempelli M, Tantucci C, Grassi V: Neutrophilic inflammation and IL-8 levels in induced sputum of alpha-1-antitrypsin PiMZ subjects. Thorax 2006, 61(2):129-133.
• [16]Stone H, McNab G, Wood AM, Stockley RA, Sapey E: Variability of sputum inflammatory mediators in COPD and alpha1-antitrypsin deficiency. Eur Respir J 2012, 40(3):561-569.
• [17]Pott GB, Chan ED, Dinarello CA, Shapiro L: Alpha-1-antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood. J Leukoc Biol 2009, 85(5):886-895.
• [18]Churg A, Wang X, Wang RD, Meixner SC, Pryzdial ELG, Wright JL: α1-Antitrypsin Suppresses TNF-α and MMP-12 Production by Cigarette Smoke–Stimulated Macrophages. Am J Respir Cell Mol Biol 2007, 37(2):144-151.
• [19]Stockley RA, Bayley DL, Unsal I, Dowson LJ: The Effect of Augmentation Therapy on Bronchial Inflammation in α1-Antitrypsin Deficiency. Am J Respir Crit Care Med 2002, 165(11):1494-1498.
• [20]Jonigk D, Al-Omari M, Maegel L, Müller M, Izykowski N, Hong J, Hong K, Kim S-H, Dorsch M, Mahadeva R, Laenger F, Kreipe H, Braun A, Shahaf G, Lewis EC, Welte T, Dinarell CA, Janciauskiene S: Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase. Proc Natl Acad Sci 2013, 110(37):15007-15012.
• [21]Collins CB, Aherne CM, Ehrentraut SF, Gerich ME, McNamee EN, McManus MC, Lebsack MDP, Jedlicka P, Azam T, De Zoeten EF, Dinarello CA, Rivera-Nieves J: Alpha-1-antitrypsin Therapy Ameliorates Acute Colitis and Chronic Murine Ileitis. Inflamm Bowel Dis 2013, 19(9):1964-1973.
• [22]Schmid ST, Koepke J, Dresel M, Hattesohl A, Frenzel E, Perez J, Lomas DA, Miranda E, Greulich T, Noeske S, Wencker M, Teschler H, Vogelmeier C, Janciauskiene S, Koczulla AR: The effects of weekly augmentation therapy in patients with PiZZ alpha1-antitrypsin deficiency. Int J Chron Obstruct Pulmon Dis 2012, 7:687-696.
• [23]Lieberman J: Augmentation therapy reduces frequency of lung infections in antitrypsin deficiency: a new hypothesis with supporting data. Chest 2000, 118(5):1480-1485.
• [24]Pedersen BK, Hoffman-Goetz L: Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev 2000, 80(3):1055-1081.
• [25]Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen BK: Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans. J Physiol 1999, 515(Pt 1):287-291.
• [26]Petersen AM, Pedersen BK: The anti-inflammatory effect of exercise. J Appl Physiol 2005, 98(4):1154-1162.
• [27]Petersen AM, Pedersen BK: The role of IL-6 in mediating the anti-inflammatory effects of exercise. J Physiol Pharmacol 2006, 57(Suppl 10):43-51.
• [28]Rabinovich RA, Figueras M, Ardite E, Carbo N, Troosters T, Filella X, Barbera JA, Fernandez-Checa JC, Argiles JM, Roca J: Increased tumour necrosis factor-alpha plasma levels during moderate-intensity exercise in COPD patients. Eur Respir J 2003, 21(5):789-794.
• [29]Van Helvoort HA, Heijdra YF, Thijs HM, Vina J, Wanten GJ, Dekhuijzen PN: Exercise-induced systemic effects in muscle-wasted patients with COPD. Med Sci Sports Exerc 2006, 38(9):1543-1552.
• [30]Van Helvoort HA, van de Pol MH, Heijdra YF, Dekhuijzen PN: Systemic inflammatory response to exhaustive exercise in patients with chronic obstructive pulmonary disease. Respir Med 2005, 99(12):1555-1567.
• [31]Van Helvoort HA, Heijdra YF, De Boer RC, Swinkels A, Thijs HM, Dekhuijzen PN: Six-minute walking-induced systemic inflammation and oxidative stress in muscle-wasted COPD patients. Chest 2007, 131(2):439-445.
• [32]Spruit MA, Troosters T, Gosselink R, Kasran A, Decramer M: Acute inflammatory and anabolic systemic responses to peak and constant-work-rate exercise bout in hospitalized patients with COPD. Int J Chron Obstruct Pulmon Dis 2007, 2(4):575-583.
• [33]Canavan J, Garrod R, Marshall J, Jackson D, Ansley P, Jewell A: Measurement of the acute inflammatory response to walking exercise in COPD: effects of pulmonary rehabilitation. Int J Chron Obstruct Pulmon Dis 2007, 2(3):347-353.
• [34]Garrod R, Ansley P, Canavan J, Jewell A: Exercise and the inflammatory response in chronic obstructive pulmonary disease (COPD)–Does training confer anti-inflammatory properties in COPD? Med Hypotheses 2007, 68(2):291-298.
• [35]Vogiatzis I, Stratakos G, Simoes DC, Terzis G, Georgiadou O, Roussos C, Zakynthinos S: Effects of rehabilitative exercise on peripheral muscle TNFalpha, IL-6, IGF-I and MyoD expression in patients with COPD. Thorax 2007, 62(11):950-956.
• [36]Davidson WJ, Verity WS, Traves SL, Leigh R, Ford GT, Eves ND: Effect of incremental exercise on airway and systemic inflammation in patients with COPD. J Appl Physiol 2012, 112(12):2049-2056.
• [37]Richardson R, Leek B, Gavin T, Haseler L, Mudaliar S, Henry R, Mathieu-Costello O, Wagner P: Reduced mechanical efficiency in chronic obstructive pulmonary disease but normal peak VO2 with small muscle mass exercise. Am J Respir Crit Care Med 2004, 169:89-96.
• [38]Esposito F, Mathieu-Costello O, Shabetai R, Wagner PD, Richardson RS: Limited maximal exercise capacity in patients with chronic heart failure: partitioning the contributors. J Am Coll Cardiol 2010, 55(18):1945-1954.
• [39]Esposito F, Reese V, Shabetai R, Wagner PD, Richardson RS: Isolated quadriceps training increases maximal exercise capacity in chronic heart failure: the role of skeletal muscle convective and diffusive oxygen transport. J Am Coll Cardiol 2011, 58(13):1353-1362.
• [40]Louis E, Raue U, Yang Y, Jemiolo B, Trappe S: Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle. J Appl Physiol 2007, 103(5):1744-1751.
• [41]Gan WQ, Man SF, Senthilselvan A, Sin DD: Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004, 59(7):574-580.
• [42]Hancox RJ, Poulton R, Greene JM, Filsell S, McLachlan CR, Rasmussen F, Taylor DR, Williams MJ, Williamson A, Sears MR: Systemic inflammation and lung function in young adults. Thorax 2007, 62(12):1064-1068.
• [43]Alam S, Li Z, Janciauskiene S, Mahadeva R: Oxidation of Z alpha1-antitrypsin by cigarette smoke induces polymerization: a novel mechanism of early-onset emphysema. Am J Respir Cell Mol Biol 2011, 45(2):261-269.
• [44]Aldonyte R, Jansson L, Janciauskiene S: Concentration-dependent effects of native and polymerised alpha1-antitrypsin on primary human monocytes, in vitro. BMC Cell Biol 2004, 5:11.
• [45]Aldonyte R, Jansson L, Ljungberg O, Larsson S, Janciauskiene S: Polymerized alpha-antitrypsin is present on lung vascular endothelium. New insights into the biological significance of alpha-antitrypsin polymerization. Histopathology 2004, 45(6):587-592.
• [46]Yende S, Waterer GW, Tolley EA, Newman AB, Bauer DC, Taaffe DR, Jensen R, Crapo R, Rubin S, Nevitt M, Simonsick EM, Satterfield S, Harris T, Kritchevsky SB: Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects. Thorax 2006, 61(1):10-16.
• [47]Eagan TML, Ueland T, Wagner PD, Hardie JA, Mollnes TE, Damås JK, Aukrust P, Bakke PS: Systemic inflammatory markers in COPD: results from the Bergen COPD Cohort Study. Eur Respir J 2010, 35(3):540-548.
• [48]Duckers JM, Shale DJ, Stockley RA, Gale NS, Evans BA, Cockcroft JR, Bolton CE: Cardiovascular and musculskeletal co-morbidities in patients with alpha 1 antitrypsin deficiency. Respir Res 2010, 11:173.
• [49]Ahlgren AR, Piitulainen E, Sonesson B, Lanne T: Changes in aortic wall stiffness in men with alpha 1-antitrypsin deficiency. Eur J Vasc Endovasc Surg 1997, 14(4):252-257.
• [50]Talmud PJ, Martin S, Steiner G, Flavell DM, Whitehouse DB, Nagl S, Jackson R, Taskinen MR, Frick MH, Nieminen MS, Kesaniemi YA, Pasternack A, Humphries SE, Syvanne M: Progression of atherosclerosis is associated with variation in the alpha1-antitrypsin gene. Arterioscler Thromb Vasc Biol 2003, 23(4):644-649.
• [51]Stakisaitis D, Basys V, Benetis R: Does alpha-1-proteinase inhibitor play a protective role in coronary atherosclerosis? Med Sci Monit 2001, 7(4):701-711.
• [52]Wood A, Simmonds M, Bayley D, Newby P, Gough S, Stockley R: The TNFalpha gene relates to clinical phenotype in alpha-1-antitrypsin deficiency. Respir Res 2008, 9(1):52.
• [53]Barreiro E, Schols AM, Polkey MI, Galdiz JB, Gosker HR, Swallow EB, Coronell C, Gea J: Cytokine Profile in Quadriceps Muscles of Patients with Severe Chronic Obstructive Pulmonary Disease. Thorax 2008, 63:100-107.
• [54]Montes de Oca M, Torres SH, De Sanctis J, Mata A, Hernandez N, Talamo C: Skeletal muscle inflammation and nitric oxide in patients with COPD. Eur Respir J 2005, 26(3):390-397.
• [55]Gouzi F, Préfaut C, Abdellaoui A, Roudier E, De Rigal P, Molinari N, Laoudj-Chenivesse D, Mercier J, Birot O, Hayot M: Blunted muscle angiogenic training-response in copd patients versus sedentary controls. Eur Respir J 2012, 41(4):806-814.
• [56]Koechlin C, Maltais F, Saey D, Michaud A, LeBlanc P, Hayot M, Prefaut C: Hypoxaemia enhances peripheral muscle oxidative stress in chronic obstructive pulmonary disease. Thorax 2005, 60(10):834-841.
• [57]Petersen AM, Penkowa M, Iversen M, Frydelund-Larsen L, Andersen JL, Mortensen J, Lange P, Pedersen BK: Elevated levels of IL-18 in plasma and skeletal muscle in chronic obstructive pulmonary disease. Lung 2007, 185(3):161-171.
• [58]van der Vlist J, Janssen TW: The potential anti-inflammatory effect of exercise in chronic obstructive pulmonary disease. Respiration 2010, 79(2):160-174.
• [59]Ploeger HE, Takken T, De Greef MH, Timmons BW: The effects of acute and chronic exercise on inflammatory markers in children and adults with a chronic inflammatory disease: a systematic review. Exerc Immunol Rev 2009, 15:6-41.
• [60]Dowson LJ, Newall C, Guest PJ, Hill SL, Stockley RA: Exercise capacity predicts health status in alpha(1)-antitrypsin deficiency. Am J Respir Crit Care Med 2001, 163(4):936-941.