Abstract
Background: Cystic fibrosis (CF) is an autosomal recessive disease characterized by a progressive and recurrent lung infection.
Objective: This study aimed to evaluate the levels of pro-inflammatory cytokines and their correlations with lung function in CF patients.
Methods: A matched case-control study was conducted among 18 CF (children and adults) and 18 control patients (age and gender-matched) who were admitted to Masih Daneshvari Hospital (Tehran, Iran). The controls had no obvious inflammatory lung disease. The samples of bronchoalveolar lavage (BAL) fluid, serum, and sputum of participants were collected to determine concentrations of inflammatory cytokines such as interleukins (IL-8, IL-1β) and tumour necrosis factor- alpha (TNF-α) using enzyme-linked immunosorbent assay (ELISA). Spirometry was applied and functional pulmonary indices [forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1)] were assessed.
Results: The mean age of CF patients was 15.43 ± 5.970 years (range 4-24). The FVC in a majority of the CF patients (66.7%) was below 60% and only 33.3% of the patients exhibited normal or mild respiratory dysfunction. There were significant differences between FVC and FEV1 measurements before and after bronchoscopy. In addition, IL-8 levels in all three samples (serum, sputum, and BAL) of CF patients and levels of IL-1β and TNF-α in BAL and sputum samples of CF patients were significantly higher than the control group (p<0.001). However, increased cytokine levels were not associated with lung function.
Conclusion: Increased IL-8 and TNF-α levels seemed to be associated with signs of clinical deterioration and might be useful as diagnostic markers.
Keywords: Cystic fibrosis, sputum, BAL, interleukin, Iran, children.
Graphical Abstract
[1]
Duruel O, Berker E, Özşin-Özler C, et al. Levels of pro- and anti-inflammatory cytokines in cystic fibrosis patients with or without gingivitis. Cytokine 2020; 127154987
[http://dx.doi.org/10.1016/j.cyto.2020.154987] [PMID: 31927460]
[http://dx.doi.org/10.1016/j.cyto.2020.154987] [PMID: 31927460]
[2]
van Gool K, Norman R, Delatycki MB, Hall J, Massie J. Understanding the costs of care for cystic fibrosis: an analysis by age and health state. Value Health 2013; 16(2): 345-55.
[http://dx.doi.org/10.1016/j.jval.2012.12.003] [PMID: 23538187]
[http://dx.doi.org/10.1016/j.jval.2012.12.003] [PMID: 23538187]
[3]
Spielberg DR, Clancy JP. Cystic fibrosis and its management through established and emerging therapies. Annu Rev Genom Hum G 2016; 17: 155-75.
[http://dx.doi.org/10.1146/annurev-genom-090314-050024] [PMID: 26905785]
[http://dx.doi.org/10.1146/annurev-genom-090314-050024] [PMID: 26905785]
[4]
Elborn JS. Cystic fibrosis. Lancet 2016; 388(10059): 2519-31.
[http://dx.doi.org/10.1016/S0140-6736(16)00576-6] [PMID: 27140670]
[http://dx.doi.org/10.1016/S0140-6736(16)00576-6] [PMID: 27140670]
[5]
Donaldson SH, Boucher RC. Sodium channels and cystic fibrosis. Chest 2007; 132(5): 1631-6.
[http://dx.doi.org/10.1378/chest.07-0288] [PMID: 17998363]
[http://dx.doi.org/10.1378/chest.07-0288] [PMID: 17998363]
[6]
Cohen-Cymberknoh M, Kerem E, Ferkol T, Elizur A. Airway inflammation in cystic fibrosis: molecular mechanisms and clinical implications. Thorax 2013; 68(12): 1157-62.
[http://dx.doi.org/10.1136/thoraxjnl-2013-203204] [PMID: 23704228]
[http://dx.doi.org/10.1136/thoraxjnl-2013-203204] [PMID: 23704228]
[7]
Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic fibrosis lung disease. N Engl J Med 2015; 372(4): 351-62.
[http://dx.doi.org/10.1056/NEJMra1300109] [PMID: 25607428]
[http://dx.doi.org/10.1056/NEJMra1300109] [PMID: 25607428]
[8]
Mott LS, Park J, Murray CP, et al. AREST CF. Progression of early structural lung disease in young children with cystic fibrosis assessed using CT. Thorax 2012; 67(6): 509-16.
[http://dx.doi.org/10.1136/thoraxjnl-2011-200912] [PMID: 22201161]
[http://dx.doi.org/10.1136/thoraxjnl-2011-200912] [PMID: 22201161]
[9]
Pagin A, Sermet-Gaudelus I, Burgel PR. Genetic diagnosis in practice: From cystic fibrosis to CFTR-related disorders. Arch Pediatr 2020; 27(Suppl. 1): eS25-9.
[http://dx.doi.org/10.1016/S0929-693X(20)30047-6] [PMID: 32172933]
[http://dx.doi.org/10.1016/S0929-693X(20)30047-6] [PMID: 32172933]
[10]
Twigg MS, Brockbank S, Lowry P, et al. The role of serine proteases and antiproteases in the cystic fibrosis lung. Mediat Inflamm 2015.
[http://dx.doi.org/10.1155/2015/293053]
[http://dx.doi.org/10.1155/2015/293053]
[11]
Watt AP, Courtney J, Moore J, Ennis M, Elborn JS. Neutrophil cell death, activation and bacterial infection in cystic fibrosis. Thorax 2005; 60(8): 659-64.
[http://dx.doi.org/10.1136/thx.2004.038240] [PMID: 16061707]
[http://dx.doi.org/10.1136/thx.2004.038240] [PMID: 16061707]
[12]
McElvaney OJ, Wade P, Murphy M, Reeves EP, McElvaney NG. Targeting airway inflammation in cystic fibrosis. Expert Rev Respir Med 2019; 13(11): 1041-55.
[http://dx.doi.org/10.1080/17476348.2019.1666715] [PMID: 31530195]
[http://dx.doi.org/10.1080/17476348.2019.1666715] [PMID: 31530195]
[13]
Grasemann H, Ratjen F. Early lung disease in cystic fibrosis. Lancet Respir Med 2013; 1(2): 148-57.
[http://dx.doi.org/10.1016/S2213-2600(13)70026-2] [PMID: 24429095]
[http://dx.doi.org/10.1016/S2213-2600(13)70026-2] [PMID: 24429095]
[14]
Bell SC, Mall MA, Gutierrez H, et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med 2020; 8(1): 65-124.
[http://dx.doi.org/10.1016/S2213-2600(19)30337-6] [PMID: 31570318]
[http://dx.doi.org/10.1016/S2213-2600(19)30337-6] [PMID: 31570318]
[15]
Courtney JM, Ennis M, Elborn JS. Cytokines and inflammatory mediators in cystic fibrosis. J Cyst Fibros 2004; 3(4): 223-31.
[http://dx.doi.org/10.1016/j.jcf.2004.06.006] [PMID: 15698939]
[http://dx.doi.org/10.1016/j.jcf.2004.06.006] [PMID: 15698939]
[16]
Eyns H, Piérard D, De Wachter E, Eeckhout L, Vaes P, Malfroot A. Respiratory bacterial culture sampling in expectorating and non-expectorating patients with cystic fibrosis. Front Pediatr 2018; 6: 403.
[http://dx.doi.org/10.3389/fped.2018.00403] [PMID: 30619797]
[http://dx.doi.org/10.3389/fped.2018.00403] [PMID: 30619797]
[17]
Forton JT. Detecting respiratory infection in children with cystic fibrosis: Cough swab, sputum induction or bronchoalveolar lavage. Paediatr Respir Rev 2019; 31: 28-31.
[PMID: 31153794]
[PMID: 31153794]
[18]
Sagel SD, Chmiel JF, Konstan MW. Sputum biomarkers of inflammation in cystic fibrosis lung disease. Proc Am Thorac Soc 2007; 4(4): 406-17.
[http://dx.doi.org/10.1513/pats.200703-044BR] [PMID: 17652508]
[http://dx.doi.org/10.1513/pats.200703-044BR] [PMID: 17652508]
[19]
Wainwright CE, Grimwood K, Carlin JB, et al. Safety of bronchoalveolar lavage in young children with cystic fibrosis. Pediatr Pulmonol 2008; 43(10): 965-72.
[http://dx.doi.org/10.1002/ppul.20885] [PMID: 18780333]
[http://dx.doi.org/10.1002/ppul.20885] [PMID: 18780333]
[20]
Szczesniak R, Heltshe SL, Stanojevic S, Mayer-Hamblett N. Use of FEV1 in cystic fibrosis epidemiologic studies and clinical trials: A statistical perspective for the clinical researcher. J Cyst Fibros 2017; 16(3): 318-26.
[http://dx.doi.org/10.1016/j.jcf.2017.01.002] [PMID: 28117136]
[http://dx.doi.org/10.1016/j.jcf.2017.01.002] [PMID: 28117136]
[21]
Seery D, Hill L. Spirometry in Cystic Fibrosis.Cystic Fibrosis in Primary Care. Cham, Germany: Springer 2020; pp. 27-39.
[http://dx.doi.org/10.1007/978-3-030-25909-9_4]
[http://dx.doi.org/10.1007/978-3-030-25909-9_4]
[22]
Ranu H, Wilde M, Madden B. Pulmonary function tests. Ulster Med J 2011; 80(2): 84-90.
[PMID: 22347750]
[PMID: 22347750]
[23]
Liou TG, Elkin EP, Pasta DJ, et al. Year-to-year changes in lung function in individuals with cystic fibrosis. J Cyst Fibros 2010; 9(4): 250-6.
[http://dx.doi.org/10.1016/j.jcf.2010.04.002] [PMID: 20471331]
[http://dx.doi.org/10.1016/j.jcf.2010.04.002] [PMID: 20471331]
[24]
VanDevanter DR, Konstan MW. Outcome measures for clinical trials assessing treatment of cystic fibrosis lung disease. J Clin Invest 2012; 2(2): 163-75.
[http://dx.doi.org/10.4155/cli.11.174] [PMID: 26146539]
[http://dx.doi.org/10.4155/cli.11.174] [PMID: 26146539]
[25]
Aurora P, Edwards LB, Christie JD, et al. Registry of the International Society for Heart and Lung Transplantation: twelfth official pediatric lung and heart/lung transplantation report—2009. J Heart Lung Transplant 2009; 28(10): 1023-30.
[http://dx.doi.org/10.1016/j.healun.2009.08.002] [PMID: 19782284]
[http://dx.doi.org/10.1016/j.healun.2009.08.002] [PMID: 19782284]
[26]
Laguna TA, Williams CB, Nunez MG, et al. Biomarkers of inflammation in infants with cystic fibrosis. Respir Res 2018; 19(1): 6.
[http://dx.doi.org/10.1186/s12931-017-0713-8] [PMID: 29310632]
[http://dx.doi.org/10.1186/s12931-017-0713-8] [PMID: 29310632]
[27]
European Medicines Committee. Guideline on the clinical development of medicinal products for the treatment of cystic fibrosis 2009. Available from: https://www.ema.europa.eu/en/clinical-development-medicinal-products-treatment-cystic-fibrosis
[28]
Elizur A, Cannon CL, Ferkol TW. Airway inflammation in cystic fibrosis. Chest 2008; 133(2): 489-95.
[http://dx.doi.org/10.1378/chest.07-1631] [PMID: 18252915]
[http://dx.doi.org/10.1378/chest.07-1631] [PMID: 18252915]
[29]
Eickmeier O, Huebner M, Herrmann E, et al. Sputum biomarker profiles in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) and association between pulmonary function. Cytokine 2010; 50(2): 152-7.
[http://dx.doi.org/10.1016/j.cyto.2010.02.004] [PMID: 20181491]
[http://dx.doi.org/10.1016/j.cyto.2010.02.004] [PMID: 20181491]
[30]
de Vries L, Griffiths A, Armstrong D, Robinson PJ. Cytokine gene polymorphisms and severity of CF lung disease. J Cyst Fibros 2014; 13(6): 699-705.
[http://dx.doi.org/10.1016/j.jcf.2014.04.007] [PMID: 24853301]
[http://dx.doi.org/10.1016/j.jcf.2014.04.007] [PMID: 24853301]
[31]
Montgomery ST, Dittrich AS, Garratt LW, et al. AREST CF. Interleukin-1 is associated with inflammation and structural lung disease in young children with cystic fibrosis. J Cyst Fibros 2018; 17(6): 715-22.
[http://dx.doi.org/10.1016/j.jcf.2018.05.006] [PMID: 29884450]
[http://dx.doi.org/10.1016/j.jcf.2018.05.006] [PMID: 29884450]
[32]
Bergin DA, Hurley K, Mehta A, et al. Airway inflammatory markers in individuals with cystic fibrosis and non-cystic fibrosis bronchiectasis. J Inflamm Res 2013; 6: 1-11.
[PMID: 23426081]
[PMID: 23426081]
[33]
Sagel SD, Wagner BD, Anthony MM, Emmett P, Zemanick ET. Sputum biomarkers of inflammation and lung function decline in children with cystic fibrosis. Am J Respir Crit Care Med 2012; 186(9): 857-65.
[http://dx.doi.org/10.1164/rccm.201203-0507OC] [PMID: 22904182]
[http://dx.doi.org/10.1164/rccm.201203-0507OC] [PMID: 22904182]
[34]
El-Shimy WS, El-Dib AS, Nagy HM, et al. A study of IL-6, IL-8, and TNF-α as inflammatory markers in COPD patients. Egypt J Bronchol 2014; 8(2): 91.
[http://dx.doi.org/10.4103/1687-8426.145698]
[http://dx.doi.org/10.4103/1687-8426.145698]
[35]
Balamugesh T, Behera D, Bhatnagar A, Majumdar S. Inflammatory cytokine levels in induced sputum and bronchoalveolar lavage fluid in pulmonary sarcoidosis. Indian J Chest Dis Allied Sci 2006; 48(3): 177-81.
[PMID: 18610674]
[PMID: 18610674]
[36]
Paats MS, Bergen IM, Bakker M, et al. Cytokines in nasal lavages and plasma and their correlation with clinical parameters in cystic fibrosis. J Cyst Fibros 2013; 12(6): 623-9.
[http://dx.doi.org/10.1016/j.jcf.2013.05.002] [PMID: 23751406]
[http://dx.doi.org/10.1016/j.jcf.2013.05.002] [PMID: 23751406]
[37]
Ngan DA, Wilcox PG, Aldaabil M, et al. The relationship of systemic inflammation to prior hospitalization in adult patients with cystic fibrosis. BMC Pulm Med 2012; 12(1): 3.
[http://dx.doi.org/10.1186/1471-2466-12-3] [PMID: 22333132]
[http://dx.doi.org/10.1186/1471-2466-12-3] [PMID: 22333132]
[38]
Loh G, Ryaboy I, Skabelund A, French A. Procalcitonin, erythrocyte sedimentation rate and C-reactive protein in acute pulmonary exacerbations of cystic fibrosis. Clin Respir J 2018; 12(4): 1545-9.
[http://dx.doi.org/10.1111/crj.12703] [PMID: 28884501]
[http://dx.doi.org/10.1111/crj.12703] [PMID: 28884501]
[39]
Pereira LC, Moreira EA, Bennemann GD, et al. Influence of inflammatory response, infection, and pulmonary function in cystic fibrosis. Life Sci 2014; 109(1): 30-6.
[http://dx.doi.org/10.1016/j.lfs.2014.06.002] [PMID: 24931908]
[http://dx.doi.org/10.1016/j.lfs.2014.06.002] [PMID: 24931908]
[40]
Mayer-Hamblett N, Aitken ML, Accurso FJ, et al. Association between pulmonary function and sputum biomarkers in cystic fibrosis. Am J Respir Crit Care Med 2007; 175(8): 822-8.
[http://dx.doi.org/10.1164/rccm.200609-1354OC] [PMID: 17234902]
[http://dx.doi.org/10.1164/rccm.200609-1354OC] [PMID: 17234902]
[41]
Steinkamp G, Wiedemann B. Relationship between nutritional status and lung function in cystic fibrosis: cross sectional and longitudinal analyses from the German CF quality assurance (CFQA) project. Thorax 2002; 57(7): 596-601.
[http://dx.doi.org/10.1136/thorax.57.7.596] [PMID: 12096202]
[http://dx.doi.org/10.1136/thorax.57.7.596] [PMID: 12096202]
[42]
Karpati F, Hjelte FL, Wretlind B. TNF-alpha and IL-8 in consecutive sputum samples from cystic fibrosis patients during antibiotic treatment. Scand J Infect Dis 2000; 32(1): 75-9.
[http://dx.doi.org/10.1080/00365540050164263] [PMID: 10716082]
[http://dx.doi.org/10.1080/00365540050164263] [PMID: 10716082]
[43]
Carrabino S, Carpani D, Livraghi A, et al. Dysregulated interleukin-8 secretion and NF-kappaB activity in human cystic fibrosis nasal epithelial cells. J Cyst Fibros 2006; 5(2): 113-9.
[http://dx.doi.org/10.1016/j.jcf.2005.12.003] [PMID: 16481223]
[http://dx.doi.org/10.1016/j.jcf.2005.12.003] [PMID: 16481223]
[44]
Guan X, Hou Y, Sun F, Yang Z, Li C. Dysregulated chemokine signaling in cystic fibrosis lung disease: a potential therapeutic target. Curr Drug Targets 2016; 17(13): 1535-44.
[http://dx.doi.org/10.2174/1389450117666151209120516] [PMID: 26648071]
[http://dx.doi.org/10.2174/1389450117666151209120516] [PMID: 26648071]
[45]
McGarvey LP, Dunbar K, Martin SL, et al. Cytokine concentrations and neutrophil elastase activity in bronchoalveolar lavage and induced sputum from patients with cystic fibrosis, mild asthma and healthy volunteers. J Cyst Fibros 2002; 1(4): 269-75.
[http://dx.doi.org/10.1016/S1569-1993(02)00098-X] [PMID: 15463826]
[http://dx.doi.org/10.1016/S1569-1993(02)00098-X] [PMID: 15463826]
[46]
Cantin AM, Hartl D, Konstan MW, Chmiel JF. Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy. J Cyst Fibros 2015; 14(4): 419-30.
[http://dx.doi.org/10.1016/j.jcf.2015.03.003] [PMID: 25814049]
[http://dx.doi.org/10.1016/j.jcf.2015.03.003] [PMID: 25814049]
[47]
Fodor AA, Klem ER, Gilpin DF, et al. The adult cystic fibrosis airway microbiota is stable over time and infection type, and highly resilient to antibiotic treatment of exacerbations. PLoS One 2012; 7(9)e45001
[http://dx.doi.org/10.1371/journal.pone.0045001] [PMID: 23049765]
[http://dx.doi.org/10.1371/journal.pone.0045001] [PMID: 23049765]
[48]
Paul L. Is bronchoscopy an obsolete tool in cystic fibrosis? The role of bronchoscopy in cystic fibrosis and its clinical use. J Thorac Dis 2017; 9(Suppl. 10): S1139-45.
[http://dx.doi.org/10.21037/jtd.2017.06.143] [PMID: 29214071]
[http://dx.doi.org/10.21037/jtd.2017.06.143] [PMID: 29214071]
[49]
Marques A, Cruz J, Jácome C, et al. Outcome measures for respiratory physiotherapy in cystic fibrosis—challenges and advances. Cystic Fibrosis in the Light of New Research 2015; p. 37.
[http://dx.doi.org/10.5772/60674]
[http://dx.doi.org/10.5772/60674]
[50]
Drumm ML, Konstan MW, Schluchter MD, et al. Gene Modifier Study Group. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 2005; 353(14): 1443-53.
[http://dx.doi.org/10.1056/NEJMoa051469] [PMID: 16207846]
[http://dx.doi.org/10.1056/NEJMoa051469] [PMID: 16207846]
[51]
Garth J, Barnes JW, Krick S. Targeting cytokines as evolving treatment strategies in chronic inflammatory airway diseases. Int J Mol Sci 2018; 19(11): 3402.
[http://dx.doi.org/10.3390/ijms19113402] [PMID: 30380761]
[http://dx.doi.org/10.3390/ijms19113402] [PMID: 30380761]
[52]
Hackshaw A. Small studies: strengths and limitations. Eur Respir J 2008; 32(5): 1141-3.
[http://dx.doi.org/10.1183/09031936.00136408] [PMID: 18978131]
[http://dx.doi.org/10.1183/09031936.00136408] [PMID: 18978131]
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