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Review Article

Neutrophilic Inflammation in the Pathogenesis of Chronic Obstructive Pulmonary Disease

, &
Pages 392-404 | Received 12 Sep 2017, Accepted 07 May 2018, Published online: 31 Jul 2018

References

  • Calverley PMA, Rabe KF, Goehring U-M, Kristiansen S, Fabbri LM, Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374(9691):685–94.
  • Løkke A, Lange P, Scharling H, Fabricius P, Vestbo J. Developing COPD: a 25 year follow up study of the general population. Thorax. 2006;61(11):935.
  • Jeffery PK. Comparison of the structural and inflammatory features of COPD and asthma. Giles F. Filley lecture. Chest. 2000;117(5 Suppl 1):251S–60S.
  • Bignon J, Khoury F, Even P, Andre J, Brouet G. Morphometric study in chronic obstructive bronchopulmonary disease. Pathologic, clinical, and physiologic correlations. Am Rev Respir Dis. 1969;99(5):669–95.
  • Wedzicha JA, Brill SE, Allinson JP, Donaldson GC. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 2013;11:181.
  • Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agusti A, Bakke P, et al. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med. 2011;365(13):1184–92.
  • Patel BD, Coxson HO, Pillai SG, Agustí AGN, Calverley PMA, Donner CF, et al. Airway wall thickening and emphysema show independent familial aggregation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;178(5):500–5.
  • Probert K, Miller S, Kheirallah AK, Hall IP. Developmental genetics of the COPD lung. COPD Res Pract. 2015;1(1):10.
  • Wain LV, Shrine N, Artigas MS, Erzurumluoglu AM, Noyvert B, Bossini-Castillo L, et al. Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets. Nature Genet. 2017;49:416.
  • Ferkol T, Schraufnagel D. The global burden of respiratory disease. Ann Am Thoracic Soc. 2014;11(3):404–6.
  • Barnes PJ, Chowdhury B, Kharitonov SA, Magnussen H, Page CP, Postma D, et al. Pulmonary biomarkers in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;174(1):6–14.
  • Sapey E, Bayley D, Ahmad A, Stockley R. The validation of assays used to measure biomarkers in exhaled breath condensate. Eur Respir J. 2008;32(5):1408–9; author reply 9.
  • Hoonhorst SJM, Timens W, Koenderman L, Lo Tam Loi AT, Lammers J-WJ, Boezen HM, et al. Increased activation of blood neutrophils after cigarette smoking in young individuals susceptible to COPD. Respir Res. 2014;15(1):121.
  • Rutgers SR, Postma DS, H. tHN, Kauffman HF, W. vDMT, Koeter GH, et al. Ongoing airway inflammation in patients with COPD who Do not currently smoke. Chest. 2000;117(1931–3543 (Electronic)):262S.
  • Churg A., Wang RD, Tai H, Wang X, Xie C, Wright JL. Tumour necrosis factor alpha drives 70% of cigarette smoke-induced emphysema in the mouse. Am J Respir Crit Care Med. 2004;170:492–8.
  • Pauwels NS, Bracke KR, Dupont LL, Van Pottelberge GR, Provoost S, Vanden Berghe T, et al. Role of IL-1α and the Nlrp3/caspase-1/IL-1β axis in cigarette smoke-induced pulmonary inflammation and COPD. Eur Respir J. 2011;38(5):1019.
  • Rennard SI, Fogarty C, Kelson S, Long W, Ramsdell J, Allison J, et al. The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175:926–34.
  • Calverley PMA, Sethi S, Dawson M, Ward CK, Finch DK, Penney M, et al. A randomised, placebo-controlled trial of anti–interleukin-1 receptor 1 monoclonal antibody MEDI8968 in chronic obstructive pulmonary disease. Respir Res. 2017;18:153.
  • Stone H, McNab G, Wood AM, Stockley RA, Sapey E. Variability of sputum inflammatory mediators in COPD and α1-antitrypsin deficiency. Eur Respir J. 2012;40(3):561–9.
  • Sapey E, Wood AM, Ahmad A, Stockley RA. Tumor necrosis factor-{alpha} rs361525 polymorphism is associated with increased local production and downstream inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;182(2):192–9.
  • Xie Z-K, Huang Q-P, Huang J, Xie Z-F. Association between the IL1B, IL1RN polymorphisms and COPD risk: a meta-analysis. Sci Rep. 2014;4:6202.
  • Sapey E, Bayley D, Ahmad A, Newbold P, Snell N, Stockley RA. Inter-relationships between inflammatory markers in patients with stable COPD with bronchitis: intra-patient and inter-patient variability. Thorax. 2008;63(6):493–9.
  • Nish S, Medzhitov R. Host defense pathways: role of redundancy and compensation in infectious disease phenotypes. Immunity. 2011;34(5):629–36.
  • Verstrepen L, Bekaert T, Chau TL, Tavernier J, Chariot A, Beyaert R. TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme. Cell Mol Life Sci.. 2008;65(19):2964–78.
  • Summers C, Rankin SM, Condliffe AM, Singh N, Peters AM, Chilvers ER. Neutrophil kinetics in health and disease. Trends Immunol. 2010;31(8):318–24.
  • Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol.. 2013;13:159.
  • Eash KJ, Greenbaum AM, Gopalan PK, Link DC. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J Clin Invest. 2010;120(7):2423–31.
  • Wagner C, Iking-Konert C, Denefleh B, Stegmaier S, Hug F, Hänsch GM. Granzyme B and perforin: constitutive expression in human polymorphonuclear neutrophils. Blood. 2004;103(3):1099.
  • Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol. 2012;30:459–89.
  • Harada Y, Kato Y, Miyaji T, Omote H, Moriyama Y, Hiasa M. Vesicular nucleotide transporter mediates ATP release and migration in neutrophils. J Biol Chem. 2018;293(10):3770–3779. doi: 10.1074/jbc.M117.810168. Epub 2018 Jan 23
  • Wagner JG, Roth RA. Neutrophil migration mechanisms, with an emphasis on the pulmonary vasculature. Pharmacol Rev. 2000;52:349–74.
  • Kienle K, Lämmermann T. Neutrophil swarming: an essential process of the neutrophil tissue response. Immunol Rev. 2016;273(1):76–93.
  • Reátegui E, Jalali F, Khankhel AH, Wong E, Cho H, Lee J, et al. Microscale arrays for the profiling of start and stop signals coordinating human-neutrophil swarming. Nat Biomed Eng. 2017;1:0094.
  • Greenberg S, Grinstein S. Phagocytosis and innate immunity. Curr Opin Immunol. 2002;14(1):136–45.
  • Segal AW, Dorling J, Coade S. Kinetics of fusion of the cytoplasmic granules with phagocytic vacuoles in human polymorphonuclear leukocytes. Biochemical and morphological studies. J Cell Biol. 1980;85(1):42–59.
  • Henry RM, Hoppe AD, Joshi N, Swanson JA. The uniformity of phagosome maturation in macrophages. J Cell Biol. 2004;164(2):185.
  • Lee WL, Harrison RE, Grinstein S. Phagocytosis by neutrophils. Microbes Infect.. 2003;5(14):1299–306.
  • Silverstein SC, Greenberg S, Di Virgilio F, Steinberg TH. Phagocytosis. In: William PE, editor. Fundamental immunology. New York: Raven Press; 1989. p. 703.
  • van Kessel KP, Bestebroer J, van Strijp JA. Neutrophil-mediated phagocytosis of Staphylococcus aureus. Front Immunol. 2014;5:467.
  • Ehlers MR. CR3: a general purpose adhesion-recognition receptor essential for innate immunity. Microbes Infect. 2000;2(3):289–94.
  • Jankowski A, Scott CC, Grinstein S. Determinants of the phagosomal pH in neutrophils. J Biol Chem. 2002;277(8):6059–66.
  • Segal AW, Geisow M, Garcia R, Harper A, Miller R. The respiratory burst of phagocytic cells is associated with a rise in vacuolar pH. Nature. 1981;290(5805):406–9.
  • Korkmaz B, Moreau T, Gauthier F. Neutrophil elastase, proteinase 3 and cathepsin G: physicochemical properties, activity and physiopathological functions. Biochimie. 2008;90(2):227–42.
  • Segal AW. How neutrophils kill microbes. Annu Rev Immunol. 2005;23:197–223.
  • Winterbourn CC, Hampton MB, Livesey JH, Kettle AJ. Modeling the reactions of superoxide and myeloperoxidase in the neutrophil phagosome: implications for microbial killing. J Biol Chem. 2006;281(52):39860–9.
  • McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969;244(22):6049–55.
  • Klebanoff SJ. Myeloperoxidase. Proc Assoc Am Physicians. 1999;111(5):383–9.
  • Levine AP, Segal AW. The NADPH oxidase and microbial killing by neutrophils, with a particular emphasis on the proposed antimicrobial role of myeloperoxidase within the phagocytic vacuole. Microbiol Spect. 2016;4(4): doi:10.1128/microbiolspec.MCHD-0018-2015. DOA 3/2/2017.
  • Klebanoff SJ. Iodination of bacteria: a bactericidal mechanism. J Exp Med. 1967;126(6):1063–78.
  • Klebanoff SJ, Clark RA. Iodination by human polymorphonuclear leukocytes: a re-evaluation. J Lab Clin Med. 1977;89(3):675–86.
  • Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5.
  • Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, et al. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol. 2006;16(4):396–400.
  • Urban CF, Reichard U, Brinkmann V, Zychlinsky A. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol. 2006;8(4):668–76.
  • Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol. 2007;5(8):577–82.
  • Francke U, Hsieh CL, Foellmer BE, Lomax KJ, Malech HL, Leto TL. Genes for two autosomal recessive forms of chronic granulomatous disease assigned to 1q25 (NCF2) and 7q11.23 (NCF1). Am J Hum Genet. 1990;47(3):483–92.
  • Ganz T, Metcalf JA, Gallin JI, Boxer LA, Lehrer RI. Microbicidal/cytotoxic proteins of neutrophils are deficient in two disorders: Chediak-Higashi syndrome and "specific" granule deficiency. J Clin Invest. 1988;82(2):552–6.
  • Lomax KJ, Gallin JI, Rotrosen D, Raphael GD, Kaliner MA, Benz EJ, et al. Selective defect in myeloid cell lactoferrin gene expression in neutrophil specific granule deficiency. J Clin Invest. 1989;83(2):514–19.
  • Leiding JW. Neutrophil evolution and their diseases in humans. Front Immunol. 2017;8:1009.
  • Damiano VV, Kucich U, Murer E, Laudenslager N, Weinbaum G. Ultrastructural quantitation of peroxidase- and elastase-containing granules in human neutrophils. Am J Pathol. 1988;131(2):235–45.
  • Liou TG, Campbell EJ. Quantum proteolysis resulting from release of single granules by human neutrophils: a novel, nonoxidative mechanism of extracellular proteolytic activity. J Immunol. 1996;157(6):2624–31.
  • Kessenbrock K, Fröhlich L, Sixt M, Lämmermann T, Pfister H, Bateman A, et al. Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin. J Clin Invest. 2008;118(7):2438–47.
  • McGuinness AJ, Sapey E. Oxidative stress in COPD: sources, markers, and potential mechanisms. J Clin Med. 2017;6(2):21. https://doi.org/10.3390/jcm6020021. DOA 2/2/2017
  • Ricciardolo FLM, Caramori G, Ito K, Capelli A, Brun P, Abatangelo G, et al. Nitrosative stress in the bronchial mucosa of severe chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2005;116(5):1028–35.
  • Tosi MF, Zakem H, Berger M. Neutrophil elastase cleaves C3bi on opsonised pseudomonas as well as CR1 on neutrophils to create a functionally important opsonin receptor mismatch. J Clin INvest. 1990;86:300–8.
  • Smallman LA, Hill SL, Stockley RA. Reduction of ciliary beat frequency in vitro by sputum from patients with bronchiectasis: a serine proteinase effect. Thorax. 1984;39:663–7.
  • Hall CHT, Campbell EL, Colgan SP. Neutrophils as components of mucosal homeostasis. Cell Mol Gastroenterol Hepatol.. 2017;4(3):329–37.
  • Slater TW, Finkielsztein A, Mascarenhas LA, Mehl LC, Butin-Israeli V, Sumagin R. Neutrophil microparticles deliver active myeloperoxidase to injured mucosa to inhibit epithelial wound healing. J Immunol. 2017;198(7):2886–97.
  • Parmar JS, Mahadeva R, Reed BJ, Farahi N, Cadwallader KA, Keogan MT, et al. Polymers of α1-antitrypsin are chemotactic for human neutrophils. Am J Respir Cell Mol Biol. 2002;26(6):723–30.
  • Nakajoh M, Fukushima T, Suzuki K, Yamaya M, Nakayama K, Sekizawa K, et al. Retinoic acid inhibits elastase-induced injury in human lung epithelial cell lines. Am J Respir Cell Mol Biol. 2002;28(3):296–304.
  • Hubbard RC, Fells G, Gadek J, Pacholok S, Humes J, Crystal RG. Neutrophil accumulation in the lung in alpha 1-antitrypsin deficiency. Spontaneous release of leukotriene B4 by alveolar macrophages. J Clin Invest. 1991;88(3):891–7.
  • Sapey E, Stockley RA. Red, amber and green: the role of the lung in de-priming active systemic neutrophils. Thorax. 2014;69(7):606–8.
  • Rossaint J, Kühne K, Skupski J, Van Aken H, Looney MR, Hidalgo A, et al. Directed transport of neutrophil-derived extracellular vesicles enables platelet-mediated innate immune response. Nat Commun. 2016;7:13464.
  • Sengelov H, Kjeldsen L, Borregaard N. Control of exocytosis in early neutrophil activation. J Immunol. 1993;150(4):1535–43.
  • Yost CC, Denis MM, Lindemann S, Rubner FJ, Marathe GK, Buerke M, et al. Activated polymorphonuclear leukocytes rapidly synthesize retinoic acid receptor-alpha: a mechanism for translational control of transcriptional events. J Exp Med. 2004;200(5):671.
  • Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, et al. Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med. 2005;201(1):105–15.
  • Buckley CD, Ross EA, McGettrick HM, Osborne CE, Haworth O, Schmutz C, et al. Identification of a phenotypically and functionally distinct population of long-lived neutrophils in a model of reverse endothelial migration. J Leukoc Biol. 2006;79(2):303–11.
  • Sagiv Jitka Y, Michaeli J, Assi S, Mishalian I, Kisos H, Levy L, et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 2015;10(4):562–73.
  • Pillay J, Kamp VM, van Hoffen E, Visser T, Tak T, Lammers JW, et al. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1. J Clin Invest. 2012;122(1):327–36.
  • Yang K-Y, Arcaroli JJ, Abraham E. Early alterations in neutrophil activation are associated with outcome in acute lung injury. Am J Respir Crit Care Med. 2003;167(11):1567–74.
  • Bekes EM, Schweighofer B, Kupriyanova TA, Zajac E, Ardi VC, Quigley JP, et al. Tumor-recruited neutrophils and neutrophil TIMP-free MMP-9 regulate coordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasation. Am J Pathol. 2011;179(1525–2191 (Electronic)):1455–70.
  • Christoffersson G, Vågesjö E, Vandooren J, Lidén M, Massena S, Reinert RB, et al. VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue. Blood. 2012;120(23):4653.
  • Massena S, Christoffersson G, Vågesjö E, Seignez C, Gustafsson K, Binet F, et al. Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans. Blood. 2015;126(17):2016.
  • Blázquez-Prieto J, López-Alonso I, Amado-Rodríguez L, et al. Impaired lung repair during neutropenia can be reverted by matrix metalloproteinase-9. Thorax. 2018;73:321–330.
  • Brightling CE, Monteiro W, Ward R, Parker D, Morgan MDL, Wardlaw AJ, et al. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2000;356(9240):1480–5.
  • Thompson AB, Daughton D, Robbins RA, Ghafouri MA, Oehlerking M, Rennard SI. Intraluminal airway inflammation in chronic bronchitis. Characterization and correlation with clinical parameters. Am Rev Respir Dis. 1989;140(6):1527–37.
  • Pilette C, Colinet B, Kiss R, Andre S, Kaltner H, Gabius HJ, et al. Increased galectin-3 expression and intra-epithelial neutrophils in small airways in severe COPD. Eur Respir J. 2007;29(5):914–22.
  • Donaldson GC, Seemungal TA, Patel IS, Bhowmik A, Wilkinson TM, Hurst JR, et al. Airway and systemic inflammation and decline in lung function in patients with COPD. Chest. 2005;128(4):1995–2004.
  • Parr DG, White AJ, Bayley DL, Guest PJ, Stockley RA. Inflammation in sputum relates to progression of disease in subjects with COPD: a prospective descriptive study. Respir Res. 2006;7:136.
  • Di Stefano A, Capelli A, Lusuardi M, Balbo P, Vecchio C, Maestrelli P, et al. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med. 1998;158(4):1277–85.
  • O'Shaughnessy TC, Ansari TW, Barnes NC, Jeffery PK. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8+ T lymphocytes with FEV1. Am J Respir Crit Care Med. 1997;155(3):852–7.
  • Stoller JK, Aboussouan LS. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2012;185(3):246–59.
  • Balbi B, Ferrarotti I, Miravitlles M. Efficacy of augmentation therapy for emphysema associated with alpha1-antitrypsin deficiency: enough is enough. Eur Respir J. 2016;47(1):35–8.
  • Stockley RA, Miravitlles M, Vogelmeier C. Augmentation therapy for alpha-1 antitrypsin deficiency: towards a personalised approach. Orphanet J Rare Dis. 2013;8:149.
  • Shamamian P, Schwartz Jess D, Pocock Ben JZ, Monea S, Whiting D, Marcus Stuart G, et al. Activation of progelatinase A (MMP‐2) by neutrophil elastase, cathepsin G, and proteinase‐3: A role for inflammatory cells in tumor invasion and angiogenesis.J Cell Physiol Biochem. 2001;189(2):197–206.
  • Demedts IK, Morel-Montero A, Lebecque S, Pacheco Y, Cataldo D, Joos GF, et al. Elevated MMP-12 protein levels in induced sputum from patients with COPD. Thorax. 2006;61(3):196.
  • Fahy JV, Dickey BF. Airway mucus function and dysfunction. N Engl J Med. 2010;363(23):2233–47.
  • Leopold PL, O'Mahony MJ, Lian XJ, Tilley AE, Harvey BG, Crystal RG. Smoking is associated with shortened airway cilia. PLoS one. 2009;4(12):e8157.
  • Tamashiro E, Xiong G, Anselmo-Lima WT, Kreindler JL, Palmer JN, Cohen NA. Cigarette smoke exposure impairs respiratory epithelial ciliogenesis. Am J Rhinol Allergy. 2009;23(2):117–22.
  • Gill N, Ferreira RBR, Antunes LCM, Willing BP, Sekirov I, Al-Zahrani F, et al. Neutrophil elastase alters the murine gut microbiota resulting in enhanced Salmonella colonization. PLoS ONE. 2012;7(11):e49646.
  • Margaroli C, Tirouvanziam R. Neutrophil plasticity enables the development of pathological microenvironments: implications for cystic fibrosis airway disease.Mol Cell Pediatr. 2016;3:38.
  • Dicker AJ, Crichton ML, Pumphrey EG, Cassidy AJ, Suarez-Cuartin G, Sibila O, et al. Neutrophil extracellular traps are associated with disease severity and microbiota diversity in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol Pract. 2018;141(1):117–27.
  • Carter RI, Ungurs MJ, Mumford RA, Stockley RA. Aα-Val360: a marker of neutrophil elastase and COPD disease activity. Eur Respir J. 2012;41(1):31.
  • Keatings VM, Barnes PJ. Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma, and normal subjects. Am J Respir Crit Care Med. 1997;155(2):449–53.
  • Subramanian DR, Jenkins L, Edgar R, Quraishi N, Stockley RA, Parr DG. Assessment of pulmonary neutrophilic inflammation in emphysema by quantitative positron emission tomography. Am J Respir Crit Care Med. 2012;186(11):1125–32.
  • Barnes PJ. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2016;138(1):16–27.
  • Abboud RT, Vimalanathan S. Pathogenesis of COPD. Part I. The role of protease-antiprotease imbalance in emphysema. Int J Tuberc Lung Dis. 2008;12(4):361–7.
  • McDonough JE, Yuan R, Suzuki M, Seyednejad N, Elliott WM, Sanchez PG, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med. 2011;365(17):1567–75.
  • Berger P, Laurent F, Begueret H, Perot V, Rouiller R, Raherison C, et al. Structure and function of small airways in smokers: relationship between air trapping at CT and airway inflammation. Radiology. 2003;228(1):85–94.
  • Sapey E, Stockley JA, Greenwood H, Ahmad A, Bayley D, Lord JM, et al. Behavioral and structural differences in migrating peripheral neutrophils from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;183(9):1176–86.
  • Burnett D, Chamba A, Hill SL, Stockley RA. Neutrophils from subjects with chronic obstructive lung disease show enhanced chemotaxis and extracellular proteolysis. Lancet. 1987;2(8567):1043–6.
  • Prieto A, Reyes E, Bernstein ED, Martinez B, Monserrat J, Izquierdo JL, et al. Defective natural killer and phagocytic activities in chronic obstructive pulmonary disease are restored by glycophosphopeptical (inmunoferón) Am J Respir Crit Care Med. 2001;163(7):1578–83.
  • Shanmugam L, Ravinder SS, Johnson P, Padmavathi R, Rajagopalan B, Kindo AJ. Assessment of phagocytic activity of neutrophils in chronic obstructive pulmonary disease. Lung India. 2015;32(5):437–40.
  • Venge P, Rak S, Steinholtz L, Hakansson L, Lindblad G. Neutrophil function in chronic bronchitis. Eur Respir J. 1991;4(5):536–43.
  • Muns G, Rubinstein I, Bergmann KC. Phagocytosis and oxidative burst of blood phagocytes in chronic obstructive airway disease. Scand J Infect Dis. 1995;27(4):369–73.
  • Noguera A, Batle S, Miralles C, Iglesias J, Busquets X, MacNee W, et al. Enhanced neutrophil response in chronic obstructive pulmonary disease. Thorax. 2001;56(6):432–7.
  • Rahman I. The role of oxidative stress in the pathogenesis of COPD: implications for therapy.Treatment Respir Med. 2005;4(3):175–200.
  • Grabcanovic-Musija F, Obermayer A, Stoiber W, Krautgartner WD, Steinbacher P, Winterberg N, et al. Neutrophil extracellular trap (NET) formation characterises stable and exacerbated COPD and correlates with airflow limitation. Respir Res. 2015;16:59.
  • Obermayer A, Stoiber W, Krautgartner WD, Klappacher M, Kofler B, Steinbacher P, et al. New aspects on the structure of neutrophil extracellular traps from chronic obstructive pulmonary disease and in vitro generation. PLoS one. 2014;9(5):e97784.
  • Adib-Conquy M, Pedron T, Petit-Bertron A-F, Tabary O, Corvol H, Jacquot J, et al. Neutrophils in cystic fibrosis display a distinct gene expression pattern. Molec Med. 2008;14(1–2):36–44.
  • Loi ALT, Hoonhorst S, van Aalst C, Langereis J, Kamp V, Sluis-Eising S, et al. Proteomic profiling of peripheral blood neutrophils identifies two inflammatory phenotypes in stable COPD patients. Respir Res. 2017;18(1):100.
  • Neofytou E, Tzortzaki EG, Chatziantoniou A, Siafakas NM. DNA damage due to oxidative stress in chronic obstructive pulmonary disease (COPD). Int J Mol Sci. 2012;13(12):16853–64.
  • Kato T, Suzuki K, Okada S, Kamiyama H, Maeda T, Saito M, et al. Aberrant methylation of PSD disturbs Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis in ulcerative colitis-associated carcinogenesis. Int J Oncol. 2012;40(4):942–50.
  • Coit P, Yalavarthi S, Ognenovski M, Zhao W, Hasni S, Wren JD, et al. Epigenome profiling reveals significant DNA demethylation of interferon signature genes in lupus neutrophils.J Autoimmun. 2015;58:59–66.
  • Gallagher KA, Joshi A, Carson WF, Schaller M, Allen R, Mukerjee S, et al. Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes. Diabetes. 2015;64(4):1420–30.
  • Hurst JR, Bafadhel M, Bolton CE, Quint JK, Sapey E, Wilkinson TMA. COPD exacerbations: transforming outcomes through research. Lancet Respir Med. 2018;6(3):172–4.
  • Qiu Y, Zhu J, Bandi V, Atmar RL, Hattotuwa K, Guntupalli KK, et al. Biopsy neutrophilia, neutrophil chemokine and receptor gene expression in severe exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003;168(8):968–75.
  • Pouwels SD, van Geffen WH, Jonker MR, Kerstjens HA, Nawijn MC, Heijink IH. Increased neutrophil expression of pattern recognition receptors during COPD exacerbations. Respirology. 2017;22(2):401–4.
  • Thulborn SJ, Akram N, Mistry V, Brightling CE, Moffitt K, Ribeiro D, et al. S45 Evaluating the sensitivity and specificity of active neutrophil elastase as a biomarker for bacterial infection in subjects with copd. Thorax. 2016;71(Suppl 3):A28.
  • Vaitkus M, Lavinskiene S, Bieksiene K, Jeroch J, Sakalauskas R. Analysis of reactive oxygen species in sputum neutrophils during acute exacerbation of COPD. Eur Respir J. 2012;40(Suppl 56):P793.
  • Barnes PJ. Alveolar macrophages as orchestrators of COPD. COPD. 2004;1(1):59–70.
  • Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645–53.
  • Kirkham PA, Caramori G, Casolari P, Papi AA, Edwards M, Shamji B, et al. Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;184(7):796–802.
  • Brightling CE, Monteiro W, Ward R, Parker D, Morgan MD, Wardlaw AJ, et al. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2000;356(9240):1480–5.
  • Maclay JD, McAllister DA, Johnston S, Raftis J, McGuinnes C, Deans A, et al. Increased platelet activation in patients with stable and acute exacerbation of COPD. Thorax. 2011;66(9):769.
  • Taylor AE, Finney-Hayward TK, Quint JK, Thomas CMR, Tudhope SJ, Wedzicha JA, et al. Defective macrophage phagocytosis of bacteria in COPD. Eur Respir J. 2010;35(5):1039.
  • Freeman CM, Martinez FJ, Han MK, Washko GR, McCubbrey AL, Chensue SW, et al. Lung CD8+ T cells in COPD have increased expression of bacterial TLRs. Respir Res. 2013;14(1):13.
  • Hodge S, Hodge G, Scicchitano R, Reynolds PN, Holmes M. Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunol Cell Biol. 2003;81(4):289–96.
  • Togo S, Holz O, Liu X, Sugiura H, Kamio K, Wang X, et al. Lung fibroblast repair functions in patients with chronic obstructive pulmonary disease are altered by multiple mechanisms. Am J Respir Crit Care Med. 2008;178(3):248–60.
  • Polverino F, Celli BR, Owen CA. COPD as an endothelial disorder: endothelial injury linking lesions in the lungs and other organs? (2017 Grover Conference Series). Pulm Circ. 2018;8(1):2045894018758528.
  • Caramori G, Romagnoli M, Casolari P, Bellettato C, Casoni G, Boschetto P, et al. Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations. Thorax. 2003;58(4):348–51.
  • Calverley PA, Anderson JA, Celli BC, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. NEJM. 2007;356:775–89.
  • Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011;163(1):53–67.
  • Martinez FJ, Rabe KF, Sethi S, Pizzichini E, McIvor A, Anzueto A, et al. Effect of roflumilast and inhaled corticosteroid/long-acting β2-agonist on chronic obstructive pulmonary disease exacerbations (RE2SPOND). A randomized clinical trial. Am J Respir Crit Care Med. 2016;194(5):559–67.
  • Wedzicha JA, Calverley PMA, Rabe KF. Roflumilast: a review of its use in the treatment of COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:81–90.
  • Gompertz S, Stockley RA. A randomised controlled trial of a Leukotriene synthesis inhibitor in patients with COPD. Chest. 2002;112:289–94.
  • Rennard SI, Dale DC, Donohue JF, Kanniess F, Magnussen H, Sutherland ER, et al. CXCR2 antagonist MK-7123. A phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191(9):1001–11.
  • Bewley MA, Belchamber KB, Chana KK, Budd RC, Donaldson G, Wedzicha JA, et al. Differential effects of p38, MAPK, PI3K or Rho kinase inhibitors on bacterial phagocytosis and efferocytosis by macrophages in COPD. PLoS One. 2016;11(9):e0163139.
  • Kim D, Haynes CL. The role of p38 MAPK in neutrophil functions: single cell chemotaxis and surface marker expression. Analyst. Eur Respir J. 2008 Jan;31(1):62–9.
  • Renda T, Baraldo S, Pelaia G, Bazzan E, Turato G, Papi A, et al. Increased activation of p38 MAPK in COPD. Eur Respir J. 2008;31(1):62.
  • Fisk M, Cheriyan J, Mohan D, Forman J, Mäki-Petäjä KM, McEniery CM, et al. The p38 mitogen activated protein kinase inhibitor losmapimod in chronic obstructive pulmonary disease patients with systemic inflammation, stratified by fibrinogen: a randomised double-blind placebo-controlled trial. PLOS ONE. 2018;13(3):e0194197.
  • Watz H, Barnacle H, Hartley BF, Chan R. Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial Watz, Henrik et al. The Lancet Respiratory Medicine, Volume 2, Issue 1, 63–72.
  • Lomas David A, Lipson David A, Miller Bruce E, Willits L, Keene O, Barnacle H, et al. An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J Clin Pharmacol Toxicol. 2013;52(3):416–24.
  • Dahl R, Titlestad I, Lindqvist A, Wielders P, Wray H, Wang M, et al. Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: A randomised controlled trial. Pulm. Pharmacol. Ther. 2012;25(2):169–77.
  • Sapey E, Greenwood H, Walton G, Mann E, Love A, Aaronson N, et al. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood. 2014;123(2):239–48.
  • Sriskantharajah S, Hamblin N, Worsley S, Calver Andrew R, Hessel Edith M, Amour A. Targeting phosphoinositide 3‐kinase δ for the treatment of respiratory diseases. Ann N Y Acad Sci. 2013;1280(1):35–9.
  • Sapey E, Patel JM, Greenwood HL, Walton GM, Hazeldine J, Sadhra C, et al. Pulmonary infections in the elderly lead to impaired neutrophil targeting, which is improved by simvastatin. Am J Respir Crit Care Med. 2017;196(10):1325–36.
  • Stockley JA, Walton GM, Lord JM, Sapey E. Aberrant neutrophil functions in stable chronic obstructive pulmonary disease: the neutrophil as an immunotherapeutic target. Int Immunopharmacol. 2013;17(4):1211–17.
  • Park DW, Jiang S, Tadie J-M, Stigler WS, Gao Y, Deshane J, et al. Activation of AMPK enhances neutrophil chemotaxis and bacterial killing. Molec Med. 2013;19(1):387–98.
  • Bishwakarma R, Zhang W, Lin Y-L, Kuo Y-F, Cardenas VJ, Sharma G. Metformin use and health care utilization in patients with coexisting chronic obstructive pulmonary disease and diabetes mellitus. Int J Chron Obstruct Pulmon Dis. 2018;13:793–800.
  • GOLD. The global strategy for the diagnosis, management and prevention of COPD, global initiative for chronic obstructive lung disease (GOLD) 2017. Available from: http://goldcopdorg. 2017;DOA 11.11.2017.
  • Nordenfelt P, Tapper H. Phagosome dynamics during phagocytosis by neutrophils. J Leukoc Biol. 2011;90(2):271–84.
  • Uriarte SM, Powell DW, Luerman GC, Merchant ML, Cummins TD, Jog NR, et al. Comparison of proteins expressed on secretory vesicle membranes and plasma membranes of human neutrophils. J Immunol. 2008;180(8):5575.
  • Borregaard N, Cowland JB. Granules of the human neutrophilic polymorphonuclear leukocyte. Blood. 1997;89:350321.

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