Chronic Obstructive Pulmonary Disease: Epidemiology, Biomarkers, and Paving the Way to Lung Cancer

Klára Szalontai, Nikolett Gémes, József Furák, Tünde Varga, Patrícia Neuperger, József Á Balog, László G Puskás, Gábor J Szebeni, Klára Szalontai, Nikolett Gémes, József Furák, Tünde Varga, Patrícia Neuperger, József Á Balog, László G Puskás, Gábor J Szebeni

Abstract

Chronic obstructive pulmonary disease (COPD), the frequently fatal pathology of the respiratory tract, accounts for half a billion cases globally. COPD manifests via chronic inflammatory response to irritants, frequently to tobacco smoke. The progression of COPD from early onset to advanced disease leads to the loss of the alveolar wall, pulmonary hypertension, and fibrosis of the respiratory epithelium. Here, we focus on the epidemiology, progression, and biomarkers of COPD with a particular connection to lung cancer. Dissecting the cellular and molecular players in the progression of the disease, we aim to shed light on the role of smoking, which is responsible for the disease, or at least for the more severe symptoms and worse patient outcomes. We summarize the inflammatory conditions, as well as the role of EMT and fibroblasts in establishing a cancer-prone microenvironment, i.e., the soil for 'COPD-derived' lung cancer. We highlight that the major health problem of COPD can be alleviated via smoking cessation, early diagnosis, and abandonment of the usage of biomass fuels on a global basis.

Keywords: COPD; chronic airway inflammation; lung cancer; smoking.

Conflict of interest statement

The authors declare no conflict of interest. László G. Puskás is the owner and CEO of Avicor Ltd. Gabor J. Szebeni is lead biologist employee at Cs-Smartlab Devices Ltd.

Figures

Figure 1
Figure 1
Signaling pathways and inflammatory mediators sustaining a cancer-prone microenvironment in COPD. See explanation in the text.

References

    1. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2020. CA Cancer J. Clin. 2020;70:7–30. doi: 10.3322/caac.21590.
    1. Mouronte-Roibas C., Leiro-Fernandez V., Fernandez-Villar A., Botana-Rial M., Ramos-Hernandez C., Ruano-Ravina A. COPD, emphysema and the onset of lung cancer. A systematic review. Cancer Lett. 2016;382:240–244. doi: 10.1016/j.canlet.2016.09.002.
    1. Bogos K., Kiss Z., Galffy G., Tamasi L., Ostoros G., Muller V., Urban L., Bittner N., Sarosi V., Vastag A., et al. Lung Cancer in Hungary. J. Thorac. Oncol. 2020;15:692–699. doi: 10.1016/j.jtho.2019.11.001.
    1. Barta J.A., Powell C.A., Wisnivesky J.P. Global Epidemiology of Lung Cancer. Ann. Glob Health. 2019;85 doi: 10.5334/aogh.2419.
    1. Lortet-Tieulent J., Soerjomataram I., Ferlay J., Rutherford M., Weiderpass E., Bray F. International trends in lung cancer incidence by histological subtype: Adenocarcinoma stabilizing in men but still increasing in women. Lung Cancer. 2014;84:13–22. doi: 10.1016/j.lungcan.2014.01.009.
    1. Travis W.D. Pathology of lung cancer. Clin. Chest Med. 2011;32:669–692. doi: 10.1016/j.ccm.2011.08.005.
    1. Peters E.N., Warren G.W., Sloan J.A., Marshall J.R. Tobacco assessment in completed lung cancer treatment trials. Cancer. 2016;122:3260–3262. doi: 10.1002/cncr.30223.
    1. Gomes M., Teixeira A.L., Coelho A., Araujo A., Medeiros R. The role of inflammation in lung cancer. Adv. Exp. Med. Biol. 2014;816:1–23. doi: 10.1007/978-3-0348-0837-8_1.
    1. Goldstraw P., Chansky K., Crowley J., Rami-Porta R., Asamura H., Eberhardt W.E., Nicholson A.G., Groome P., Mitchell A., Bolejack V., et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J. Thorac. Oncol. 2016;11:39–51. doi: 10.1016/j.jtho.2015.09.009.
    1. Yoshida T., Tuder R.M. Pathobiology of cigarette smoke-induced chronic obstructive pulmonary disease. Physiol. Rev. 2007;87:1047–1082. doi: 10.1152/physrev.00048.2006.
    1. Almagro P., Martinez-Camblor P., Soriano J.B., Marin J.M., Alfageme I., Casanova C., Esteban C., Soler-Cataluna J.J., de-Torres J.P., Celli B.R., et al. Finding the best thresholds of FEV1 and dyspnea to predict 5-year survival in COPD patients: The COCOMICS study. PLoS ONE. 2014;9:e89866. doi: 10.1371/journal.pone.0089866.
    1. WHO The Top 10 Causes of Death. [(accessed on 28 June 2021)];Published by World Health Organization (WHO) 2020 Dec 9; Available online: .
    1. Laniado-Laborin R. Smoking and chronic obstructive pulmonary disease (COPD). Parallel epidemics of the 21 century. Int. J. Environ. Res. Public Health. 2009;6:209–224. doi: 10.3390/ijerph6010209.
    1. Durham A.L., Adcock I.M. The relationship between COPD and lung cancer. Lung Cancer. 2015;90:121–127. doi: 10.1016/j.lungcan.2015.08.017.
    1. Proctor R.N. The history of the discovery of the cigarette-lung cancer link: Evidentiary traditions, corporate denial, global toll. Tob. Control. 2012;21:87–91. doi: 10.1136/tobaccocontrol-2011-050338.
    1. Oh J.Y., Sin D.D. Lung inflammation in COPD: Why does it matter? F1000 Med. Rep. 2012;4:23. doi: 10.3410/M4-23.
    1. Raviv S., Hawkins K.A., DeCamp M.M., Jr., Kalhan R. Lung cancer in chronic obstructive pulmonary disease: Enhancing surgical options and outcomes. Am. J. Respir Crit. Care Med. 2011;183:1138–1146. doi: 10.1164/rccm.201008-1274CI.
    1. Balkwill F., Mantovani A. Inflammation and cancer: Back to Virchow? Lancet. 2001;357:539–545. doi: 10.1016/S0140-6736(00)04046-0.
    1. Hanahan D., Weinberg R.A. Hallmarks of cancer: The next generation. Cell. 2011;144:646–674. doi: 10.1016/j.cell.2011.02.013.
    1. Szebeni G.J., Vizler C., Kitajka K., Puskas L.G. Inflammation and Cancer: Extra- and Intracellular Determinants of Tumor-Associated Macrophages as Tumor Promoters. Mediators Inflamm. 2017;2017:9294018. doi: 10.1155/2017/9294018.
    1. Dunn G.P., Bruce A.T., Ikeda H., Old L.J., Schreiber R.D. Cancer immunoediting: From immunosurveillance to tumor escape. Nat. Immunol. 2002;3:991–998. doi: 10.1038/ni1102-991.
    1. Schreiber R.D., Old L.J., Smyth M.J. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–1570. doi: 10.1126/science.1203486.
    1. Bremnes R.M., Al-Shibli K., Donnem T., Sirera R., Al-Saad S., Andersen S., Stenvold H., Camps C., Busund L.T. The role of tumor-infiltrating immune cells and chronic inflammation at the tumor site on cancer development, progression, and prognosis: Emphasis on non-small cell lung cancer. J. Thorac. Oncol. 2011;6:824–833. doi: 10.1097/JTO.0b013e3182037b76.
    1. Dunn G.P., Old L.J., Schreiber R.D. The three Es of cancer immunoediting. Annu. Rev. Immunol. 2004;22:329–360. doi: 10.1146/annurev.immunol.22.012703.104803.
    1. Shankaran V., Ikeda H., Bruce A.T., White J.M., Swanson P.E., Old L.J., Schreiber R.D. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410:1107–1111. doi: 10.1038/35074122.
    1. Postmus P.E., Kerr K.M., Oudkerk M., Senan S., Waller D.A., Vansteenkiste J., Escriu C., Peters S., Committee E.G. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2017;28:iv1–iv21. doi: 10.1093/annonc/mdx222.
    1. Fruh M., De Ruysscher D., Popat S., Crino L., Peters S., Felip E., Group E.G.W. Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2013;24(Suppl. 6):vi99–vi105. doi: 10.1093/annonc/mdt178.
    1. Planchard D., Popat S., Kerr K., Novello S., Smit E.F., Faivre-Finn C., Mok T.S., Reck M., Van Schil P.E., Hellmann M.D., et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2018;29:iv192–iv237. doi: 10.1093/annonc/mdy275.
    1. Xie M., Liu X., Cao X., Guo M., Li X. Trends in prevalence and incidence of chronic respiratory diseases from 1990 to 2017. Respir Res. 2020;21:49. doi: 10.1186/s12931-020-1291-8.
    1. GBD Chronic Respiratory Disease Collaborators Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir. Med. 2020;8:585–596. doi: 10.1016/S2213-2600(20)30105-3.
    1. Agarwal A.K., Raja A., Brown B.D. StatPearls. StatPearls Publishing; Treasure Island, FL, USA: 2020. [(accessed on 28 June 2021)]. Chronic Obstructive Pulmonary Disease. Available online:
    1. Atsou K., Chouaid C., Hejblum G. Variability of the chronic obstructive pulmonary disease key epidemiological data in Europe: Systematic review. BMC Med. 2011;9:7. doi: 10.1186/1741-7015-9-7.
    1. Rycroft C.E., Heyes A., Lanza L., Becker K. Epidemiology of chronic obstructive pulmonary disease: A literature review. Int. J. Chron. Obstruct Pulmon Dis. 2012;7:457–494. doi: 10.2147/COPD.S32330.
    1. Halbert R.J., Natoli J.L., Gano A., Badamgarav E., Buist A.S., Mannino D.M. Global burden of COPD: Systematic review and meta-analysis. Eur. Respir. J. 2006;28:523–532. doi: 10.1183/09031936.06.00124605.
    1. Terzikhan N., Verhamme K.M., Hofman A., Stricker B.H., Brusselle G.G., Lahousse L. Prevalence and incidence of COPD in smokers and non-smokers: The Rotterdam Study. Eur. J. Epidemiol. 2016;31:785–792. doi: 10.1007/s10654-016-0132-z.
    1. Raherison C., Girodet P.O. Epidemiology of COPD. Eur. Respir. Rev. 2009;18:213–221. doi: 10.1183/09059180.00003609.
    1. Niu S.R., Yang G.H., Chen Z.M., Wang J.L., Wang G.H., He X.Z., Schoepff H., Boreham J., Pan H.C., Peto R. Emerging tobacco hazards in China: 2. Early mortality results from a prospective study. BMJ. 1998;317:1423–1424. doi: 10.1136/bmj.317.7170.1423.
    1. Mannino D.M., Buist A.S., Petty T.L., Enright P.L., Redd S.C. Lung function and mortality in the United States: Data from the First National Health and Nutrition Examination Survey follow up study. Thorax. 2003;58:388–393. doi: 10.1136/thorax.58.5.388.
    1. Marsh S., Aldington S., Shirtcliffe P., Weatherall M., Beasley R. Smoking and COPD: What really are the risks? Eur. Respir. J. 2006;28:883–884. doi: 10.1183/09031936.06.00074806.
    1. Salvi S.S., Barnes P.J. Chronic obstructive pulmonary disease in non-smokers. Lancet. 2009;374:733–743. doi: 10.1016/S0140-6736(09)61303-9.
    1. Salvi S., Barnes P.J. Is exposure to biomass smoke the biggest risk factor for COPD globally? Chest. 2010;138:3–6. doi: 10.1378/chest.10-0645.
    1. Zeng G., Sun B., Zhong N. Non-smoking-related chronic obstructive pulmonary disease: A neglected entity? Respirology. 2012;17:908–912. doi: 10.1111/j.1440-1843.2012.02152.x.
    1. Postma D.S., Bush A., van den Berge M. Risk factors and early origins of chronic obstructive pulmonary disease. Lancet. 2015;385:899–909. doi: 10.1016/S0140-6736(14)60446-3.
    1. Fullerton D.G., Bruce N., Gordon S.B. Indoor air pollution from biomass fuel smoke is a major health concern in the developing world. Trans. R Soc. Trop. Med. Hyg. 2008;102:843–851. doi: 10.1016/j.trstmh.2008.05.028.
    1. Ingebrigtsen T., Thomsen S.F., Vestbo J., van der Sluis S., Kyvik K.O., Silverman E.K., Svartengren M., Backer V. Genetic influences on Chronic Obstructive Pulmonary Disease-A twin study. Respir. Med. 2010;104:1890–1895. doi: 10.1016/j.rmed.2010.05.004.
    1. Zhou J.J., Cho M.H., Castaldi P.J., Hersh C.P., Silverman E.K., Laird N.M. Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers. Am. J. Respir. Crit. Care Med. 2013;188:941–947. doi: 10.1164/rccm.201302-0263OC.
    1. Pillai S.G., Ge D., Zhu G., Kong X., Shianna K.V., Need A.C., Feng S., Hersh C.P., Bakke P., Gulsvik A., et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): Identification of two major susceptibility loci. PLoS Genet. 2009;5:e1000421. doi: 10.1371/journal.pgen.1000421.
    1. Wilk J.B., Chen T.H., Gottlieb D.J., Walter R.E., Nagle M.W., Brandler B.J., Myers R.H., Borecki I.B., Silverman E.K., Weiss S.T., et al. A genome-wide association study of pulmonary function measures in the Framingham Heart Study. PLoS Genet. 2009;5:e1000429. doi: 10.1371/journal.pgen.1000429.
    1. Cho M.H., Boutaoui N., Klanderman B.J., Sylvia J.S., Ziniti J.P., Hersh C.P., DeMeo D.L., Hunninghake G.M., Litonjua A.A., Sparrow D., et al. Variants in FAM13A are associated with chronic obstructive pulmonary disease. Nat. Genet. 2010;42:200–202. doi: 10.1038/ng.535.
    1. Cho M.H., Castaldi P.J., Wan E.S., Siedlinski M., Hersh C.P., Demeo D.L., Himes B.E., Sylvia J.S., Klanderman B.J., Ziniti J.P., et al. A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13. Hum. Mol. Genet. 2012;21:947–957. doi: 10.1093/hmg/ddr524.
    1. Stoller J.K., Aboussouan L.S. Alpha1-antitrypsin deficiency. Lancet. 2005;365:2225–2236. doi: 10.1016/S0140-6736(05)66781-5.
    1. Flenley D.C. Chronic obstructive pulmonary disease. Dis. Mon. 1988;34:537–599. doi: 10.1016/0011-5029(88)90015-6.
    1. Kim V., Crapo J., Zhao H., Jones P.W., Silverman E.K., Comellas A., Make B.J., Criner G.J., Investigators C.O. Comparison between an alternative and the classic definition of chronic bronchitis in COPDGene. Ann. Am. Thorac. Soc. 2015;12:332–339. doi: 10.1513/AnnalsATS.201411-518OC.
    1. Han M.K., Agusti A., Calverley P.M., Celli B.R., Criner G., Curtis J.L., Fabbri L.M., Goldin J.G., Jones P.W., Macnee W., et al. Chronic obstructive pulmonary disease phenotypes: The future of COPD. Am. J. Respir. Crit. Care Med. 2010;182:598–604. doi: 10.1164/rccm.200912-1843CC.
    1. Soler-Cataluna J.J., Cosio B., Izquierdo J.L., Lopez-Campos J.L., Marin J.M., Aguero R., Baloira A., Carrizo S., Esteban C., Galdiz J.B., et al. Consensus document on the overlap phenotype COPD-asthma in COPD. Arch. Bronconeumol. 2012;48:331–337. doi: 10.1016/j.arbr.2012.06.017.
    1. Halpin D.M., Decramer M., Celli B., Kesten S., Liu D., Tashkin D.P. Exacerbation frequency and course of COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 2012;7:653–661. doi: 10.2147/COPD.S34186.
    1. Fishman A., Martinez F., Naunheim K., Piantadosi S., Wise R., Ries A., Weinmann G., Wood D.E., National Emphysema Treatment Trial Research Group A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N. Engl. J. Med. 2003;348:2059–2073. doi: 10.1056/NEJMoa030287.
    1. Pinto L.M., Alghamdi M., Benedetti A., Zaihra T., Landry T., Bourbeau J. Derivation and validation of clinical phenotypes for COPD: A systematic review. Respir. Res. 2015;16:50. doi: 10.1186/s12931-015-0208-4.
    1. Koskela J., Kilpelainen M., Kupiainen H., Mazur W., Sintonen H., Boezen M., Lindqvist A., Postma D., Laitinen T. Co-morbidities are the key nominators of the health related quality of life in mild and moderate COPD. BMC Pulm. Med. 2014;14:102. doi: 10.1186/1471-2466-14-102.
    1. Mirza S., Benzo R. Chronic Obstructive Pulmonary Disease Phenotypes: Implications for Care. Mayo Clin. Proc. 2017;92:1104–1112. doi: 10.1016/j.mayocp.2017.03.020.
    1. Lahousse L., Ziere G., Verlinden V.J., Zillikens M.C., Uitterlinden A.G., Rivadeneira F., Tiemeier H., Joos G.F., Hofman A., Ikram M.A., et al. Risk of Frailty in Elderly With COPD: A Population-Based Study. J. Gerontol. A Biol. Sci. Med. Sci. 2016;71:689–695. doi: 10.1093/gerona/glv154.
    1. Mittal N., Raj R., Islam E.A., Nugent K. The Frequency of Frailty in Ambulatory Patients With Chronic Lung Diseases. J. Prim. Care Community Health. 2016;7:10–15. doi: 10.1177/2150131915603202.
    1. Laurin C., Moullec G., Bacon S.L., Lavoie K.L. Impact of anxiety and depression on chronic obstructive pulmonary disease exacerbation risk. Am. J. Respir. Crit. Care Med. 2012;185:918–923. doi: 10.1164/rccm.201105-0939PP.
    1. Van Buul A.R., Kasteleyn M.J., Chavannes N.H., Taube C. Association between morning symptoms and physical activity in COPD: A systematic review. Eur. Respir. Rev. 2017;26 doi: 10.1183/16000617.0033-2016.
    1. Fazleen A., Wilkinson T. Early COPD: Current evidence for diagnosis and management. Ther. Adv. Respir. Dis. 2020;14 doi: 10.1177/1753466620942128.
    1. Halpin D.M.G., Criner G.J., Papi A., Singh D., Anzueto A., Martinez F.J., Agusti A.A., Vogelmeier C.F. Global Initiative for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease. The 2020 GOLD Science Committee Report on COVID-19 and Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2021;203:24–36. doi: 10.1164/rccm.202009-3533SO.
    1. Bhatta L., Leivseth L., Mai X.M., Henriksen A.H., Carslake D., Chen Y., Langhammer A., Brumpton B.M. GOLD Classifications, COPD Hospitalization, and All-Cause Mortality in Chronic Obstructive Pulmonary Disease: The HUNT Study. Int. J. Chron. Obstruct. Pulmon. Dis. 2020;15:225–233. doi: 10.2147/COPD.S228958.
    1. Besa V., Teschler H., Kurth I., Khan A.M., Zarogoulidis P., Baumbach J.I., Sommerwerck U., Freitag L., Darwiche K. Exhaled volatile organic compounds discriminate patients with chronic obstructive pulmonary disease from healthy subjects. Int. J. Chron. Obstruct. Pulmon. Dis. 2015;10:399–406. doi: 10.2147/COPD.S76212.
    1. Harvey B.G., Strulovici-Barel Y., Kaner R.J., Sanders A., Vincent T.L., Mezey J.G., Crystal R.G. Risk of COPD with obstruction in active smokers with normal spirometry and reduced diffusion capacity. Eur. Respir. J. 2015;46:1589–1597. doi: 10.1183/13993003.02377-2014.
    1. Cukic V. The changes of arterial blood gases in COPD during four-year period. Med. Arch. 2014;68:14–18. doi: 10.5455/medarh.2014.68.14-18.
    1. Frantz S., Nihlen U., Dencker M., Engstrom G., Lofdahl C.G., Wollmer P. Impulse oscillometry may be of value in detecting early manifestations of COPD. Respir. Med. 2012;106:1116–1123. doi: 10.1016/j.rmed.2012.04.010.
    1. Lipworth B.J., Jabbal S. What can we learn about COPD from impulse oscillometry? Respir. Med. 2018;139:106–109. doi: 10.1016/j.rmed.2018.05.004.
    1. Miravitlles M., Dirksen A., Ferrarotti I., Koblizek V., Lange P., Mahadeva R., McElvaney N.G., Parr D., Piitulainen E., Roche N., et al. European Respiratory Society statement: Diagnosis and treatment of pulmonary disease in alpha1-antitrypsin deficiency. Eur. Respir. J. 2017;50 doi: 10.1183/13993003.00610-2017.
    1. Greulich T., Nell C., Hohmann D., Grebe M., Janciauskiene S., Koczulla A.R., Vogelmeier C.F. The prevalence of diagnosed alpha1-antitrypsin deficiency and its comorbidities: Results from a large population-based database. Eur. Respir. J. 2017;49 doi: 10.1183/13993003.00154-2016.
    1. Jeffery P.K. Remodeling and inflammation of bronchi in asthma and chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 2004;1:176–183. doi: 10.1513/pats.200402-009MS.
    1. Vestbo J., Edwards L.D., Scanlon P.D., Yates J.C., Agusti A., Bakke P., Calverley P.M., Celli B., Coxson H.O., Crim C., et al. Changes in forced expiratory volume in 1 second over time in COPD. N. Engl. J. Med. 2011;365:1184–1192. doi: 10.1056/NEJMoa1105482.
    1. Vestbo J., Agusti A., Wouters E.F., Bakke P., Calverley P.M., Celli B., Coxson H., Crim C., Edwards L.D., Locantore N., et al. Should we view chronic obstructive pulmonary disease differently after ECLIPSE? A clinical perspective from the study team. Am. J. Respir. Crit. Care Med. 2014;189:1022–1030. doi: 10.1164/rccm.201311-2006PP.
    1. Baughman P., Marott J.L., Lange P., Martin C.J., Shankar A., Petsonk E.L., Hnizdo E. Combined effect of lung function level and decline increases morbidity and mortality risks. Eur. J. Epidemiol. 2012;27:933–943. doi: 10.1007/s10654-012-9750-2.
    1. Haruna A., Muro S., Nakano Y., Ohara T., Hoshino Y., Ogawa E., Hirai T., Niimi A., Nishimura K., Chin K., et al. CT scan findings of emphysema predict mortality in COPD. Chest. 2010;138:635–640. doi: 10.1378/chest.09-2836.
    1. O’Brien C., Guest P.J., Hill S.L., Stockley R.A. Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax. 2000;55:635–642. doi: 10.1136/thorax.55.8.635.
    1. Patel I.S., Vlahos I., Wilkinson T.M., Lloyd-Owen S.J., Donaldson G.C., Wilks M., Reznek R.H., Wedzicha J.A. Bronchiectasis, exacerbation indices, and inflammation in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2004;170:400–407. doi: 10.1164/rccm.200305-648OC.
    1. Williams M.C., Murchison J.T., Edwards L.D., Agusti A., Bakke P., Calverley P.M., Celli B., Coxson H.O., Crim C., Lomas D.A., et al. Coronary artery calcification is increased in patients with COPD and associated with increased morbidity and mortality. Thorax. 2014;69:718–723. doi: 10.1136/thoraxjnl-2012-203151.
    1. Hackler L., Jr., Dorman G., Kele Z., Urge L., Darvas F., Puskas L.G. Development of chemically modified glass surfaces for nucleic acid, protein and small molecule microarrays. Mol. Divers. 2003;7:25–36. doi: 10.1023/B:MODI.0000006534.36417.06.
    1. Kalman J., Palotas A., Juhasz A., Rimanoczy A., Hugyecz M., Kovacs Z., Galsi G., Szabo Z., Pakaski M., Feher L.Z., et al. Impact of venlafaxine on gene expression profile in lymphocytes of the elderly with major depression--evolution of antidepressants and the role of the "neuro-immune" system. Neurochem. Res. 2005;30:1429–1438. doi: 10.1007/s11064-005-8513-9.
    1. Darvas F., Dorman G., Krajcsi P., Puskas L.G., Kovari Z., Lorincz Z., Urge L. Recent advances in chemical genomics. Curr. Med. Chem. 2004;11:3119–3145. doi: 10.2174/0929867043363848.
    1. Bhattacharya S., Mariani T.J. Array of hope: Expression profiling identifies disease biomarkers and mechanism. Biochem. Soc. Trans. 2009;37:855–862. doi: 10.1042/BST0370855.
    1. Alfoldi R., Balog J.A., Farago N., Halmai M., Kotogany E., Neuperger P., Nagy L.I., Feher L.Z., Szebeni G.J., Puskas L.G. Single Cell Mass Cytometry of Non-Small Cell Lung Cancer Cells Reveals Complexity of In vivo And Three-Dimensional Models over the Petri-dish. Cells. 2019;8:1093. doi: 10.3390/cells8091093.
    1. Rong B., Fu T., Gao W., Li M., Rong C., Liu W., Liu H. Reduced Serum Concentration of CC16 Is Associated with Severity of Chronic Obstructive Pulmonary Disease and Contributes to the Diagnosis and Assessment of the Disease. Int. J. Chron. Obstruct. Pulmon. Dis. 2020;15:461–470. doi: 10.2147/COPD.S230323.
    1. Pouwels S.D., Klont F., Kwiatkowski M., Wiersma V.R., Faiz A., van den Berge M., Horvatovich P., Bischoff R., Ten Hacken N.H.T. Cigarette Smoking Acutely Decreases Serum Levels of the Chronic Obstructive Pulmonary Disease Biomarker sRAGE. Am. J. Respir. Crit. Care Med. 2018;198:1456–1458. doi: 10.1164/rccm.201807-1249LE.
    1. Li D., Wu Y., Guo S., Qin J., Feng M., An Y., Zhang J., Li Y., Xiong S., Zhou H., et al. Circulating syndecan-1 as a novel biomarker relates to lung function, systemic inflammation, and exacerbation in COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 2019;14:1933–1941. doi: 10.2147/COPD.S207855.
    1. Stockley R.A., Halpin D.M.G., Celli B.R., Singh D. Chronic Obstructive Pulmonary Disease Biomarkers and Their Interpretation. Am. J. Respir. Crit. Care Med. 2019;199:1195–1204. doi: 10.1164/rccm.201810-1860SO.
    1. Shaw J.G., Vaughan A., Dent A.G., O’Hare P.E., Goh F., Bowman R.V., Fong K.M., Yang I.A. Biomarkers of progression of chronic obstructive pulmonary disease (COPD) J. Thorac. Dis. 2014;6:1532–1547. doi: 10.3978/j.issn.2072-1439.2014.11.33.
    1. Yonchuk J.G., Silverman E.K., Bowler R.P., Agusti A., Lomas D.A., Miller B.E., Tal-Singer R., Mayer R.J. Circulating soluble receptor for advanced glycation end products (sRAGE) as a biomarker of emphysema and the RAGE axis in the lung. Am. J. Respir. Crit. Care Med. 2015;192:785–792. doi: 10.1164/rccm.201501-0137PP.
    1. Shahriary A., Panahi Y., Shirali S., Rahmani H. Relationship of serum levels of interleukin 6, interleukin 8, and C-reactive protein with forced expiratory volume in first second in patients with mustard lung and chronic obstructive pulmonary diseases: Systematic review and meta-analysis. Postepy Dermatol. Alergol. 2017;34:192–198. doi: 10.5114/ada.2017.67841.
    1. Lopez-Campos J.L., Arellano E., Calero C., Delgado A., Marquez E., Cejudo P., Ortega F., Rodriguez-Panadero F., Montes-Worboys A. Determination of inflammatory biomarkers in patients with COPD: A comparison of different assays. BMC Med. Res. Methodol. 2012;12:40. doi: 10.1186/1471-2288-12-40.
    1. Lai T., Wu D., Chen M., Cao C., Jing Z., Huang L., Lv Y., Zhao X., Lv Q., Wang Y., et al. YKL-40 expression in chronic obstructive pulmonary disease: Relation to acute exacerbations and airway remodeling. Respir. Res. 2016;17:31. doi: 10.1186/s12931-016-0338-3.
    1. Han S.S., Lee W.H., Hong Y., Kim W.J., Yang J., Lim M.N., Lee S.J., Kwon J.W. Comparison of serum biomarkers between patients with asthma and with chronic obstructive pulmonary disease. J. Asthma. 2016;53:583–588. doi: 10.3109/02770903.2015.1056347.
    1. Sin D.D., Miller B.E., Duvoix A., Man S.F., Zhang X., Silverman E.K., Connett J.E., Anthonisen N.A., Wise R.A., Tashkin D., et al. Serum PARC/CCL-18 concentrations and health outcomes in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2011;183:1187–1192. doi: 10.1164/rccm.201008-1220OC.
    1. Wu Y., Qin J., He J., Shen Y., Wang H., Li Y., Zeng Q., Dong J., An Y., Xiong S., et al. Serum Endostatin Is a Novel Marker for COPD Associated with Lower Lung Function, Exacerbation and Systemic Inflammation. Int. J. Chron. Obstruct. Pulmon. Dis. 2020;15:397–407. doi: 10.2147/COPD.S234760.
    1. Ronnow S.R., Sand J.M.B., Langholm L.L., Manon-Jensen T., Karsdal M.A., Tal-Singer R., Miller B.E., Vestbo J., Leeming D.J. Type IV collagen turnover is predictive of mortality in COPD: A comparison to fibrinogen in a prospective analysis of the ECLIPSE cohort. Respir. Res. 2019;20:63. doi: 10.1186/s12931-019-1026-x.
    1. Poznanski M., Brzezianska-Lasota E., Kiszalkiewicz J., Kurnatowska I., Kroczynska-Bednarek J., Pekala-Wojciechowska A., Pietras T., Antczak A. Serum levels and gene expression of pentraxin 3 are elevated in COPD. Adv. Med. Sci. 2019;64:85–89. doi: 10.1016/j.advms.2018.08.006.
    1. Akiki Z., Fakih D., Jounblat R., Chamat S., Waked M., Holmskov U., Sorensen G.L., Nadif R., Salameh P. Surfactant protein D, a clinical biomarker for chronic obstructive pulmonary disease with excellent discriminant values. Exp. Ther. Med. 2016;11:723–730. doi: 10.3892/etm.2016.2986.
    1. Paone G., Conti V., Vestri A., Leone A., Puglisi G., Benassi F., Brunetti G., Schmid G., Cammarella I., Terzano C. Analysis of sputum markers in the evaluation of lung inflammation and functional impairment in symptomatic smokers and COPD patients. Dis. Markers. 2011;31:91–100. doi: 10.1155/2011/139493.
    1. Koutsokera A., Kostikas K., Nicod L.P., Fitting J.W. Pulmonary biomarkers in COPD exacerbations: A systematic review. Respir. Res. 2013;14:111. doi: 10.1186/1465-9921-14-111.
    1. Celejewska-Wojcik N., Kania A., Gorka K., Nastalek P., Wojcik K., Gielicz A., Mastalerz L., Sanak M., Sladek K. Eicosanoids and Eosinophilic Inflammation of Airways in Stable COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 2021;16:1415–1424. doi: 10.2147/COPD.S298678.
    1. Di Stefano A., Capelli A., Lusuardi M., Balbo P., Vecchio C., Maestrelli P., Mapp C.E., Fabbri L.M., Donner C.F., Saetta M. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am. J. Respir. Crit. Care Med. 1998;158:1277–1285. doi: 10.1164/ajrccm.158.4.9802078.
    1. Saha S., Brightling C.E. Eosinophilic airway inflammation in COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 2006;1:39–47. doi: 10.2147/copd.2006.1.1.39.
    1. Barnes P.J. Therapeutic approaches to asthma-chronic obstructive pulmonary disease overlap syndromes. J. Allergy Clin. Immunol. 2015;136:531–545. doi: 10.1016/j.jaci.2015.05.052.
    1. Christenson S.A., Steiling K., van den Berge M., Hijazi K., Hiemstra P.S., Postma D.S., Lenburg M.E., Spira A., Woodruff P.G. Asthma-COPD overlap. Clinical relevance of genomic signatures of type 2 inflammation in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2015;191:758–766. doi: 10.1164/rccm.201408-1458OC.
    1. Shin S.H., Park H.Y., Kang D., Cho J., Kwon S.O., Park J.H., Lee J.S., Oh Y.M., Sin D.D., Kim W.J., et al. Serial blood eosinophils and clinical outcome in patients with chronic obstructive pulmonary disease. Respir. Res. 2018;19:134. doi: 10.1186/s12931-018-0840-x.
    1. Dweik R.A., Comhair S.A., Gaston B., Thunnissen F.B., Farver C., Thomassen M.J., Kavuru M., Hammel J., Abu-Soud H.M., Erzurum S.C. NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response. Proc. Natl. Acad. Sci. USA. 2001;98:2622–2627. doi: 10.1073/pnas.051629498.
    1. Jo Y.S., Choe J., Shin S.H., Koo H.K., Lee W.Y., Kim Y.I., Ra S.W., Yoo K.H., Jung K.S., Park H.Y., et al. Exhaled Nitric Oxide in Patients with Stable Chronic Obstructive Pulmonary Disease: Clinical Implications of the Use of Inhaled Corticosteroids. Tuberc. Respir. Dis. 2020;83:42–50. doi: 10.4046/trd.2019.0050.
    1. Antus B., Barta I., Horvath I., Csiszer E. Relationship between exhaled nitric oxide and treatment response in COPD patients with exacerbations. Respirology. 2010;15:472–477. doi: 10.1111/j.1440-1843.2010.01711.x.
    1. Montuschi P., Kharitonov S.A., Ciabattoni G., Barnes P.J. Exhaled leukotrienes and prostaglandins in COPD. Thorax. 2003;58:585–588. doi: 10.1136/thorax.58.7.585.
    1. Kirkham S., Kolsum U., Rousseau K., Singh D., Vestbo J., Thornton D.J. MUC5B is the major mucin in the gel phase of sputum in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2008;178:1033–1039. doi: 10.1164/rccm.200803-391OC.
    1. Manzel L.J., Shi L., O’Shaughnessy P.T., Thorne P.S., Look D.C. Inhibition by cigarette smoke of nuclear factor-kappaB-dependent response to bacteria in the airway. Am. J. Respir. Cell Mol. Biol. 2011;44:155–165. doi: 10.1165/rcmb.2009-0454OC.
    1. Yang J., Zuo W.L., Fukui T., Chao I., Gomi K., Lee B., Staudt M.R., Kaner R.J., Strulovici-Barel Y., Salit J., et al. Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium. Am. J. Respir. Crit. Care Med. 2017;196:340–352. doi: 10.1164/rccm.201608-1672OC.
    1. Sohal S.S., Eapen M.S., Ward C., Walters E.H. Epithelial-Mesenchymal Transition: A Necessary New Therapeutic Target in Chronic Obstructive Pulmonary Disease? Am. J. Respir. Crit. Care Med. 2017;196:393–394. doi: 10.1164/rccm.201704-0771LE.
    1. Willis B.C., Borok Z. TGF-beta-induced EMT: Mechanisms and implications for fibrotic lung disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 2007;293:L525–L534. doi: 10.1152/ajplung.00163.2007.
    1. Mahmood M.Q., Walters E.H., Shukla S.D., Weston S., Muller H.K., Ward C., Sohal S.S. beta-catenin, Twist and Snail: Transcriptional regulation of EMT in smokers and COPD, and relation to airflow obstruction. Sci. Rep. 2017;7:10832. doi: 10.1038/s41598-017-11375-x.
    1. Eapen M.S., Sharma P., Gaikwad A.V., Lu W., Myers S., Hansbro P.M., Sohal S.S. Epithelial-mesenchymal transition is driven by transcriptional and post transcriptional modulations in COPD: Implications for disease progression and new therapeutics. Int. J. Chron. Obstruct. Pulmon. Dis. 2019;14:1603–1610. doi: 10.2147/COPD.S208428.
    1. Milara J., Peiro T., Serrano A., Cortijo J. Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke. Thorax. 2013;68:410–420. doi: 10.1136/thoraxjnl-2012-201761.
    1. Wang N., Wang Q., Du T., Gabriel A.N.A., Wang X., Sun L., Li X., Xu K., Jiang X., Zhang Y. The Potential Roles of Exosomes in Chronic Obstructive Pulmonary Disease. Front. Med. 2020;7:618506. doi: 10.3389/fmed.2020.618506.
    1. Holtzman J., Lee H. Emerging role of extracellular vesicles in the respiratory system. Exp. Mol. Med. 2020;52:887–895. doi: 10.1038/s12276-020-0450-9.
    1. Pastor L., Vera E., Marin J.M., Sanz-Rubio D. Extracellular Vesicles from Airway Secretions: New Insights in Lung Diseases. Int. J. Mol. Sci. 2021;22:583. doi: 10.3390/ijms22020583.
    1. O’Farrell H.E., Yang I.A. Extracellular vesicles in chronic obstructive pulmonary disease (COPD) J. Thorac. Dis. 2019;11:S2141–S2154. doi: 10.21037/jtd.2019.10.16.
    1. Fujii S., Hara H., Araya J., Takasaka N., Kojima J., Ito S., Minagawa S., Yumino Y., Ishikawa T., Numata T., et al. Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease. Oncoimmunology. 2012;1:630–641. doi: 10.4161/onci.20297.
    1. Moon H.G., Kim S.H., Gao J., Quan T., Qin Z., Osorio J.C., Rosas I.O., Wu M., Tesfaigzi Y., Jin Y. CCN1 secretion and cleavage regulate the lung epithelial cell functions after cigarette smoke. Am. J. Physiol. Lung Cell. Mol. Physiol. 2014;307:L326–337. doi: 10.1152/ajplung.00102.2014.
    1. Mohan A., Agarwal S., Clauss M., Britt N.S., Dhillon N.K. Extracellular vesicles: Novel communicators in lung diseases. Respir. Res. 2020;21:175. doi: 10.1186/s12931-020-01423-y.
    1. Genschmer K.R., Russell D.W., Lal C., Szul T., Bratcher P.E., Noerager B.D., Abdul Roda M., Xu X., Rezonzew G., Viera L., et al. Activated PMN Exosomes: Pathogenic Entities Causing Matrix Destruction and Disease in the Lung. Cell. 2019;176:113–126.e115. doi: 10.1016/j.cell.2018.12.002.
    1. Kadota T., Fujita Y., Yoshioka Y., Araya J., Kuwano K., Ochiya T. Extracellular Vesicles in Chronic Obstructive Pulmonary Disease. Int. J. Mol. Sci. 2016;17:1801. doi: 10.3390/ijms17111801.
    1. Kubo H. Extracellular Vesicles in Lung Disease. Chest. 2018;153:210–216. doi: 10.1016/j.chest.2017.06.026.
    1. Trappe A., Donnelly S.C., McNally P., Coppinger J.A. Role of extracellular vesicles in chronic lung disease. Thorax. 2021 doi: 10.1136/thoraxjnl-2020-216370.
    1. Le T.T., Berg N.K., Harting M.T., Li X., Eltzschig H.K., Yuan X. Purinergic Signaling in Pulmonary Inflammation. Front. Immunol. 2019;10:1633. doi: 10.3389/fimmu.2019.01633.
    1. Esther C.R., Jr., Lazaar A.L., Bordonali E., Qaqish B., Boucher R.C. Elevated airway purines in COPD. Chest. 2011;140:954–960. doi: 10.1378/chest.10-2471.
    1. Pelleg A., Schulman E.S., Barnes P.J. Extracellular Adenosine 5’-Triphosphate in Obstructive Airway Diseases. Chest. 2016;150:908–915. doi: 10.1016/j.chest.2016.06.045.
    1. Karmouty-Quintana H., Xia Y., Blackburn M.R. Adenosine signaling during acute and chronic disease states. J. Mol. Med. 2013;91:173–181. doi: 10.1007/s00109-013-0997-1.
    1. Collum S.D., Molina J.G., Hanmandlu A., Bi W., Pedroza M., Mertens T.C.J., Wareing N., Wei W., Wilson C., Sun W., et al. Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema. Dis. Model. Mech. 2019;12 doi: 10.1242/dmm.038711.
    1. Karmouty-Quintana H., Weng T., Garcia-Morales L.J., Chen N.Y., Pedroza M., Zhong H., Molina J.G., Bunge R., Bruckner B.A., Xia Y., et al. Adenosine A2B receptor and hyaluronan modulate pulmonary hypertension associated with chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 2013;49:1038–1047. doi: 10.1165/rcmb.2013-0089OC.
    1. Boo H.J., Park S.J., Noh M., Min H.Y., Jeong L.S., Lee H.Y. LJ-2698, an Adenosine A3 Receptor Antagonist, Alleviates Elastase-Induced Pulmonary Emphysema in Mice. Biomol. Ther. 2020;28:250–258. doi: 10.4062/biomolther.2019.162.
    1. Johannes L., Jacob R., Leffler H. Galectins at a glance. J. Cell Sci. 2018;131 doi: 10.1242/jcs.208884.
    1. Ion G., Fajka-Boja R., Kovacs F., Szebeni G., Gombos I., Czibula A., Matko J., Monostori E. Acid sphingomyelinase mediated release of ceramide is essential to trigger the mitochondrial pathway of apoptosis by galectin-1. Cell Signal. 2006;18:1887–1896. doi: 10.1016/j.cellsig.2006.02.007.
    1. Kovacs-Solyom F., Blasko A., Fajka-Boja R., Katona R.L., Vegh L., Novak J., Szebeni G.J., Krenacs L., Uher F., Tubak V., et al. Mechanism of tumor cell-induced T-cell apoptosis mediated by galectin-1. Immunol. Lett. 2010;127:108–118. doi: 10.1016/j.imlet.2009.10.003.
    1. Szebeni G.J., Kriston-Pal E., Blazso P., Katona R.L., Novak J., Szabo E., Czibula A., Fajka-Boja R., Hegyi B., Uher F., et al. Identification of galectin-1 as a critical factor in function of mouse mesenchymal stromal cell-mediated tumor promotion. PLoS ONE. 2012;7:e41372. doi: 10.1371/journal.pone.0041372.
    1. Kathiriya J.J., Nakra N., Nixon J., Patel P.S., Vaghasiya V., Alhassani A., Tian Z., Allen-Gipson D., Dave V. Galectin-1 inhibition attenuates profibrotic signaling in hypoxia-induced pulmonary fibrosis. Cell. Death Discov. 2017;3:17010. doi: 10.1038/cddiscovery.2017.10.
    1. Pilette C., Colinet B., Kiss R., Andre S., Kaltner H., Gabius H.J., Delos M., Vaerman J.P., Decramer M., Sibille Y. Increased galectin-3 expression and intra-epithelial neutrophils in small airways in severe COPD. Eur. Respir. J. 2007;29:914–922. doi: 10.1183/09031936.00073005.
    1. Nishi Y., Sano H., Kawashima T., Okada T., Kuroda T., Kikkawa K., Kawashima S., Tanabe M., Goto T., Matsuzawa Y., et al. Role of galectin-3 in human pulmonary fibrosis. Allergol. Int. 2007;56:57–65. doi: 10.2332/allergolint.O-06-449.
    1. Feng W., Wu X., Li S., Zhai C., Wang J., Shi W., Li M. Association of Serum Galectin-3 with the Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Med. Sci. Monit. 2017;23:4612–4618. doi: 10.12659/MSM.903472.
    1. Sundqvist M., Andelid K., Ekberg-Jansson A., Bylund J., Karlsson-Bengtsson A., Linden A. Systemic Galectin-3 in Smokers with Chronic Obstructive Pulmonary Disease and Chronic Bronchitis: The Impact of Exacerbations. Int. J. Chron. Obstruct. Pulmon. Dis. 2021;16:367–377. doi: 10.2147/COPD.S283372.
    1. Horio Y., Ichiyasu H., Kojima K., Saita N., Migiyama Y., Iriki T., Fujii K., Niki T., Hirashima M., Kohrogi H. Protective effect of Galectin-9 in murine model of lung emphysema: Involvement of neutrophil migration and MMP-9 production. PLoS ONE. 2017;12:e0180742. doi: 10.1371/journal.pone.0180742.
    1. Parris B.A., O’Farrell H.E., Fong K.M., Yang I.A. Chronic obstructive pulmonary disease (COPD) and lung cancer: Common pathways for pathogenesis. J. Thorac. Dis. 2019;11:S2155–S2172. doi: 10.21037/jtd.2019.10.54.
    1. Refaee T., Wu G., Ibrahim A., Halilaj I., Leijenaar R.T.H., Rogers W., Gietema H.A., Hendriks L.E.L., Lambin P., Woodruff H.C. The Emerging Role of Radiomics in COPD and Lung Cancer. Respiration. 2020;99:99–107. doi: 10.1159/000505429.
    1. Papi A., Casoni G., Caramori G., Guzzinati I., Boschetto P., Ravenna F., Calia N., Petruzzelli S., Corbetta L., Cavallesco G., et al. COPD increases the risk of squamous histological subtype in smokers who develop non-small cell lung carcinoma. Thorax. 2004;59:679–681. doi: 10.1136/thx.2003.018291.
    1. Young R.P., Hopkins R.J., Christmas T., Black P.N., Metcalf P., Gamble G.D. COPD prevalence is increased in lung cancer, independent of age, sex and smoking history. Eur. Respir. J. 2009;34:380–386. doi: 10.1183/09031936.00144208.
    1. Young R.P., Hopkins R.J., Gamble G.D., Etzel C., El-Zein R., Crapo J.D. Genetic evidence linking lung cancer and COPD: A new perspective. Appl. Clin. Genet. 2011;4:99–111. doi: 10.2147/TACG.S20083.
    1. Cui K., Ge X., Ma H. Four SNPs in the CHRNA3/5 alpha-neuronal nicotinic acetylcholine receptor subunit locus are associated with COPD risk based on meta-analyses. PLoS ONE. 2014;9:e102324. doi: 10.1371/journal.pone.0102324.
    1. Young R.P., Hopkins R.J., Hay B.A., Whittington C.F., Epton M.J., Gamble G.D. FAM13A locus in COPD is independently associated with lung cancer-evidence of a molecular genetic link between COPD and lung cancer. Appl. Clin. Genet. 2011;4:1–10. doi: 10.2147/TACG.S15758.
    1. Young R.P., Whittington C.F., Hopkins R.J., Hay B.A., Epton M.J., Black P.N., Gamble G.D. Chromosome 4q31 locus in COPD is also associated with lung cancer. Eur. Respir. J. 2010;36:1375–1382. doi: 10.1183/09031936.00033310.
    1. Lee Y.J., Choi S., Kwon S.Y., Lee Y., Lee J.K., Heo E.Y., Chung H.S., Kim D.K. A Genome-Wide Association Study in Early COPD: Identification of One Major Susceptibility Loci. Int. J. Chron. Obstruct. Pulmon. Dis. 2020;15:2967–2975. doi: 10.2147/COPD.S269263.
    1. Wang H., Yang L., Deng J., Wang B., Yang X., Yang R., Cheng M., Fang W., Qiu F., Zhang X., et al. Genetic variant in the 3’-untranslated region of VEGFR1 gene influences chronic obstructive pulmonary disease and lung cancer development in Chinese population. Mutagenesis. 2014;29:311–317. doi: 10.1093/mutage/geu020.
    1. Mateu-Jimenez M., Curull V., Rodriguez-Fuster A., Aguilo R., Sanchez-Font A., Pijuan L., Gea J., Barreiro E. Profile of epigenetic mechanisms in lung tumors of patients with underlying chronic respiratory conditions. Clin. Epigenetics. 2018;10:7. doi: 10.1186/s13148-017-0437-0.
    1. Denkceken T., Pala E. Investigation of key miRNAs and potential mechanisms in non-small cell lung cancer development from chronic obstructive pulmonary disease. Gen. Physiol. Biophys. 2020;39:69–77. doi: 10.4149/gpb_2019042.
    1. Barnes P.J. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 2016;138:16–27. doi: 10.1016/j.jaci.2016.05.011.
    1. Hogg J.C., Chu F., Utokaparch S., Woods R., Elliott W.M., Buzatu L., Cherniack R.M., Rogers R.M., Sciurba F.C., Coxson H.O., et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 2004;350:2645–2653. doi: 10.1056/NEJMoa032158.
    1. Tian W., Jiang X., Kim D., Guan T., Nicolls M.R., Rockson S.G. Leukotrienes in Tumor-Associated Inflammation. Front Pharmacol. 2020;11:1289. doi: 10.3389/fphar.2020.01289.
    1. Drakatos P., Lykouras D., Sampsonas F., Karkoulias K., Spiropoulos K. Targeting leukotrienes for the treatment of COPD? Inflamm. Allergy Drug Targets. 2009;8:297–306. doi: 10.2174/187152809789352177.
    1. Iacona J.R., Monteleone N.J., Lutz C.S. miR-146a suppresses 5-lipoxygenase activating protein (FLAP) expression and Leukotriene B4 production in lung cancer cells. Oncotarget. 2018;9:26751–26769. doi: 10.18632/oncotarget.25482.
    1. Dong R., Xie L., Zhao K., Zhang Q., Zhou M., He P. Cigarette smoke-induced lung inflammation in COPD mediated via LTB4/BLT1/SOCS1 pathway. Int. J. Chron. Obstruct. Pulmon. Dis. 2016;11:31–41. doi: 10.2147/COPD.S96412.
    1. Cazzola M., Boveri B., Carlucci P., Santus P., DiMarco F., Centanni S., Allegra L. Lung function improvement in smokers suffering from COPD with zafirlukast, a CysLT(1)-receptor antagonist. Pulm. Pharmacol. Ther. 2000;13:301–305. doi: 10.1006/pupt.2000.0258.
    1. Thomsen M., Dahl M., Lange P., Vestbo J., Nordestgaard B.G. Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2012;186:982–988. doi: 10.1164/rccm.201206-1113OC.
    1. Gwilt C.R., Donnelly L.E., Rogers D.F. The non-neuronal cholinergic system in the airways: An unappreciated regulatory role in pulmonary inflammation? Pharmacol. Ther. 2007;115:208–222. doi: 10.1016/j.pharmthera.2007.05.007.
    1. Calzetta L., Coppola A., Ritondo B.L., Matino M., Chetta A., Rogliani P. The Impact of Muscarinic Receptor Antagonists on Airway Inflammation: A Systematic Review. Int. J. Chron. Obstruct. Pulmon. Dis. 2021;16:257–279. doi: 10.2147/COPD.S285867.
    1. Szebeni G.J., Vizler C., Nagy L.I., Kitajka K., Puskas L.G. Pro-Tumoral Inflammatory Myeloid Cells as Emerging Therapeutic Targets. Int. J. Mol. Sci. 2016;17:1958. doi: 10.3390/ijms17111958.
    1. Strauss L., Sangaletti S., Consonni F.M., Szebeni G., Morlacchi S., Totaro M.G., Porta C., Anselmo A., Tartari S., Doni A., et al. RORC1 Regulates Tumor-Promoting "Emergency" Granulo-Monocytopoiesis. Cancer Cell. 2015;28:253–269. doi: 10.1016/j.ccell.2015.07.006.
    1. Chu S., Zhong X., Zhang J., Lao Q., He Z., Bai J. The expression of Foxp3 and ROR gamma t in lung tissues from normal smokers and chronic obstructive pulmonary disease patients. Int. Immunopharmacol. 2011;11:1780–1788. doi: 10.1016/j.intimp.2011.06.010.
    1. Capone A., Volpe E. Transcriptional Regulators of T Helper 17 Cell Differentiation in Health and Autoimmune Diseases. Front. Immunol. 2020;11:348. doi: 10.3389/fimmu.2020.00348.
    1. Vaguliene N., Zemaitis M., Lavinskiene S., Miliauskas S., Sakalauskas R. Local and systemic neutrophilic inflammation in patients with lung cancer and chronic obstructive pulmonary disease. BMC Immunol. 2013;14:36. doi: 10.1186/1471-2172-14-36.
    1. Le Rouzic O., Pichavant M., Frealle E., Guillon A., Si-Tahar M., Gosset P. Th17 cytokines: Novel potential therapeutic targets for COPD pathogenesis and exacerbations. Eur. Respir. J. 2017;50 doi: 10.1183/13993003.02434-2016.
    1. Ponce-Gallegos M.A., Ramirez-Venegas A., Falfan-Valencia R. Th17 profile in COPD exacerbations. Int. J. Chron. Obstruct. Pulmon. Dis. 2017;12:1857–1865. doi: 10.2147/COPD.S136592.
    1. Silva L.E.F., Lourenco J.D., Silva K.R., Santana F.P.R., Kohler J.B., Moreira A.R., Velosa A.P.P., Prado C.M., Vieira R.P., Aun M.V., et al. Th17/Treg imbalance in COPD development: Suppressors of cytokine signaling and signal transducers and activators of transcription proteins. Sci. Rep. 2020;10:15287. doi: 10.1038/s41598-020-72305-y.
    1. Armstrong D., Chang C.Y., Lazarus D.R., Corry D., Kheradmand F. Lung Cancer Heterogeneity in Modulation of Th17/IL17A Responses. Front. Oncol. 2019;9:1384. doi: 10.3389/fonc.2019.01384.
    1. Peng D.H., Rodriguez B.L., Diao L., Gaudreau P.O., Padhye A., Konen J.M., Ochieng J.K., Class C.A., Fradette J.J., Gibson L., et al. Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers. Nat. Commun. 2021;12:2606. doi: 10.1038/s41467-021-22875-w.
    1. Saha S.P., Bhalla D.K., Whayne T.F., Jr., Gairola C. Cigarette smoke and adverse health effects: An overview of research trends and future needs. Int. J. Angiol. 2007;16:77–83. doi: 10.1055/s-0031-1278254.
    1. Fantozzi A., Gruber D.C., Pisarsky L., Heck C., Kunita A., Yilmaz M., Meyer-Schaller N., Cornille K., Hopfer U., Bentires-Alj M., et al. VEGF-mediated angiogenesis links EMT-induced cancer stemness to tumor initiation. Cancer Res. 2014;74:1566–1575. doi: 10.1158/0008-5472.CAN-13-1641.
    1. Wang R.D., Wright J.L., Churg A. Transforming growth factor-beta1 drives airway remodeling in cigarette smoke-exposed tracheal explants. Am. J. Respir. Cell Mol. Biol. 2005;33:387–393. doi: 10.1165/rcmb.2005-0203OC.
    1. Saito A., Horie M., Nagase T. TGF-beta Signaling in Lung Health and Disease. Int. J. Mol. Sci. 2018;19:2460. doi: 10.3390/ijms19082460.
    1. Zhang L., Zhou F., ten Dijke P. Signaling interplay between transforming growth factor-beta receptor and PI3K/AKT pathways in cancer. Trends Biochem. Sci. 2013;38:612–620. doi: 10.1016/j.tibs.2013.10.001.
    1. Huang F., Shi Q., Li Y., Xu L., Xu C., Chen F., Wang H., Liao H., Chang Z., Liu F., et al. HER2/EGFR-AKT Signaling Switches TGFbeta from Inhibiting Cell Proliferation to Promoting Cell Migration in Breast Cancer. Cancer Res. 2018;78:6073–6085. doi: 10.1158/0008-5472.CAN-18-0136.
    1. Sohal S.S., Hansbro P.M., Walters E.H. Epithelial Mesenchymal Transition in Chronic Obstructive Pulmonary Disease, a Precursor for Epithelial Cancers: Understanding and Translation to Early Therapy. Ann. Am. Thorac. Soc. 2017;14:1491–1492. doi: 10.1513/AnnalsATS.201705-387LE.
    1. Romero-Palacios P.J., Alcazar-Navarrete B., Diaz Mochon J.J., de Miguel-Perez D., Lopez Hidalgo J.L., Garrido-Navas M.D.C., Quero Valenzuela F., Lorente J.A., Serrano M.J. Liquid biopsy beyond of cancer: Circulating pulmonary cells as biomarkers of COPD aggressivity. Crit. Rev. Oncol. Hematol. 2019;136:31–36. doi: 10.1016/j.critrevonc.2019.02.003.
    1. Kalluri R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer. 2016;16:582–598. doi: 10.1038/nrc.2016.73.
    1. Nishioka M., Venkatesan N., Dessalle K., Mogas A., Kyoh S., Lin T.Y., Nair P., Baglole C.J., Eidelman D.H., Ludwig M.S., et al. Fibroblast-epithelial cell interactions drive epithelial-mesenchymal transition differently in cells from normal and COPD patients. Respir. Res. 2015;16:72. doi: 10.1186/s12931-015-0232-4.
    1. Courtney J.M., Spafford P.L. The Role of Epithelial-Mesenchymal Transition in Chronic Obstructive Pulmonary Disease. Cells Tissues Organs. 2017;203:99–104. doi: 10.1159/000450919.
    1. Gascard P., Tlsty T.D. Carcinoma-associated fibroblasts: Orchestrating the composition of malignancy. Genes Dev. 2016;30:1002–1019. doi: 10.1101/gad.279737.116.
    1. Meads M.B., Gatenby R.A., Dalton W.S. Environment-mediated drug resistance: A major contributor to minimal residual disease. Nat. Rev. Cancer. 2009;9:665–674. doi: 10.1038/nrc2714.
    1. Patsouras D., Papaxoinis K., Kostakis A., Safioleas M.C., Lazaris A.C., Nicolopoulou-Stamati P. Fibroblast activation protein and its prognostic significance in correlation with vascular endothelial growth factor in pancreatic adenocarcinoma. Mol. Med. Rep. 2015;11:4585–4590. doi: 10.3892/mmr.2015.3259.
    1. Yang X., Lin Y., Shi Y., Li B., Liu W., Yin W., Dang Y., Chu Y., Fan J., He R. FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling. Cancer Res. 2016;76:4124–4135. doi: 10.1158/0008-5472.CAN-15-2973.
    1. Shi J., Hou Z., Yan J., Qiu W., Liang L., Meng M., Li L., Wang X., Xie Y., Jiang L., et al. The prognostic significance of fibroblast activation protein-alpha in human lung adenocarcinoma. Ann. Transl. Med. 2020;8:224. doi: 10.21037/atm.2020.01.82.
    1. Wang L.C., Lo A., Scholler J., Sun J., Majumdar R.S., Kapoor V., Antzis M., Cotner C.E., Johnson L.A., Durham A.C., et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol. Res. 2014;2:154–166. doi: 10.1158/2326-6066.CIR-13-0027.
    1. Loeffler M., Kruger J.A., Niethammer A.G., Reisfeld R.A. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J. Clin. Investig. 2006;116:1955–1962. doi: 10.1172/JCI26532.
    1. D’Anna C., Cigna D., Costanzo G., Bruno A., Ferraro M., Di Vincenzo S., Bianchi L., Bini L., Gjomarkaj M., Pace E. Cigarette smoke alters the proteomic profile of lung fibroblasts. Mol. Biosyst. 2015;11:1644–1652. doi: 10.1039/C5MB00188A.
    1. Woldhuis R.R., Heijink I.H., van den Berge M., Timens W., Oliver B.G.G., de Vries M., Brandsma C.A. COPD-derived fibroblasts secrete higher levels of senescence-associated secretory phenotype proteins. Thorax. 2020 doi: 10.1136/thoraxjnl-2020-215114.
    1. Woldhuis R.R., de Vries M., Timens W., van den Berge M., Demaria M., Oliver B.G.G., Heijink I.H., Brandsma C.A. Link between increased cellular senescence and extracellular matrix changes in COPD. Am. J. Physiol. Lung Cell Mol. Physiol. 2020;319:L48–L60. doi: 10.1152/ajplung.00028.2020.
    1. Charlson E.S., Bittinger K., Haas A.R., Fitzgerald A.S., Frank I., Yadav A., Bushman F.D., Collman R.G. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am. J. Respir. Crit. Care Med. 2011;184:957–963. doi: 10.1164/rccm.201104-0655OC.
    1. Mammen M.J., Sethi S. COPD and the microbiome. Respirology. 2016;21:590–599. doi: 10.1111/resp.12732.
    1. Wang Z., Bafadhel M., Haldar K., Spivak A., Mayhew D., Miller B.E., Tal-Singer R., Johnston S.L., Ramsheh M.Y., Barer M.R., et al. Lung microbiome dynamics in COPD exacerbations. Eur. Respir. J. 2016;47:1082–1092. doi: 10.1183/13993003.01406-2015.
    1. Wang Z., Maschera B., Lea S., Kolsum U., Michalovich D., Van Horn S., Traini C., Brown J.R., Hessel E.M., Singh D. Airway host-microbiome interactions in chronic obstructive pulmonary disease. Respir. Res. 2019;20:113. doi: 10.1186/s12931-019-1085-z.
    1. Bowerman K.L., Rehman S.F., Vaughan A., Lachner N., Budden K.F., Kim R.Y., Wood D.L.A., Gellatly S.L., Shukla S.D., Wood L.G., et al. Disease-associated gut microbiome and metabolome changes in patients with chronic obstructive pulmonary disease. Nat. Commun. 2020;11:5886. doi: 10.1038/s41467-020-19701-0.
    1. Liu N.N., Ma Q., Ge Y., Yi C.X., Wei L.Q., Tan J.C., Chu Q., Li J.Q., Zhang P., Wang H. Microbiome dysbiosis in lung cancer: From composition to therapy. NPJ Precis. Oncol. 2020;4:33. doi: 10.1038/s41698-020-00138-z.
    1. Ramirez-Labrada A.G., Isla D., Artal A., Arias M., Rezusta A., Pardo J., Galvez E.M. The Influence of Lung Microbiota on Lung Carcinogenesis, Immunity, and Immunotherapy. Trends Cancer. 2020;6:86–97. doi: 10.1016/j.trecan.2019.12.007.

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