Abstract
Cigarette smoking is the leading cause of the respiratory diseases collectively known as chronic obstructive pulmonary disease (COPD). While the pathogenesis of COPD is complex, there is abundant evidence that alveolar macrophages (AM) play an important role. Based on the concept that COPD is a slow-progressing disorder likely involving multiple mediators released by AM activated by cigarette smoke, the present study focuses on the identification of previously unrecognized genes that may be linked to early events in the molecular pathogenesis of COPD, as opposed to factors associated with the presence of disease. To accomplish this, microarray analysis using Affymetrix microarrays was used to carry out an unbiased survey of the differences in gene expression profiles in the AM of phenotypically normal, ∼20 pack-year smokers compared to healthy nonsmokers. Although smoking did not alter the global gene expression pattern of AM, 75 genes were modulated by smoking, with 40 genes up-regulated and 35 down-regulated in the AM of smokers compared to nonsmokers. Most of these genes belong to the functional categories of immune/inflammatory response, cell adhesion and extracellular matrix, proteolysis and antiproteolysis, lysosomal function, antioxidant-related function, signal transduction, and regulation of transcription. Of these 75 genes, 69 have not been previously recognized to be up- or down-regulated in AM in association with smoking or COPD, including genes coding for proteins belonging to all of the above categories, and others belonging to various functional categories or of unknown function. These observations suggest that gene expression responses of AM associated with the stress of cigarette smoking are more complex than previously thought, and offer a variety of new insights into the complex pathogenesis of smoking-induced lung diseases.
Similar content being viewed by others
References
American Thoracic Society (1996) Cigarette smoking and health. Am J Respir Crit Care Med 153:861–865
Pauwels RA, Rabe KF (2004) Burden and clinical features of chronic obstructive pulmonary disease (COPD). Lancet 364:613–620
MacNee W (2000) Oxidants/antioxidants and COPD. Chest 117:303S–317S
Sethi JM, Rochester CL (2000) Smoking and chronic obstructive pulmonary disease. Clin Chest Med 21:67–86, viii
American Thoracic Society (1995) Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 152:S77–S121
Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD (1997) Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277:2002–2004
Joos L, He JQ, Shepherdson MB, Connett JE, Anthonisen NR, Pare PD, Sandford AJ (2002) The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function. Hum Mol Genet 11:569–576
Bezdicek P, Crystal RG (1997) Pulmonary macrophages. In: Crystal RG, West JB, Weibel ER, Barnes PJ (eds) The lung: scientific foundations, 2nd edn. Lippincott-Raven Publishers, Philadelphia, pp 859–875
Shapiro SD (1999) The macrophage in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 160:S29–S32
Barnes PJ (2003) New concepts in chronic obstructive pulmonary disease. Annu Rev Med 54:113–129
Reilly JJ, Chapman HA (1988) Association between alveolar macrophage plasminogen activator activity and indices of lung function in young cigarette smokers. Am Rev Respir Dis 138:1422–1428
Wright JL, Hobson JE, Wiggs B, Pare PD, Hogg JC (1988) Airway inflammation and peribronchiolar attachments in the lungs of nonsmokers, current and ex-smokers. Lung 166:277–286
Kirkham PA, Spooner G, Ffoulkes-Jones C, Calvez R (2003) Cigarette smoke triggers macrophage adhesion and activation: role of lipid peroxidation products and scavenger receptor. Free Radic Biol Med 35:697–710
Koch A, Giembycz M, Stirling RG, Lim S, Adcock I, Wassermann K, Erdmann E, Chung KF (2004) Effect of smoking on MAP kinase-induced modulation of IL-8 in human alveolar macrophages. Eur Respir J 23:805–812
Russi TJ, Crystal RG (1997) Use of bronchoalveolar lavage and airway brushing to investigate the human lung. In: Crystal RG, West JB, Weibel ER, Barnes PJ (eds) The lung: scientific foundations, 2nd edn. Lippincott-Raven Publishers, Philadelphia, pp 371–382
Eisen MB, Spellman PT, Brown PO, Botstein D (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95:14863–14868
Chuaqui RF, Bonner RF, Best CJ, Gillespie JW, Flaig MJ, Hewitt SM, Phillips JL, Krizman DB, Tangrea MA, Ahram M, Linehan WM, Knezevic V, Emmert-Buck MR (2002) Post-analysis follow-up and validation of microarray experiments. Nat Genet (Suppl) 32:509–514
Capelli A, Di Stefano A, Gnemmi I, Balbo P, Cerutti CG, Balbi B, Lusuardi M, Donner CF (1999) Increased MCP-1 and MIP-1beta in bronchoalveolar lavage fluid of chronic bronchitis. Eur Respir J 14:160–165
de Boer WI, Sont JK, van Schadewijk A, Stolk J, van Krieken JH, Hiemstra PS (2000) Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD. J Pathol 190:619–626
Traves SL, Culpitt SV, Russell RE, Barnes PJ, Donnelly LE (2002) Increased levels of the chemokines GROalpha and MCP-1 in sputum samples from patients with COPD. Thorax 57:590–595
Rose RM, Kobzik L, Filderman AE, Vermeulen MW, Dushay K, Donahue RE (1992) Characterization of colony stimulating factor activity in the human respiratory tract. Comparison of healthy smokers and nonsmokers. Am Rev Respir Dis 145:394–399
Finlay GA, O’Driscoll LR, Russell KJ, D’Arcy EM, Masterson JB, Fitz Gerald MX, O’Connor CM (1997) Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am J Respir Crit Care Med 156:240–247
Fujita J, Skold CM, Daughton DM, Ertl RF, Takahara J, Rennard SI (1999) Modulation of elastase binding to elastin by human alveolar macrophage-derived lipids. Am J Respir Crit Care Med 160:802–807
Chu CT, Howard GC, Misra UK, Pizzo SV (1994) Alpha 2-macroglobulin: a sensor for proteolysis. Ann N Y Acad Sci 737:291–307
Hackett NR, Heguy A, Harvey BG, O’Connor TP, Luettich K, Flieder DB, Kaplan R, Crystal RG (2003) Variability of antioxidant-related gene expression in the airway epithelium of cigarette smokers. Am J Respir Cell Mol Biol 29:331–343
Betsuyaku T, Nishimura M, Takeyabu K, Tanino M, Venge P, Xu S, Kawakami Y (1999) Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with subclinical emphysema. Am J Respir Crit Care Med 159:1985–1991
Ekberg-Jansson A, Andersson B, Bake B, Boijsen M, Enanden I, Rosengren A, Skoogh BE, Tylen U, Venge P, Lofdahl CG (2001) Neutrophil-associated activation markers in healthy smokers relates to a fall in DL(CO) and to emphysematous changes on high resolution CT. Respir Med 95:363–373
Keatings VM, Barnes PJ (1997) Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma, and normal subjects. Am J Respir Crit Care Med 155:449–453
O’Regan A (2003) The role of osteopontin in lung disease. Cytokine Growth Factor Rev 14:479–488
Gravallese EM (2003) Osteopontin: a bridge between bone and the immune system. J Clin Invest 112:147–149
Mazzali M, Kipari T, Ophascharoensuk V, Wesson JA, Johnson R, Hughes J (2002) Osteopontin—a molecule for all seasons. QJM 95:3–13
Takahashi F, Takahashi K, Okazaki T, Maeda K, Ienaga H, Maeda M, Kon S, Uede T, Fukuchi Y (2001) Role of osteopontin in the pathogenesis of bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 24:264–271
Berman JS, Serlin D, Li X, Whitley G, Hayes J, Rishikof DC, Ricupero DA, Liaw L, Goetschkes M, O’Regan AW (2004) Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice. Am J Physiol Lung Cell Mol Physiol 286:L1311–L1318
Van Damme J, Wuyts A, Froyen G, Van Coillie E, Struyf S, Billiau A, Proost P, Wang JM, Opdenakker G (1997) Granulocyte chemotactic protein-2 and related CXC chemokines: from gene regulation to receptor usage. J Leukoc Biol 62:563–569
Snider GL, Ciccolella DE, Morris SM, Stone PJ, Lucey EC (1991) Putative role of neutrophil elastase in the pathogenesis of emphysema. Ann N Y Acad Sci 624:45–59
Suki B, Lutchen KR, Ingenito EP (2003) On the progressive nature of emphysema: roles of proteases, inflammation, and mechanical forces. Am J Respir Crit Care Med 168:516–521
Saitoh H, Heguy A, O’Connor TP, Harvey BG, Leopold PL, Hackett NR, Cieciuch A, Crystal RG (2004) Adenovirus-mediated delivery of ADAM10, a novel candidate gene for COPD, results in emphysematous changes in the mouse lung. Mol Ther 9:S185
Martinet N, Alla F, Farre G, Labib T, Drouot H, Vidili R, Picard E, Gaube MP, Le Faou D, Siat J, Borelly J, Vermylen P, Bazarbachi T, Vignaud JM, Martinet Y (2000) Retinoic acid receptor and retinoid X receptor alterations in lung cancer precursor lesions. Cancer Res 60:2869–2875
Xu XC, Lee JS, Lee JJ, Morice RC, Liu X, Lippman SM, Hong WK, Lotan R (1999) Nuclear retinoid acid receptor beta in bronchial epithelium of smokers before and during chemoprevention. J Natl Cancer Inst 91:1317–1321
Soria JC, Xu X, Liu DD, Lee JJ, Kurie J, Morice RC, Khuri F, Mao L, Hong WK, Lotan R (2003) Retinoic acid receptor beta and telomerase catalytic subunit expression in bronchial epithelium of heavy smokers. J Natl Cancer Inst 95:165–168
Spira A, Beane J, Shah V, Liu G, Schembri F, Yang X, Palma J, Brody JS (2004) Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proc Natl Acad Sci USA 101:10143–10148
Ning W, Li CJ, Kaminski N, Feghali-Bostwick CA, Alber SM, Di YP, Otterbein SL, Song R, Hayashi S, Zhou Z, Pinsky DJ, Watkins SC, Pilewski JM, Sciurba FC, Peters DG, Hogg JC, Choi AM (2004) Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease. Proc Natl Acad Sci USA 101:14895–14900
Miura K, Bowman ED, Simon R, Peng AC, Robles AI, Jones RT, Katagiri T, He P, Mizukami H, Charboneau L, Kikuchi T, Liotta LA, Nakamura Y, Harris CC (2002) Laser capture microdissection and microarray expression analysis of lung adenocarcinoma reveals tobacco smoking- and prognosis-related molecular profiles. Cancer Res 62:3244–3250
Masuya M, Katayama N, Hoshino N, Nishikawa H, Sakano S, Araki H, Mitani H, Suzuki H, Miyashita H, Kobayashi K, Nishii K, Minami N, Shiku H (2002) The soluble Notch ligand, Jagged-1, inhibits proliferation of CD34+ macrophage progenitors. Int J Hematol 75:269–276
Rahman I, MacNee W (2000) Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 16:534–554
Amin K, Ekberg-Jansson A, Lofdahl CG, Venge P (2003) Relationship between inflammatory cells and structural changes in the lungs of asymptomatic and never smokers: a biopsy study. Thorax 58:135–142
Pinot F, el Yaagoubi A, Christie P, Dinh-Xuan AT, Polla BS (1997) Induction of stress proteins by tobacco smoke in human monocytes: modulation by antioxidants. Cell Stress Chaperones 2:156–161
Vayssier M, Banzet N, Francois D, Bellmann K, Polla BS (1998) Tobacco smoke induces both apoptosis and necrosis in mammalian cells: differential effects of HSP70. Am J Physiol 275:L771–L779
Acknowledgements
We thank N Mohamed for help in preparing this manuscript. These studies were supported, in part, by R01 HL074326-01; M01RR00047; and the Will Rogers Memorial Fund.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Heguy, A., O’Connor, T.P., Luettich, K. et al. Gene expression profiling of human alveolar macrophages of phenotypically normal smokers and nonsmokers reveals a previously unrecognized subset of genes modulated by cigarette smoking. J Mol Med 84, 318–328 (2006). https://doi.org/10.1007/s00109-005-0008-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-005-0008-2