A Causal Model of COPD

  • Louis Anthony CoxJr.
Chapter
Part of the International Series in Operations Research & Management Science book series (ISOR, volume 185)

Abstract

Chapter 1 suggested that good causal modeling is at the heart of good risk analysis. Some of the most important and enjoyable challenges for risk analysis practitioners are understanding, validating, modeling, and documenting causal mechanisms in sufficient detail to predict how changes in controllable inputs, such as exposures, will affect changes in outputs of concern, such as risk of disease and mortality. Typically, a risk analyst needs to learn only part of what scientists, who study causal mechanisms in detail, know: the part providing valid causal relations between changes in inputs and outputs. The deeper questions of how and why these relations function are not needed for purposes or accurate risk modeling, although they may be of great (or even primary) interest to the scientist.

Keywords

Surfactant Migration Quartz Hydrogen Peroxide Dust 

References

  1. Babusyte A, Stravinskaite K, Jeroch J, Lötvall J, Sakalauskas R, Sitkauskiene B (2007) Patterns of airway inflammation and MMP-12 expression in smokers and ex-smokers with COPD. Respir Res 8:81CrossRefGoogle Scholar
  2. Barceló B, Pons J, Ferrer JM, Sauleda J, Fuster A, Agustí AG (2008) Phenotypic characterisation of T-lymphocytes in COPD: abnormal CD4 + CD25+ regulatory T-lymphocyte response to tobacco smoking. Eur Respir J 31(3):555–562CrossRefGoogle Scholar
  3. Barnes PJ, Cosio MG (2004) Characterization of T lymphocytes in chronic obstructive pulmonary disease. PLoS Med 1(1):e20. Epub 2004 Oct 19Google Scholar
  4. Bautista MV, Chen Y, Ivanova VS, Rahimi MK, Watson AM, Rose MC (2009) IL-8 regulates Mucin gene expression at the posttranscriptional level in lung epithelial cells. J ImmunolGoogle Scholar
  5. Borchers MT, Wesselkamper SC, Harris NL, Deshmukh H, Beckman E, Vitucci M, Tichelaar JW, Leikauf GD (2007) CD8+ T cells contribute to macrophage accumulation and airspace enlargement following repeated irritant exposure. Exp Mol Pathol 83(3):301–310CrossRefGoogle Scholar
  6. Boschetto P, Quintavalle S, Miotto D, Lo Cascio N, Zeni E, Mapp CE (2006) Chronic obstructive pulmonary disease (COPD) and occupational exposures. J Occup Med Toxicol 1Google Scholar
  7. Bracke K, Cataldo D, Maes T, Gueders M, Noël A, Foidart JM, Brusselle G, Pauwels RA (2005) Matrix metalloproteinase-12 and cathepsin D expression in pulmonary macrophages and dendritic cells of cigarette smoke-exposed mice. Int Arch Allergy Immunol 138(2):169–179CrossRefGoogle Scholar
  8. Burgel PR, Nadel JA (2008) Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases. Eur Respir J 32(4):1068–1081CrossRefGoogle Scholar
  9. Cai S, Chen P, Zhang C, Chen JB, Wu J (2009) Oral N-acetylcysteine attenuates pulmonary emphysema and alveolar septal cell apoptosis in smoking-induced COPD in rats. Respirology 14(3):354–359CrossRefGoogle Scholar
  10. Chen YE (2004) MMP-12, an old enzyme plays a new role in the pathogenesis of rheumatoid arthritis? Am J Pathol 165(4):1069–1070CrossRefGoogle Scholar
  11. Chua F, Laurent GJ (2006) Neutrophil elastase: mediator of extracellular matrix destruction and accumulation. Proc Am Thorac Soc 3(5):424–427CrossRefGoogle Scholar
  12. Churg A, Wang RD, Tai H, Wang X, Xie C, Wright JL (2004) Tumor necrosis factor-alpha drives 70 % of cigarette smoke-induced emphysema in the mouse. Am J Respir Crit Care Med 170(5):492–498CrossRefGoogle Scholar
  13. Cosio MG, Majo J, Cosio MG (2002) Inflammation of the airways and lung parenchyma in COPD: role of T cells. Chest 121(5 Suppl):160S–165SCrossRefGoogle Scholar
  14. Cox LA Jr (2009) A mathematical model of protease-antiprotease homeostasis failure in chronic obstructive pulmonary disease (COPD). Risk Anal 29(4):576–586CrossRefGoogle Scholar
  15. Demedts IK, Demoor T, Bracke KR, Joos GF, Brusselle GG (2006a) Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema. Respir Res 7:53CrossRefGoogle Scholar
  16. Demedts IK, Morel-Montero A, Lebecque S, Pacheco Y, Cataldo D, Joos GF, Pauwels RA, Brusselle GG (2006) Elevated MMP-12 protein levels in induced sputum from patients with COPD. Thorax 61(3):196–201. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2080750 Google Scholar
  17. Dillon TJ, Walsh RL, Scicchitano R, Eckert B, Cleary EG, McLennan G (1992) Plasma elastin-derived peptide levels in normal adults, children, and emphysematous subjects. Physiologic and computed tomographic scan correlates. Am Rev Respir Dis 146(5 Pt 1):1143–1148Google Scholar
  18. Djekic UV, Gaggar A, Weathington NM (2009) Attacking the multi-tiered proteolytic pathology of COPD: new insights from basic and translational studies. Pharmacol Ther 121(2):132–146CrossRefGoogle Scholar
  19. Domagala-Kulawik J (2008) Effects of cigarette smoke on the lung and systemic immunity. J Physiol Pharmacol 59(Suppl 6):19–34Google Scholar
  20. Domagała-Kulawik J, Maskey-Warzechowska M, Chazan R, Hermanowicz-Salamon J (2006) Expression of macrophage surface markers in induced sputum of patients with chronic obstructive pulmonary disease. J Physiol Pharmacol 57(Suppl 4):75–84Google Scholar
  21. Domagała-Kulawik J, Maskey-Warzechowska M, Kraszewska I, Chazan R (2003) The cellular composition and macrophage phenotype in induced sputum in smokers and ex-smokers with COPD. Chest 123(4):1054–1059CrossRefGoogle Scholar
  22. Fletcher C, Peto R (1977) The natural history of chronic airflow obstruction. BMJ 1(6077):1645–1648CrossRefGoogle Scholar
  23. Gadgil A, Zhu X, Sciurba FC, Duncan SR (2006) Altered T-cell phenotypes in chronic obstructive pulmonary disease. Proc Am Thorac Soc 3(6):487–488CrossRefGoogle Scholar
  24. Gadgil A, Duncan SR (2008) Role of T-lymphocytes and pro-inflammatory mediators in the pathogenesis of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 3(4):531–541Google Scholar
  25. Gamble E, Grootendorst DC, Hattotuwa K, O’Shaughnessy T, Ram FS, Qiu Y, Zhu J, Vignola AM, Kroegel C, Morell F, Pavord ID, Rabe KF, Jeffery PK, Barnes NC (2007) Airway mucosal inflammation in COPD is similar in smokers and ex-smokers: a pooled analysis. Eur Respir J 30(3):467–471CrossRefGoogle Scholar
  26. Global Initiative for Chronic Obstructive Lung Disease (GOLD): Global strategy for the diagnosis, management, and prevention of Chronic Obstructive Pulmonary Disease NHLBI/WHO workshop report updated 2005. http://www.goldcopd.com
  27. Goven D, Boutten A, Leçon-Malas V, Marchal-Sommé J, Amara N, Crestani B, Fournier M, Lesèche G, Soler P, Boczkowski J, Bonay M (2008) Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema. Thorax 63(10):916–924CrossRefGoogle Scholar
  28. Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD (1997) Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277(5334):2002–2004CrossRefGoogle Scholar
  29. Henson PM, Vandivier RW, Douglas IS (2006) Cell death, remodeling, and repair in chronic obstructive pulmonary disease? Proc Am Thorac Soc 3(8):713–717CrossRefGoogle Scholar
  30. Hill AT, Bayley DL, Campbell EJ, Hill SL, Stockley RA (2000) Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency. Eur Respir J 15(5):886–890CrossRefGoogle Scholar
  31. Hodge S, Hodge G, Ahern J, Jersmann H, Holmes M, Reynolds PN (2007) Smoking alters alveolar macrophage recognition and phagocytic ability: implications in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 37(6):748–755CrossRefGoogle Scholar
  32. Hodge S, Hodge G, Holmes M, Reynolds PN (2005) Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation. Eur Respir J 25(3):447–454CrossRefGoogle Scholar
  33. Hofmann HS, Hansen G, Richter G, Taege C, Simm A, Silber RE, Burdach S (2005) Matrix metalloproteinase-12 expression correlates with local recurrence and metastatic disease in non-small cell lung cancer patients. Clin Cancer Res 11(3):1086–1092Google Scholar
  34. Houghton AM, Quintero PA, Perkins DL, Kobayashi DK, Kelley DG, Marconcini LA, Mecham RP, Senior RM, Shapiro SD (2006) Elastin fragments drive disease progression in a murine model of emphysema. J Clin Invest 116(3):753–759CrossRefGoogle Scholar
  35. Imai K, Mercer BA, Schulman LL, Sonett JR, D’Armiento JM (2005) Correlation of lung surface area to apoptosis and proliferation in human emphysema. Eur Respir J 25(2):250–258CrossRefGoogle Scholar
  36. Kanazawa H (2007) Role of vascular endothelial growth factor in the pathogenesis of chronic obstructive pulmonary disease. Med Sci Monit 13(11):RA189–RA195Google Scholar
  37. Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF (2001) Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med 163:737–744Google Scholar
  38. Kelsen SG, Aksoy MO, Georgy M, Hershman R, Ji R, Li X, Hurford M, Solomides C, Chatila W, Kim V (2009) Lymphoid follicle cells in chronic obstructive pulmonary disease overexpress the chemokine receptor CXCR3. Am J Respir Crit Care Med 179(9):799–805CrossRefGoogle Scholar
  39. Kim S, Nadel JA (2004) Role of neutrophils in mucus hypersecretion in COPD and implications for therapy. Treat Respir Med 3(3):147–159CrossRefGoogle Scholar
  40. Kirkham P (2007) Oxidative stress and macrophage function: a failure to resolve the inflammatory response. Biochem Soc Trans 35(Pt 2):284–287Google Scholar
  41. Kisseleva T, Brenner DA (2008) Fibrogenesis of parenchymal organs. Proc Am Thorac Soc 5(3):338–342CrossRefGoogle Scholar
  42. Kuwano K (2007) Epithelial cell apoptosis and lung remodeling. Cell Mol Immunol 4(6):419–429Google Scholar
  43. Lagente V, Manoury B, Nénan S, Le Quément C, Martin-Chouly C, Boichot E (2005) Role of matrix metalloproteinases in the development of airway inflammation and remodeling. Braz J Med Biol Res 38(10):1521–1530CrossRefGoogle Scholar
  44. Lagente V, Le Quement C, Boichot E (2009) Macrophage metalloelastase (MMP-12) as a target for inflammatory respiratory diseases. Expert Opin Ther Targets 13(3):287–295CrossRefGoogle Scholar
  45. Lambers C, Hacker S, Posch M, Hoetzenecker K, Pollreisz A, Lichtenauer M, Klepetko W, Ankersmit HJ (2009) T cell senescence and contraction of T cell repertoire diversity in patients with chronic obstructive pulmonary disease. Clin Exp Immunol 155(3):466–475CrossRefGoogle Scholar
  46. Lapperre TS, Sont JK, van Schadewijk A, Gosman MM, Postma DS, Bajema IM, Timens W, Mauad T, Hiemstra PS, GLUCOLD Study Group (2007) Smoking cessation and bronchial epithelial remodelling in COPD: a cross-sectional study. Respir Res 8:85CrossRefGoogle Scholar
  47. Lapperre TS, Postma DS, Gosman MM, Snoeck-Stroband JB, ten Hacken NH, Hiemstra PS, Timens W, Sterk PJ, Mauad T (2006) Relation between duration of smoking cessation and bronchial inflammation in COPD. Thorax 61(2):115–121CrossRefGoogle Scholar
  48. Li QY, Huang SG, Wan HY, Wu HC, Zhou T, Li M, Deng WW (2007) Effect of smoking cessation on airway inflammation of rats with chronic bronchitis. Chin Med J (Engl) 120(17):1511–1516Google Scholar
  49. Liu CY, Liu YH, Lin SM, Yu CT, Wang CH, Lin HC, Lin CH, Kuo HP (2003) Apoptotic neutrophils undergoing secondary necrosis induce human lung epithelial cell detachment. J Biomed Sci 10(6 Pt 2):746–756CrossRefGoogle Scholar
  50. Louhelainen N, Rytilä P, Haahtela T, Kinnula VL, Djukanović R (2009) Persistence of oxidant and protease burden in the airways after smoking cessation. BMC Pulm Med 9:25CrossRefGoogle Scholar
  51. MacNee W (2005) Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2(1):50–60CrossRefGoogle Scholar
  52. Maeno T, Houghton AM, Quintero PA, Grumelli S, Owen CA, Shapiro SD (2007) CD8+ T Cells are required for inflammation and destruction in cigarette smoke-induced emphysema in mice. J Immunol 178(12):8090–8096Google Scholar
  53. Maestrelli P, Saetta M, Mapp CE, Fabbri LM (2001) Remodeling in response to infection and injury. Airway inflammation and hypersecretion of mucus in smoking subjects with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 164(10 Pt 2):S76–S80Google Scholar
  54. Magno F, Di Stefano A (2007) Contribution of bronchial biopsies in the evaluation of pathogenesis and progression of COPD. Monaldi Arch Chest Dis 67(4):229–233Google Scholar
  55. Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, Tuder RM, Biswal S (2008) Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am J Respir Crit Care15:178(6):592–604. Epub 2008 June 12. Erratum in: Am J Respir Crit Care. 2009 Apr 1:179(7):624Google Scholar
  56. McPhillips K, Janssen WJ, Ghosh M, Byrne A, Gardai S, Remigio L, Bratton DL, Kang JL, Henson P (2007) TNF-alpha inhibits macrophage clearance of apoptotic cells via cytosolic phospholipase A2 and oxidant-dependent mechanisms. J Immunol 178(12):8117–8126Google Scholar
  57. Mizia-Stec K, Gasior Z, Zahorska-Markiewicz B, Holecki M, Kumor P (2006) Inflammatory markers in a 2-year follow-up of coronary artery disease. Heart Vessels 21(5):302–308CrossRefGoogle Scholar
  58. Mizia-Stec K, Zahorska-Markiewicz B, Gasior Z (2004) Cigarette smoking and inflammatory indices in coronary artery disease. Int J Cardiol 93(2–3):169–174CrossRefGoogle Scholar
  59. Morissette MC, Parent J, Milot J (2009) Alveolar epithelial and endothelial cell apoptosis in emphysema: what we know and what we need to know. Int J Chron Obstruct Pulmon Dis 4:19–31Google Scholar
  60. Muley T, Wiebel M, Schulz V, Ebert W (1994) Elastinolytic activity of alveolar macrophages in smoking-associated pulmonary emphysema. Clin Investig 72(4):269–276CrossRefGoogle Scholar
  61. Nénan S, Boichot E, Lagente V, Bertrand CP (2005) Macrophage elastase (MMP-12): a pro-inflammatory mediator? Mem Inst Oswaldo Cruz 100(Suppl 1):167–172CrossRefGoogle Scholar
  62. Noguera A, Batle S, Miralles C, Iglesias J, Busquets X, MacNee W, Agustí AG (2001) Enhanced neutrophil response in chronic obstructive pulmonary disease. Thorax 56(6):432–437CrossRefGoogle Scholar
  63. Nyunoya T, Monick MM, Klingelhutz A, Yarovinsky TO, Cagley JR, Hunninghake GW (2006) Cigarette smoke induces cellular senescence. Am J Respir Cell Mol Biol 35(6):681–688CrossRefGoogle Scholar
  64. Ofulue AF, Ko M, Abboud RT (1998) Time course of neutrophil and macrophage elastinolytic activities in cigarette smoke-induced emphysema. Am J Physiol 275(6 Pt 1):L1134–L1144Google Scholar
  65. O’Reilly P, Jackson PL, Noerager B, Parker S, Dransfield M, Gaggar A, Blalock JE (2009) N-alpha-PGP and PGP, potential biomarkers and therapeutic targets for COPD. Respir Res 10:38CrossRefGoogle Scholar
  66. Park JW, Ryter SW, Choi AM (2007) Functional significance of apoptosis in chronic obstructive pulmonary disease. COPD 4(4):347–353CrossRefGoogle Scholar
  67. Petrache I, Medler TR, Richter AT, Kamocki K, Chukwueke U, Zhen L, Gu Y, Adamowicz J, Schweitzer KS, Hubbard WC, Berdyshev EV, Lungarella G, Tuder RM (2008) Superoxide dismutase protects against apoptosis and alveolar enlargement induced by ceramide. Am J Physiol Lung Cell Mol Physiol 295(1):L44–L53CrossRefGoogle Scholar
  68. Plataki M, Tzortzaki E, Rytila P, Demosthenes M, Koutsopoulos A, Siafakas NM (2006) Apoptotic mechanisms in the pathogenesis of COPD. Int J Chron Obstruct Pulmon Dis 1(2):161–171Google Scholar
  69. Pons AR, Noguera A, Blanquer D, Sauleda J, Pons J, Agustí AG (2005a) Phenotypic characterisation of alveolar macrophages and peripheral blood monocytes in COPD. Eur Respir J 25(4):647–652CrossRefGoogle Scholar
  70. Pons AR, Sauleda J, Noguera A, Pons J, Barceló B, Fuster A, Agustí AG (2005b) Decreased macrophage release of TGF-beta and TIMP-1 in chronic obstructive pulmonary disease. Eur Respir J 26(1):60–66CrossRefGoogle Scholar
  71. Puchelle E, Zahm JM, Tournier JM, Coraux C (2006) Airway epithelial repair, regeneration, and remodeling after injury in chronic obstructive pulmonary disease. Proc Am Thorac Soc 3(8):726–733CrossRefGoogle Scholar
  72. Richens TR, Linderman DJ, Horstmann SA, Lambert C, Xiao YQ, Keith RL, Boé DM, Morimoto K, Bowler RP, Day BJ, Janssen WJ, Henson PM, Vandivier RW (2009) Cigarette smoke impairs clearance of apoptotic cells through oxidant-dependent activation of RhoA. Am J Respir Crit Care Med 179(11):1011–1021CrossRefGoogle Scholar
  73. Saetta M, Di Stefano A, Turato G, Facchini FM, Corbino L, Mapp CE, Maestrelli P, Ciaccia A, Fabbri LM (1998) CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 157(3 Pt 1):822–826Google Scholar
  74. Saetta M, Turato G, Baraldo S, Zanin A, Braccioni F, Mapp CE, Maestrelli P, Cavallesco G, Papi A, Fabbri LM (2000) Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am J Respir Crit Care Med 161(3 Pt 1):1016–1021Google Scholar
  75. Shapiro SD, Goldstein NM, Houghton AM, Kobayashi DK, Kelley D, Belaaouaj A (2003) Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice. Am J Pathol 163(6):2329–2335CrossRefGoogle Scholar
  76. Shaykhiev R, Krause A, Salit J, Strulovici-Barel Y, Harvey BG, O’Connor TP, Crystal RG (2009) Smoking-dependent reprogramming of alveolar macrophage polarization: Implication for pathogenesis of chronic obstructive pulmonary disease. J ImmunolGoogle Scholar
  77. Shifren A, Mecham RP (2006) The stumbling block in lung repair of emphysema: elastic fiber assembly. Proc Am Thorac Soc 3(5):428–433CrossRefGoogle Scholar
  78. Smyth LJ, Starkey C, Gordon FS, Vestbo J, Singh D (2008) CD8 chemokine receptors in chronic obstructive pulmonary disease. Clin Exp Immunol 154(1):56–63CrossRefGoogle Scholar
  79. Smyth LJ, Starkey C, Vestbo J, Singh D (2007) CD4-regulatory cells in COPD patients. Chest 132(1):156–163CrossRefGoogle Scholar
  80. Suki B, Bates JH (2008) Extracellular matrix mechanics in lung parenchymal diseases. Respir Physiol Neurobiol 163(1–3):33–43CrossRefGoogle Scholar
  81. Takami M, Terry V, Petruzzelli L (2002) Signaling pathways involved in IL-8-dependent activation of adhesion through Mac-1. J Immunol 168(9):4559–4566Google Scholar
  82. Tetley TD (2002) Macrophages and the pathogenesis of COPD. Chest 121(5 Suppl):156S–159SCrossRefGoogle Scholar
  83. Tetley TD (2005) Inflammatory cells and chronic obstructive pulmonary disease. Curr Drug Targets Inflamm Allergy 4(6):607–618CrossRefGoogle Scholar
  84. Thorley AJ, Tetley TD (2007) Pulmonary epithelium, cigarette smoke, and chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2(4):409–428Google Scholar
  85. Tsuji T, Aoshiba K, Nagai A (2006) Alveolar cell senescence in patients with pulmonary emphysema. Am J Respir Crit Care Med 174(8):886–893CrossRefGoogle Scholar
  86. Tsuji T, Aoshiba K, Nagai A (2004) Cigarette smoke induces senescence in alveolar epithelial cells. Am J Respir Cell Mol Biol 31(6):643–649CrossRefGoogle Scholar
  87. Tuder RM, Yun JH, Graham BB (2008) Cigarette smoke triggers code red: p21CIP1/WAF1/SDI1 switches on danger responses in the lung. Am J Respir Cell Mol Biol 39(1):1–6CrossRefGoogle Scholar
  88. Tuder RM, Yoshida T, Fijalkowka I, Biswal S, Petrache I (2006) Role of lung maintenance program in the heterogeneity of lung destruction in emphysema. Proc Am Thorac Soc 3(8):673–679CrossRefGoogle Scholar
  89. Tuder RM, Zhen L, Cho CY, Taraseviciene-Stewart L, Kasahara Y, Salvemini D, Voelkel NF, Flores SC (2003) Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. Am J Respir Cell Mol Biol 29(1):88–97CrossRefGoogle Scholar
  90. Valença SS, Porto LC (2008) Immunohistochemical study of lung remodeling in mice exposed to cigarette smoke. J Bras Pneumol 34(10):787–795CrossRefGoogle Scholar
  91. Van Tiel E, Peeters PH, Smit HA, Nagelkerke NJ, Van Loon AJ, Grobbee DE, Bueno-de-Mesquita HB (2002) Quitting smoking may restore hematological characteristics within five years. Ann Epidemiol 12(6):378–388CrossRefGoogle Scholar
  92. Wallace WA, Gillooly M, Lamb D (1992) Intra-alveolar macrophage numbers in current smokers and non-smokers: a morphometric study of tissue sections. Thorax 47(6):437–440CrossRefGoogle Scholar
  93. Wang H, Liu X, Umino T, Kohyama T, Zhu YK, Wen FQ, Spurzem JR, Romberger DJ, Kim HJ, Rennard SI (2003) Effect of cigarette smoke on fibroblast-mediated gel contraction is dependent on cell density. Am J Physiol Lung Cell Mol Physiol 284(1):L205–L213Google Scholar
  94. Wang H, Liu X, Umino T, Sköld CM, Zhu Y, Kohyama T, Spurzem JR, Romberger DJ, Rennard SI (2001) Cigarette smoke inhibits human bronchial epithelial cell repair processes. Am J Respir Cell Mol Biol 25(6):772–779Google Scholar
  95. Willemse BW, ten Hacken NH, Rutgers B, Lesman-Leegte IG, Postma DS, Timens W (2005) Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smokers. Eur Respir J 26(5):835–845CrossRefGoogle Scholar
  96. Xie S, Issa R, Sukkar MB, Oltmanns U, Bhavsar PK, Papi A, Caramori G, Adcock I, Chung KF (2005) Induction and regulation of matrix metalloproteinase-12 in human airway smooth muscle cells. Respir Res 6:148CrossRefGoogle Scholar
  97. Yao H, Rahman I (2009) Current concepts on the role of inflammation in COPD and lung cancer. Curr Opin Pharmacol 9(4):375–383CrossRefGoogle Scholar
  98. Yao H, Yang SR, Edirisinghe I, Rajendrasozhan S, Caito S, Adenuga D, O'Reilly MA, Rahman I (2008) Disruption of p21 attenuates lung inflammation induced by cigarette smoke, LPS, and fMLP in mice. Am J Respir Cell Mol Biol 39(1):7–18CrossRefGoogle Scholar
  99. Yokohori N, Aoshiba K, Nagai A, Respiratory Failure Research Group in Japan (2004) Increased levels of cell death and proliferation in alveolar wall cells in patients with pulmonary emphysema. Chest 125(2):626–632CrossRefGoogle Scholar
  100. Zandvoort A, Postma DS, Jonker MR, Noordhoek JA, Vos JT, Timens W (2008) Smad gene expression in pulmonary fibroblasts: indications for defective ECM repair in COPD. Respir Res 9:83CrossRefGoogle Scholar

Copyright information

© Louis Anthony Cox, Jr 2012

Authors and Affiliations

  • Louis Anthony CoxJr.
    • 1
  1. 1.Cox AssociatesDenverUSA

Personalised recommendations