Pathogenesis of Inflammation and Repair in Advanced COPD

William D Cornwell; Victor Kim; Changcheng Song; Thomas J Rogers

doi:10.1055/s-0030-1254066

Seminars in Respiratory and Critical Care Medicine, Table of Contents

Semin Respir Crit Care Med 2010; 31(3): 257-266
DOI: 10.1055/s-0030-1254066

Pathogenesis of Inflammation and Repair in Advanced COPD

William D. Cornwell¹ , Victor Kim² , Changcheng Song¹ , Thomas J. Rogers¹

¹Fels Institute for Cancer Research and Molecular Biology, Center for Substance Abuse Research, Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania
²Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania

Abstract

ABSTRACT

Chronic obstructive pulmonary disease is characterized by an abnormal persistent inflammatory response to noxious environmental stimuli, most commonly cigarette smoke. Although cigarette smoking elicits airway inflammation in all of those who smoke, persistent inflammation and clinically significant COPD occurs in only a minority of smokers. The pathogenesis of COPD involves the recruitment and regulation of neutrophils, macrophages, and lymphocytes to the lung, as well as the induction of oxidative stress, all of which result in lung parenchymal destruction and airway remodeling. Recent research has generated a greater understanding of the mechanisms responsible for COPD development, including new concepts in T cell biology and the increasing recognition that the processes governing lung cell apoptosis are upregulated. We are also starting to understand the reasons for continued inflammation even after smoking cessation, which accelerates the rate of lung function decline in COPD. Herein we review our current knowledge of the inflammatory pathways involved in COPD pathogenesis, as well as newer concepts that have begun to unfold in recent years.

KEYWORDS

Chronic obstructive pulmonary disease - oxidative stress - apoptosis - inflammatory cells - cytokines

Full Text

References

REFERENCES

1 Pauwels R A, Buist A S, Ma P, Jenkins C R, Hurd S S. GOLD Scientific Committee . Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD): executive summary. Respir Care. 2001; 46 798-825
2 Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ. 1977; 1 1645-1648
3 Xu X, Weiss S T, Rijcken B, Schouten J P. Smoking, changes in smoking habits, and rate of decline in FEV1: new insight into gender differences. Eur Respir J. 1994; 7 1056-1061
4 American Thoracic Society . Cigarette smoking and health. Am J Respir Crit Care Med. 1996; 153 861-865
5 Larsson K. Aspects on pathophysiological mechanisms in COPD. J Intern Med. 2007; 262 311-340
6 Quint J K, Wedzicha J A. The neutrophil in chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2007; 119 1065-1071
7 Barnes P J. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2008; 8 183-192
8 Beeh K M, Kornmann O, Buhl R, Culpitt S V, Giembycz M A, Barnes P J. Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4. Chest. 2003; 123 1240-1247
9 Tanino M, Betsuyaku T, Takeyabu K et al.. Increased levels of interleukin-8 in BAL fluid from smokers susceptible to pulmonary emphysema. Thorax. 2002; 57 405-411
10 Traves S L, Culpitt S V, Russell R E, Barnes P J, Donnelly L E. Increased levels of the chemokines GROalpha and MCP-1 in sputum samples from patients with COPD. Thorax. 2002; 57 590-595
11 Hartl D, Latzin P, Hordijk P et al.. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat Med. 2007; 13 1423-1430
12 Qiu Y, Zhu J, Bandi V 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; 168 968-975
13 Cosio M G, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med. 2009; 360 2445-2454
14 Saetta M, Di Stefano A, Turato G et al.. CD8 + T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998; 157(3 Pt 1) 822-826
15 Hodge S, Hodge G, Nairn J, Holmes M, Reynolds P N. Increased airway granzyme b and perforin in current and ex-smoking COPD subjects. COPD. 2006; 3 179-187
16 Barczyk A, Pierzchała W, Kon O M, Cosio B, Adcock I M, Barnes P J. Cytokine production by bronchoalveolar lavage T lymphocytes in chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2006; 117 1484-1492
17 Shaykhiev R, Krause A, Salit J et al.. Smoking-dependent reprogramming of alveolar macrophage polarization: implication for pathogenesis of chronic obstructive pulmonary disease. J Immunol. 2009; 183 2867-2883
18 Hogg J C, Chu F, Utokaparch S et al.. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004; 350 2645-2653
19 Retamales I, Elliott W M, Meshi B et al.. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med. 2001; 164 469-473
20 Sullivan A K, Simonian P L, Falta M T et al.. Oligoclonal CD4 + T cells in the lungs of patients with severe emphysema. Am J Respir Crit Care Med. 2005; 172 590-596
21 Grumelli S, Corry D B, Song L Z et al.. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Med. 2004; 1 e8
22 Di Stefano A, Caramori G, Capelli A et al.. STAT4 activation in smokers and patients with chronic obstructive pulmonary disease. Eur Respir J. 2004; 24 78-85
23 Saetta M, Di Stefano A, Maestrelli P et al.. Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am Rev Respir Dis. 1993; 147 301-306
24 Finkelstein R, Fraser R S, Ghezzo H, Cosio M G. Alveolar inflammation and its relation to emphysema in smokers. Am J Respir Crit Care Med. 1995; 152(5 Pt 1) 1666-1672
25 Corthay A. How do regulatory T cells work?. Scand J Immunol. 2009; 70 326-336
26 Barceló B, Pons J, Ferrer J M, Sauleda J, Fuster A, Agustí A G. Phenotypic characterisation of T-lymphocytes in COPD: abnormal CD4 + CD25 + regulatory T-lymphocyte response to tobacco smoking. Eur Respir J. 2008; 31 555-562
27 Korn T, Bettelli E, Oukka M, Kuchroo V K. IL-17 and Th17 Cells. Annu Rev Immunol. 2009; 27 485-517
28 Di Stefano A, Caramori G, Gnemmi I et al.. T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients. Clin Exp Immunol. 2009; 157 316-324
29 Wu C H, Lin H H, Yan F P, Wu C H, Wang C J. Immunohistochemical detection of apoptotic proteins, p53/Bax and JNK/FasL cascade, in the lung of rats exposed to cigarette smoke. Arch Toxicol. 2006; 80 328-336
30 Park H, Li Z, Yang X O et al.. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005; 6 1133-1141
31 Koenen H J, Smeets R L, Vink P M, van Rijssen E, Boots A M, Joosten I. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood. 2008; 112 2340-2352
32 Martinez F O, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009; 27 451-483
33 Serbina N V, Jia T, Hohl T M, Pamer E G. Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol. 2008; 26 421-452
34 Hoser G, Domagała-Kulawik J, Droszcz P, Droszcz W, Kawiak J. Lymphocyte subsets differences in smokers and nonsmokers with primary lung cancer: a flow cytometry analysis of bronchoalveolar lavage fluid cells. Med Sci Monit. 2003; 9 BR310-BR315
35 Mancini N M, Béné M C, Gérard H et al.. Early effects of short-time cigarette smoking on the human lung: a study of bronchoalveolar lavage fluids. Lung. 1993; 171 277-291
36 Soler P, Moreau A, Basset F, Hance A J. Cigarette smoking-induced changes in the number and differentiated state of pulmonary dendritic cells/Langerhans cells. Am Rev Respir Dis. 1989; 139 1112-1117
37 Casolaro M A, Bernaudin J F, Saltini C, Ferrans V J, Crystal R G. Accumulation of Langerhans' cells on the epithelial surface of the lower respiratory tract in normal subjects in association with cigarette smoking. Am Rev Respir Dis. 1988; 137 406-411
38 Tsoumakidou M, Elston W, Zhu J et al.. Cigarette smoking alters bronchial mucosal immunity in asthma. Am J Respir Crit Care Med. 2007; 175 919-925
39 Rogers A V, Adelroth E, Hattotuwa K, Dewar A, Jeffery P K. Bronchial mucosal dendritic cells in smokers and ex-smokers with COPD: an electron microscopic study. Thorax. 2008; 63 108-114
40 Vassallo R, Tamada K, Lau J S, Kroening P R, Chen L. Cigarette smoke extract suppresses human dendritic cell function leading to preferential induction of Th-2 priming. J Immunol. 2005; 175 2684-2691
41 Robbins C S, Dawe D E, Goncharova S I et al.. Cigarette smoke decreases pulmonary dendritic cells and impacts antiviral immune responsiveness. Am J Respir Cell Mol Biol. 2004; 30 202-211
42 D'hulst A I, Vermaelen K Y, Brusselle G G, Joos G F, Pauwels R A. Time course of cigarette smoke-induced pulmonary inflammation in mice. Eur Respir J. 2005; 26 204-213
43 Buist A S, Vollmer W M, McBurnie M A. Worldwide burden of COPD in high- and low-income countries, I: The burden of obstructive lung disease (BOLD) initiative. Int J Tuberc Lung Dis. 2008; 12 703-708
44 Niewoehner D E, Kleinerman J, Rice D B. Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med. 1974; 291 755-758
45 Bosken C H, Hards J, Gatter K, Hogg J C. Characterization of the inflammatory reaction in the peripheral airways of cigarette smokers using immunocytochemistry. Am Rev Respir Dis. 1992; 145(4 Pt 1) 911-917
46 Lams B E, Sousa A R, Rees P J, Lee T H. Immunopathology of the small-airway submucosa in smokers with and without chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998; 158(5 Pt 1) 1518-1523
47 Saetta M, Baraldo S, Corbino L et al.. CD8 + ve cells in the lungs of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999; 160 711-717
48 Amin K, Ekberg-Jansson A, Löfdahl C G, Venge P. Relationship between inflammatory cells and structural changes in the lungs of asymptomatic and never smokers: a biopsy study. Thorax. 2003; 58 135-142
49 Innes A L, Woodruff P G, Ferrando R E et al.. Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction. Chest. 2006; 130 1102-1108
50 Saetta M, Turato G, Baraldo S et al.. 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. 2000; 161(3 Pt 1) 1016-1021
51 Baraldo S, Saetta M, Cosio M G. Pathophysiology of the small airways. Semin Respir Crit Care Med. 2003; 24 465-472
52 Wright J L, Hobson J, Wiggs B R, Pare P D, Hogg J C. Effect of cigarette smoking on structure of the small airways. Lung. 1987; 165 91-100
53 Swan G E, Hodgkin J E, Roby T, Mittman C, Jacobo N, Peters J. Reversibility of airways injury over a 12-month period following smoking cessation. Chest. 1992; 101 607-612
54 Verbanck S, Schuermans D, Paiva M, Meysman M, Vincken W. Small airway function improvement after smoking cessation in smokers without airway obstruction. Am J Respir Crit Care Med. 2006; 174 853-857
55 Xu X, Dockery D W, Ware J H, Speizer F E, Ferris Jr B G. Effects of cigarette smoking on rate of loss of pulmonary function in adults: a longitudinal assessment. Am Rev Respir Dis. 1992; 146(5 Pt 1) 1345-1348
56 Anthonisen N R, Connett J E, Kiley J P et al.. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA. 1994; 272 1497-1505
57 Murray R P, Anthonisen N R, Connett J E Lung Health Study Research Group et al. Effects of multiple attempts to quit smoking and relapses to smoking on pulmonary function. J Clin Epidemiol. 1998; 51 1317-1326
58 Wright J L, Lawson L M, Pare P D, Wiggs B J, Kennedy S, Hogg J C. Morphology of peripheral airways in current smokers and ex-smokers. Am Rev Respir Dis. 1983; 127 474-477
59 Rutgers S R, Postma D S, Kauffman H F, Koeter G H, Timens W, ten Hacken N H, van Der Mark T W. Ongoing airway inflammation in patients with COPD who do not currently smoke. Chest. 2000; 117(5, Suppl 1) 262S
60 MacNee W. Pathogenesis of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005; 2 258-266 discussion 290-291
61 Sethi S, Mallia P, Johnston S L. New paradigms in the pathogenesis of chronic obstructive pulmonary disease II. Proc Am Thorac Soc. 2009; 6 532-534
62 Moghaddam S J, Clement C G, De la Garza M M et al.. Haemophilus influenzae lysate induces aspects of the chronic obstructive pulmonary disease phenotype. Am J Respir Cell Mol Biol. 2008; 38 629-638
63 Morris A, Sciurba F C, Lebedeva I P et al.. Association of chronic obstructive pulmonary disease severity and Pneumocystis colonization. Am J Respir Crit Care Med. 2004; 170 408-413
64 Sethi S, Evans N, Grant B J, Murphy T F. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 2002; 347 465-471
65 Seemungal T, Harper-Owen R, Bhowmik A et al.. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001; 164 1618-1623
66 Bandi V, Apicella M A, Mason E et al.. Nontypeable Haemophilus influenzae in the lower respiratory tract of patients with chronic bronchitis. Am J Respir Crit Care Med. 2001; 164 2114-2119
67 Sethi S. Pathogenesis and treatment of acute exacerbations of chronic obstructive pulmonary disease. Semin Respir Crit Care Med. 2005; 26 192-203
68 Nathan C, Shiloh M U. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc Natl Acad Sci U S A. 2000; 97 8841-8848
69 Daga M K, Chhabra R, Sharma B, Mishra T K. Effects of exogenous vitamin E supplementation on the levels of oxidants and antioxidants in chronic obstructive pulmonary disease. J Biosci. 2003; 28 7-11
70 Harju T H, Peltoniemi M J, Rytilä P H et al.. Glutathione S-transferase omega in the lung and sputum supernatants of COPD patients. Respir Res. 2007; 8 48
71 Nadeem A, Raj H G, Chhabra S K. Increased oxidative stress and altered levels of antioxidants in chronic obstructive pulmonary disease. Inflammation. 2005; 29 23-32
72 Kluchová Z, Petrásová D, Joppa P, Dorková Z, Tkácová R. The association between oxidative stress and obstructive lung impairment in patients with COPD. Physiol Res. 2007; 56 51-56
73 Kanazawa H, Shiraishi S, Hirata K, Yoshikawa J. Imbalance between levels of nitrogen oxides and peroxynitrite inhibitory activity in chronic obstructive pulmonary disease. Thorax. 2003; 58 106-109
74 Gumral N, Naziroglu M, Ongel K et al.. Antioxidant enzymes and melatonin levels in patients with bronchial asthma and chronic obstructive pulmonary disease during stable and exacerbation periods. Cell Biochem Funct. 2009; 27 276-283
75 Altuntaş E, Turgut T, Ilhan N, Deveci F, Muz H M, Celik I. The levels of oxidant and antioxidant in patients with COPD [in Turkish]. Tuberk Toraks. 2003; 51 373-379
76 Moretti M. Erdosteine: its relevance in COPD treatment. Expert Opin Drug Metab Toxicol. 2009; 5 333-343
77 Kirkil G, Hamdi Muz M, Seçkin D, Sahin K, Küçük O. Antioxidant effect of zinc picolinate in patients with chronic obstructive pulmonary disease. Respir Med. 2008; 102 840-844
78 van Overveld F J, Demkow U, Górecka D, de Backer W A, Zielinski J. New developments in the treatment of COPD: comparing the effects of inhaled corticosteroids and N-acetylcysteine. J Physiol Pharmacol. 2005; 56(Suppl 4) 135-142
79 Massaro G D, Massaro D. Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nat Med. 1997; 3 675-677
80 Ishizawa K, Kubo H, Yamada M et al.. Bone marrow-derived cells contribute to lung regeneration after elastase-induced pulmonary emphysema. FEBS Lett. 2004; 556 249-252
81 Murakami S, Nagaya N, Itoh T et al.. Adrenomedullin regenerates alveoli and vasculature in elastase-induced pulmonary emphysema in mice. Am J Respir Crit Care Med. 2005; 172 581-589
82 Shigemura N, Sawa Y, Mizuno S et al.. Amelioration of pulmonary emphysema by in vivo gene transfection with hepatocyte growth factor in rats. Circulation. 2005; 111 1407-1414
83 Lucey E C, Goldstein R H, Breuer R, Rexer B N, Ong D E, Snider G L. Retinoic acid does not affect alveolar septation in adult FVB mice with elastase-induced emphysema. Respiration. 2003; 70 200-205
84 March T H, Cossey P Y, Esparza D C, Dix K J, McDonald J D, Bowen L E. Inhalation administration of all-trans-retinoic acid for treatment of elastase-induced pulmonary emphysema in Fischer 344 rats. Exp Lung Res. 2004; 30 383-404
85 Roth M D, Connett J E, D'Armiento J M FORTE Study Investigators et al. Feasibility of retinoids for the treatment of emphysema study. Chest. 2006; 130 1334-1345
86 Lian X, Yan C, Yang L, Xu Y, Du H. Lysosomal acid lipase deficiency causes respiratory inflammation and destruction in the lung. Am J Physiol Lung Cell Mol Physiol. 2004; 286 L801-L807
87 Yan C, Du H. Alveolus formation: what have we learned from genetic studies?. J Appl Physiol. 2004; 97 1543-1548
88 Yokohori N, Aoshiba K, Nagai A. Respiratory Failure Research Group in Japan . Increased levels of cell death and proliferation in alveolar wall cells in patients with pulmonary emphysema. Chest. 2004; 125 626-632
89 Henson P M, Cosgrove G P, Vandivier R W. State of the art: apoptosis and cell homeostasis in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2006; 3 512-516
90 Kasahara Y, Tuder R M, Taraseviciene-Stewart L et al.. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest. 2000; 106 1311-1319
91 Tang K, Rossiter H B, Wagner P D, Breen E C. Lung-targeted VEGF inactivation leads to an emphysema phenotype in mice. J Appl Physiol. 2004; 97 1559-1566, discussion 1549
92 Tuder R M, Zhen L, Cho C Y et al.. Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. Am J Respir Cell Mol Biol. 2003; 29 88-97
93 Kasahara Y, Tuder R M, Cool C D, Lynch D A, Flores S C, Voelkel N F. 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. 2001; 163(3 Pt 1) 737-744
94 Petrache I, Natarajan V, Zhen L et al.. Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nat Med. 2005; 11 491-498
95 Yang S R, Chida A S, Bauter M R et al.. Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol. 2006; 291 L46-L57
96 Aoshiba K, Tamaoki J, Nagai A. Acute cigarette smoke exposure induces apoptosis of alveolar macrophages. Am J Physiol Lung Cell Mol Physiol. 2001; 281 L1392-L1401
97 Kuo W H, Chen J H, Lin H H, Chen B C, Hsu J D, Wang C J. Induction of apoptosis in the lung tissue from rats exposed to cigarette smoke involves p38/JNK MAPK pathway. Chem Biol Interact. 2005; 155 31-42
98 Carnevali S, Petruzzelli S, Longoni B et al.. Cigarette smoke extract induces oxidative stress and apoptosis in human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2003; 284 L955-L963
99 Taraseviciene-Stewart L, Scerbavicius R, Choe K H et al.. An animal model of autoimmune emphysema. Am J Respir Crit Care Med. 2005; 171 734-742
100 Feghali-Bostwick C A, Gadgil A S, Otterbein L E et al.. Autoantibodies in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008; 177 156-163

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