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Correspondence |

Is the Inflammatory Response of the Lungs in COPD Abnormal?Is the Inflammatory Response in COPD Abnormal? FREE TO VIEW

Nikolaos M. Siafakas, MD, PhD; Eleni G. Tzortzaki, MD, PhD
Author and Funding Information

From the Department of Thoracic Medicine, Medical School, University of Crete.

Correspondence to: Nikolaos Siafakas, MD, PhD, Department of Thoracic Medicine, Medical School, University of Crete, Panepistimiou Ave, Heraklion, 71110, Greece; e-mail:siafak@med.uoc.gr


Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;140(2):561-562. doi:10.1378/chest.11-0224
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To the Editor:

The current definition of COPD includes the statement that “the airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking.”1 The term “abnormal inflammatory response” was first introduced in the definition of COPD in the 2001 GOLD (Global Initiative for Chronic Obstructive Lung Disease) article,2 and since then the same phrase has been used in the definition of the disease. Even in a recent article in CHEST (February 2011) by van den Berge and colleagues3 on small airways disease, the same term was used in the COPD definition.

This letter aims to challenge the word “abnormal” and to propose its omission from the definition of the disease in the future. New evidence related to COPD pathogenesis has emerged to support the thought that the lungs respond against cigarette smoke in a rather normal or common way of self-defending.4-6

A cigarette contains thousands of xenobiotic compounds and free radicals that injure lung epithelium to a degree that is directly proportionate to their concentration. The first lines of lung defense are the epithelial barrier cells of the upper and lower airways and the innate immunity molecules.6,7 When toxic substances, or antigens, reach the interstitium, dendritic cells pick up the intruders and report antigenic information to the pulmonary lymph nodes, initiating an adaptive immune response.4-6

In detail, lung epithelial barrier cells (LEBCs) line the luminal surface of the airways and are attached to neighboring cells by several structures and junctions, constituting the initial mechanical barrier in lung defense.6,7 Epithelial cells, when injured by bacterial products, viruses, oxidants, or cigarette smoke, can recruit inflammatory cells by releasing chemokines and mediators. These mediators activate alveolar macrophages and neutrophils, which in turn secrete proteolytic enzymes and, together with reactive oxygen species, damage lung tissue.4-7 Although various cellular protective mechanisms constituting an antioxidant system are in place to limit oxidative events in the cell, an imbalance of oxidants and antioxidants can impose oxidative stress upon a cell, with nucleic acid being an important target for oxidation, especially the base composition of repeated sequences, such as the microsatellite DNA.5,7,8

Microsatellite DNA instability has been found in sputum cells of patients with COPD.5,8,9 Specifically, recent studies in patients with COPD have shown microsatellite instability exclusively in the lung epithelial cell subpopulation,8 supporting the hypothesis that persistent inflammation and oxidative burden in COPD could affect the cellular component of the air-lung barrier system, leading to oxidative DNA damage and consequent somatic mutations of the lung epithelia.5,8,9

When altered, LEBCs emit warning signals for detection and repair of the damage. According to the “danger theory” of Matzinger,10 the cellular injury from any cause alerts the immune system to respond, through the release of danger signals. The adaptive immune system can recognize these products as foreign antigens and trigger an immune reaction.10 Particularly in COPD, such “antigens” could be acquired from the oxidative DNA-damaged cells. At this point, the immune system reacts following the same path as in any invasion; the “danger signal” is taken up by dendritic cells and presented to the innate immune system as “non-self” danger signals,4,5 generating a cytotoxic CD8+ T lymphocyte response. Such T cells are abundant in the lungs of subjects with COPD.4,6

Similar to host immune response to a viral infection, CD8+ T cells attack the altered LEBCs, performing cytotoxic functions via perforin and granzymes.4-6 The insertion of granzymes in the LEBCs activates specific apoptotic pathways, leading to cell death. Thus, it appears that the immune system reacts in a similar manner as to any intruder, by following analogous paths toward “damaged” cells even if it must turn against its own self.4,5,10

To our way of thinking, all of the above is characterizing a normal rather than an abnormal inflammatory response. Humans have been fighting pathogens for millions of years and have developed a quite efficient immune response in most cases. We assume that the same pathway is activated against cigarette smoking, a human habit obtained rather recently—only 500 years ago.

We propose that since we do not call the defense responses against infections abnormal, we should not call the inflammatory response in COPD abnormal. At this point, we suggest the exclusion of the term “abnormal” from the definition of COPD.

Global Initiative for Chronic Obstructive Lung DiseaseGlobal Initiative for Chronic Obstructive Lung Disease Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (GOLD). GOLD Web site.http://www.goldcopd.com. Accessed November 3, 2010.
 
Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. GOLD Scientific Committee GOLD Scientific Committee Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001;1635:1256-1276. [PubMed]
 
van den Berge M, ten Hacken NHT, Cohen J, Douma WR, Postma DS. Small airway disease in asthma and COPD: clinical implications. Chest. 2011;1392:412-423. [CrossRef] [PubMed]
 
Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med. 2009;36023:2445-2454. [CrossRef] [PubMed]
 
Tzortzaki EG, Siafakas NM. A hypothesis for the initiation of COPD. Eur Respir J. 2009;342:310-315. [CrossRef] [PubMed]
 
Nicod LP. Lung defences: an overview. Eur Respir Rev. 2005;1495:45-50. [CrossRef]
 
Petecchia L, Sabatini F, Varesio L, et al. Bronchial airway epithelial cell damage following exposure to cigarette smoke includes disassembly of tight junction components mediated by the extracellular signal-regulated kinase 1/2 pathway. Chest. 2009;1356:1502-1512. [CrossRef] [PubMed]
 
Samara KD, Tzortzaki EG, Neofytou E, et al. Somatic DNA alterations in lung epithelial barrier cells in COPD patients. Pulm Pharmacol Ther. 2010;233:208-214. [CrossRef] [PubMed]
 
Makris D, Tzanakis N, Damianaki A, et al. Microsatellite DNA instability and COPD exacerbations. Eur Respir J. 2008;323:612-618. [CrossRef] [PubMed]
 
Matzinger P. The danger model: a renewed sense of self. Science. 2002;2965566:301-305. [CrossRef] [PubMed]
 

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References

Global Initiative for Chronic Obstructive Lung DiseaseGlobal Initiative for Chronic Obstructive Lung Disease Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (GOLD). GOLD Web site.http://www.goldcopd.com. Accessed November 3, 2010.
 
Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. GOLD Scientific Committee GOLD Scientific Committee Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001;1635:1256-1276. [PubMed]
 
van den Berge M, ten Hacken NHT, Cohen J, Douma WR, Postma DS. Small airway disease in asthma and COPD: clinical implications. Chest. 2011;1392:412-423. [CrossRef] [PubMed]
 
Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med. 2009;36023:2445-2454. [CrossRef] [PubMed]
 
Tzortzaki EG, Siafakas NM. A hypothesis for the initiation of COPD. Eur Respir J. 2009;342:310-315. [CrossRef] [PubMed]
 
Nicod LP. Lung defences: an overview. Eur Respir Rev. 2005;1495:45-50. [CrossRef]
 
Petecchia L, Sabatini F, Varesio L, et al. Bronchial airway epithelial cell damage following exposure to cigarette smoke includes disassembly of tight junction components mediated by the extracellular signal-regulated kinase 1/2 pathway. Chest. 2009;1356:1502-1512. [CrossRef] [PubMed]
 
Samara KD, Tzortzaki EG, Neofytou E, et al. Somatic DNA alterations in lung epithelial barrier cells in COPD patients. Pulm Pharmacol Ther. 2010;233:208-214. [CrossRef] [PubMed]
 
Makris D, Tzanakis N, Damianaki A, et al. Microsatellite DNA instability and COPD exacerbations. Eur Respir J. 2008;323:612-618. [CrossRef] [PubMed]
 
Matzinger P. The danger model: a renewed sense of self. Science. 2002;2965566:301-305. [CrossRef] [PubMed]
 
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