help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Snider, G. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Snider, G. L.
American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1045-1046, (2003)
© 2003 American Thoracic Society

Editorial

Understanding Inflammation in Chronic Obstructive Pulmonary Disease

The Process Begins

Gordon L. Snider, M.D.

Boston University School of Medicine Veterans Affairs Boston Healthcare System Boston, Massachusetts

Chronic obstructive pulmonary disease (COPD) may be defined as a disease state characterized by incompletely reversible, progressive airflow obstruction that is associated with inflammation in the lungs caused by prolonged exposure to tobacco smoke and other noxious particles and gases (1). COPD causes symptoms, disability, and death only after many decades of smoking. Inflammation is present for many years before the development of bronchiolitis and emphysema, the two structural causes of irreversible airflow obstruction. Studies of inflammation in COPD have generally been done in established disease. Little information is available on the natural history of inflammation from the time of inception of smoking (2).

Neutrophils, eosinophils, alveolar macrophages, and lymphocytes all appear to participate in the inflammatory process associated with COPD. However, the respective importance of these cells is difficult to interpret. Soon after the report in 1964 of early-onset emphysema associated with severe {alpha}1-antitrypsin deficiency (3), neutrophils and neutrophil elastase were accorded primacy in the hypotheses linking the inflammatory process and emphysema. Because of the large increase in number of alveolar macrophages in COPD, however, many thought these cells must also play a role in pathogenesis (4, 5). The discovery of a large array of metalloproteases originating in macrophages added support to this hypothesis (6).

In 1997, Hautamaki and colleagues (7) reported that wild-type mice, with the metalloelastase gene (MMP-12+/+) intact, developed emphysema after chronic exposure to cigarette smoke. Mice with the gene for metalloelastase knocked out (MMP-12-/-) did not. Neither did they develop an increase in macrophages or neutrophils in their lungs. Administration of monocyte chemoattractant protein-1 to the knockout mice resulted in increased MMP-12-/- lung macrophages but they still did not develop emphysema.

Experiments on acute cigarette smoke exposure in mice from the laboratory of Wright and Churg have provided the likely, but unexpected, explanation of why macrophage metalloprotease is essential for production of matrix damage. These investigators first reported (8) that after acute smoke exposure, mice developed a large increase in neutrophils but only a small increase in macrophages in bronchoalveolar fluid. Desmosine and hydroxyproline, marker amino acids of degradation of elastin and collagen, respectively, were also elevated. Decreasing the number of neutrophils in bronchoalveolar fluid to undetectable levels by pretreatment of the mice with antineutrophil antibody or pretreatment with human {alpha}1-antitrypsin abolished the increase in marker amino acids.

Repeated intratracheal administration of MMP-12+/+ macrophages to MMP-12-/- mice before smoke exposure restored the increase in lavage neutrophils and marker amino acids after acute smoke exposure. Pretreatment of MMP-12+/+ mice with a synthetic metalloprotease inhibitor prevented both neutrophil influx and connective tissue degradation (9).

Subsequently, these investigators found that mice with receptors for tumor necrosis factor-{alpha} knocked out, who were acutely exposed to smoke, failed to demonstrate increased gene expression for tumor necrosis factor-{alpha}, macrophage inflammatory protein-2, or macrophage chemoattractant protein-1, as did control mice. Also, the smoke-exposed, tumor necrosis factor-{alpha} receptor knockout mice failed to show an increase in lavage neutrophils, macrophages, or marker amino acids (10). Thus, both active metalloprotease and tumor necrosis factor-{alpha} were essential for neutrophil influx and matrix degradation in the acute smoking model.

The latest article from Churg and colleagues (11), published in this issue of AJRCCM (pp. 1083–1089), provides an integrated view of the events after acute cigarette smoke exposure. First, nuclear factor-{kappa}B, a transcription factor, is activated in both MMP-12+/+ and MMP-12-/- mice and is translocated from the cytoplasm to the nucleus, where it orchestrates the production of inflammatory molecules (12) (see Figure E1 in the online supplement). Macrophage chemoattractant protein-1 and macrophage inflammatory protein-2, which are chemoattractant for macrophages and neutrophils, respectively, are produced. A small (but essential) increase in macrophages follows. The macrophages are activated to produce MMP-12 that in turn leads to release of tumor necrosis factor-{alpha} from the macrophages. Tumor necrosis factor-{alpha} is essential for recruitment to the lungs of numerous neutrophils and activation of vascular endothelial cells (indicated by upregulation of E-selectin). Neutrophils adhere to activated capillary endothelium and migrate out of capillaries. Proteases are released that damage elastic and collagen fibers as indicated by release of marker amino acids (see Figure E2 in the online supplement).

To reiterate, in the acute smoking model in mice, macrophages capable of generating metalloelastases are necessary for the generation of tumor necrosis factor-{alpha}, which in turn is required for recruitment of neutrophils into the lungs, activation of endothelial cells, adherence to endothelium, and migration of neutrophils, and finally, release of proteases. Macrophages and tumor necrosis factor-{alpha} are essential to the process but neutrophils and their proteases are the final arbiters of matrix damage.

Neutrophils may or may not be the main cause of proteolytic damage in chronic smoking. The lungs likely adapt to the repeated exposures to tobacco smoke necessary to produce emphysema (7). It is important to understand this inflammatory process: the cellular and humoral events in mice at various times during chronic smoking, the effects of acute smoking engrafted on chronic smoking, the role of lymphocytes, and the role of loss of endothelial cell integrity and apoptosis in causing emphysema (13).

Damage to elastic fibers in vitro initiates a repair process that rapidly restores the fibers to structural integrity (14). Repair in vivo is poorly understood but must occur after the mild matrix damage of acute smoking. Emphysema in chronic smoking may be due to failure of repair.

Studies of chronic smoking in mice will be difficult but will provide essential guidance to investigators on how to investigate inflammation due to smoking in humans. Longitudinal studies in humans seem out of the question but cross-sectional, cohort studies are feasible. One might start with characterizing inflammation in cohorts that have smoked for periods of from 6–12 months up to periods of years. The inflammatory events can be related to the presence or absence of airflow obstruction (15) and to the presence of emphysema in computed tomograms of the lungs (16).

Detailed information on inflammation in COPD will be essential in guiding rational drug development for prevention of chronic airflow obstruction in the large proportion of smokers unable to quit after an intensive cessation program. It will also assume ever-greater importance in accurately phenotyping COPD as new information on the genetics of this disease develops. The tools are now in place to make rapid progress in understanding inflammation in COPD; we should proceed forthwith.

FOOTNOTES

This editorial has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

REFERENCES

  1. Snider GL. Nosology for our day: its application to chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;167:678–683.[Free Full Text]
  2. Saetta M, Turato G, Luppi F, Fabbri LM. Inflammation in the pathogenesis of chronic obstructive pulmonary disease. In: Voelkel NF, MacNee W, editors. Chronic obstructive pulmonary disease. Hamilton, ON, Canada: BC Decker; 2002. p. 114–126.
  3. Eriksson S. Pulmonary emphysema and {alpha}1-antitrypsin deficiency. Acta Med Scand 1964;175:197–205.[Medline]
  4. Snider GL, Lucey EC, Stone PJ. Pitfalls in antiprotease therapy of emphysema. Am J Respir Crit Care Med 1994;150:S131.
  5. Tetley TD. Macrophages and the pathogenesis of COPD. Chest 2002;121:156S–159S.[Abstract/Free Full Text]
  6. Shapiro SD. The macrophage in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:S29–S32.[Abstract/Free Full Text]
  7. Hautamaki RD, Kobayashi DM, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 1997;277:2002–2004.[Abstract/Free Full Text]
  8. Dhami R, Gilks B, Xie C, Zay K, Wright JL, Churg A. Acute cigarette smoke-induced connective tissue breakdown is mediated by neutrophils and prevented by {alpha}1-antitrypsin. Am J Respir Cell Mol Biol 2000;22:244–252.[Abstract/Free Full Text]
  9. Churg A, Zay K, Shay S, Xie C, Shapiro SD, Hendricks R, Wright JL. Acute cigarette smoke-induced connective tissue breakdown requires both neutrophils and macrophage metalloelastase in mice. Am J Respir Cell Mol Biol 2002;27:368–374.[Abstract/Free Full Text]
  10. Churg A, Dai J, Tai H, Xie C, Wright JL. Tumor necrosis factor-{alpha} is central to acute cigarette smoke-induced inflammation and connective tissue breakdown. Am J Respir Crit Care Med 2002;166:849–854.[Abstract/Free Full Text]
  11. Churg A, Wang RD, Tai H, Wang X, Xie C, Dai J, Shapiro SD, Wright JL. Macrophage metalloelastase mediates acute cigarette smoke–induced inflammation via tumor necrosis factor-{alpha} release. Am J Respir Crit Care Med 2003;167:1083–1089.[Abstract/Free Full Text]
  12. Barnes PJ, Karin M. Nuclear factor-{kappa}B: a pivotal transcription factor in chronic inflammatory disease. N Engl J Med 1997;336:1066–1071.[Free Full Text]
  13. Kasahara Y, Tuder RM, Taraseviciene-Stewart L, Le Cras TD, Abman S, Hirth PK, Waltenberger J, Voelkel NF. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000;106:1311–1319.[Medline]
  14. Stone PJ, Morris SM, Griffin S, Mithieux S, Weiss AS. Building elastin: incorporation of recombinant human tropoelastin into extracellular matrices using nonelastogenic Rat-1 fibroblasts as a source for lysyl oxidase. Am J Respir Cell Mol Biol 2001;24:733–739.[Abstract/Free Full Text]
  15. Zhu J, Majumdar S, Qiu Y, Ansari T, Oliva A, Kips JC, Pauwels RA, De Rose V, Jeffery PK. Interleukin-4 and interleukin-5 gene expression and inflammation in the mucus-secreting glands and subepithelial tissue of smokers with chronic bronchitis: lack of relationship with CD8+ cells. Am J Respir Crit Care Med 2001;164:2220–2228.[Abstract/Free Full Text]
  16. Dirksen A, Dijkman JH, Madsen F, Stoel B, Hutchison DC, Ulrik CS, Skovgaard LT, Kok-Jensen A, Rudolphus A, Seersholm N, et al. A randomized clinical trial of {alpha}1-antitrypsin augmentation therapy. Am J Respir Crit Care Med 1999;160:1468–1472.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 ChestHome page
S. Ma, Y. Y. Lin, and G. M. Turino
Measurements of Desmosine and Isodesmosine by Mass Spectrometry in COPD
Chest, May 1, 2007; 131(5): 1363 - 1371.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
J. P. de Torres, E. Cordoba-Lanus, C. Lopez-Aguilar, M. Muros de Fuentes, A. Montejo de Garcini, A. Aguirre-Jaime, B. R. Celli, and C. Casanova
C-reactive protein levels and clinically important predictive outcomes in stable COPD patients
Eur. Respir. J., May 1, 2006; 27(5): 902 - 907.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. Wenten, K. Berhane, E. B. Rappaport, E. Avol, W.-W. Tsai, W. J. Gauderman, R. McConnell, L. Dubeau, and F. D. Gilliland
TNF-308 Modifies the Effect of Second-Hand Smoke on Respiratory Illness-related School Absences
Am. J. Respir. Crit. Care Med., December 15, 2005; 172(12): 1563 - 1568.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
C. E. Girod and T. E. King Jr.
COPD: A Dust-Induced Disease?
Chest, October 1, 2005; 128(4): 3055 - 3064.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. J. Tobin
Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2003
Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 301 - 313.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
B. Suki, K. R. Lutchen, and E. P. Ingenito
On the Progressive Nature of Emphysema: Roles of Proteases, Inflammation, and Mechanical Forces
Am. J. Respir. Crit. Care Med., September 1, 2003; 168(5): 516 - 521.
[Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Snider, G. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Snider, G. L.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2003 American Thoracic Society