End-Stage Chronic Obstructive Pulmonary Disease
The Cigarette Is Burned out but Inflammation Rages on

Steven D. Shapiro, M.D.

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, School of Public Health, Boston, Massachusetts

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Cigarette smoking leads to accumulation of macrophages and neutrophils, both armed with destructive proteinases that cause lung destruction and airspace enlargement that characterize pulmonary emphysema. T cells, particularly CD8⁺ cells, also accumulate in the lungs of patients with chronic obstructive pulmonary disease (COPD), although their contribution to the disease process is unknown (1). Tantalizing links between COPD and asthma heighten awareness to other potential cell types in COPD such as the eosinophil and mast cell. In general, investigators pick their favorite cell type and focus on its importance. However, most would agree that in end-stage disease, long after the last cigarette has been lit, inflammation has died down leaving behind a ravaged lung predisposed to small airway collapse and diminished elastic recoil. The results in the study by Retamales and colleagues in this issue of the journal (pages 469-473) do not conform to these notions and should change the way that we approach inflammation in COPD in at least two fundamental ways. First, there is an abundance of many inflammatory cell types. Second, intense inflammation continues late in the disease process. Perhaps the most fascinating fact of this study, although not explicitly stated, is that the average duration of smoking cessation before lung volume reduction surgery and tissue accrual, was 9.2 yr (personal communication with authors). Our challenges now are to find out how these cells interact and contribute to the disease, not which one predominates, and to understand why inflammation persists so long after the inciting event, cigarette smoking, has ceased.

This study also addresses potential mediators of inflammation in COPD. A relationship between adenovirus and emphysema suggests that latent adenoviral infection may amplify inflammation and predispose to COPD. Previously, this group has shown that adenoviral protein E1A acts to enhance epithelial cell transcription of interleukin-8 (IL-8) and intercellular adhesion molecule-1 (ICAM-1) (2, 3). In this study, although the correlation was strong, the number of adenoviral expressing cells was low. This could be related to insensitive techniques, small amounts of adenovirus may be sufficient for the effect, or alternative mechanisms coexist.

Several cytokines/chemokines have been found in association with COPD but overall fundamental questions remain regarding the mediators and mechanisms of inflammatory cell recruitment in COPD. For example, we do not know: What is the mechanism of cigarette smoke-induced inflammation? What role do bacteria play in inflammation in COPD? Smoke-induced ciliary abnormalities likely predispose to bacterial colonization in the airways, although we generally believe that the alveolar space is sterile despite potential inhibition of macrophage antimicrobial function secondary to cigarette smoke. Thus, lipopolysaccharide (LPS), formylmethionylleucylphenylalanine (FMLP), and other bacterial mediators might contribute to airway inflammation but less likely to alveolar inflammation. This study provides a mechanism for enhanced inflammation in the lower airspace, because adenovirus infects type II epithelial cells.

The concept that infectious agents perpetuate inflammation after smoking cessation is attractive given the findings of this study regarding continued inflammation long after cigarette smoke exposure is stopped. Another mechanism for persistent inflammation involves extracellular matrix (ECM) proteolytic fragments as chemokines. It is known that elastin fragments are chemotactic for monocytes (4, 5), and laminin and fibronectin fragments recruit neutrophils and monocytes. Generation of elastin fragments appears to be important in macrophage accumulation within the lung in a murine model of cigarette smoke-induced emphysema (6). Thus, inflammatory cell- mediated proteolysis of ECM generates fragments that may perpetuate inflammation after smoking cessation.

Smokers susceptible to COPD have an accelerated rate of FEV₁ decline, losing 90 to 120 ml/yr compared with nonsmokers and nonsusceptible smokers who lose 20 to 30 ml/yr. What happens to lung function when susceptible smokers quit smoking? The best data come from the Lung Health Study that followed smokers with mild COPD and rapid decline of lung function (7). Sustained quitters (not a common occurrence even in this study with intense cigarette cessation efforts, but that is a separate commentary) had transient improvement in lung function, presumably because of nonspecific airway reactivity, followed by reversion to normal rate of decline. The natural history of patients with more severe COPD is not well defined. Although correlations between inflammation, emphysema, and FEV₁ are not direct, the intense inflammation in late disease shown in this study suggests that these patients should lose lung function at an accelerated clip. This is a very important issue that requires further study. If indeed patients continue to deteriorate after smoking is discontinued, then the need for new therapeutic measures to halt disease progression will be more urgently required. The ultimate goal, of course, is to restore lung function to these patients.

Why do only 15 to 20% of smokers develop clinically significant COPD? Clearly, this number would be higher if patients did not succumb to heart disease and lung cancer before the onset of symptoms of COPD, but the fact remains that most smokers do not develop COPD. This intriguing observation has led investigators to search for the genetic basis of emphysema susceptibility. The time is right for this area of investigation given our rapidly developing understanding of the human genome and improved methods for high-throughput genetic screening. In addition to alpha-1-antitrypsin (1-AT) deficiency, we all see patients who have early-onset COPD, minimal cigarette smoke exposure, or strong family histories for COPD with normal 1-AT levels. Silverman and coworkers have identified many families with normal 1-AT with a strong genetic predisposition (8). Identification of genetic mutations related to enhanced inflammation, proteinase release, and proteinase inhibitor deficiency is expected. The guess here is that most mutations will be related to impaired lung repair after predictable lung injury. The study in this issue reminds us that environmental susceptibility may be operative, with latent adenoviral infection predisposing to enhanced lung inflammation and destruction.

This study is remarkable in several other respects. First, the combination of a well characterized patient population in Pittsburgh with the pathology expertise in Vancouver, demonstrates the power of collaboration between centers geographically separated. Second, the elegance of this study lies in the simplicity of the observations. In this era of advanced molecular techniques, important new knowledge can still be derived from careful observation of patient material. In fact, all knowledge gained from the test tube, cell culture, and animal models must ultimately be confirmed in humans. Finally, one is glad to see that Dr. Hogg, who arguably has made greater contributions to our understanding of COPD than any other, continues to make seminal breakthroughs in the new millennium.

	Footnotes

	References

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3. Keicho N, Elliott WM, Hogg JC, Hayashi S. Adenovirus E1A upregulates IL-8 expression induced by endotoxin in pulmonary epithelial cells. Am J Physiol 1997; 272: L1046-L1052 [Abstract/Free Full Text].

4. Senior RM, Griffin GL, Mecham RP. Chemotactic activity of elastin-derived peptides. J Clin Invest 1980; 66: 859-862 .

5. Hunninghake GW, Davidson JM, Rennard S, Szapiel S, Gadek JE, Crystal RG. Elastin fragments attract macrophage precursors to diseased sites in pulmonary emphysema. Science 1981; 212: 925-927 [Abstract/Free Full Text].

6. Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Macrophage elastase is required for cigarette smoke-induced emphysema in mice. Science 1997; 277: 2002-2004 [Abstract/Free Full Text].

7. Murray RP, Anthonisen NR, Connett JE, Wise RA, Lindgren PG, Greene PG, Nides MA. Effects of multiple attempts to quit smoking and relapses to smoking on pulmonary function. Lung Health Study Research Group. J Clin Epidemiol 1998; 51: 1317-1326 [Medline].

8. Silverman EK, Weiss ST, Drazen JM, Chapman HA, Carey V, Campbell EJ, Denish P, Silverman RA, Celedon JC, Reilly JJ, Ginns LC, Speizer FE. Gender-related differences in severe, early-onset chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 162: 2152-2158 [Abstract/Free Full Text].