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Inflammation of the Airways and Lung Parenchyma in COPD^*

Role of T Cells

^* From the McGill University (Dr. Manuel Cosio), Royal Victoria Hospital, Montreal, PQ, Canada; the Department d’Anatomia Patologica (Dr. Majo), Hospitals Universitaris Vall d’Hebron, Barcelona, Spain; and the Department of Pathology (Dr. Monica Cosio), Ramon y Cajal University Hospital, Madrid, Spain.

Correspondence to: Manuel G. Cosio, MD, Professor of Medicine, McGill University, Royal Victoria Hospital, Respiratory Division, Room L4.11, 687 Pine Ave West, Montreal, PQ H3A 1A1 Canada; e-mail: manuel.cosio{at}muhc.mcgill.ca

	Abstract

TOP Abstract The Cellular Inflammatory... Biochemical Markers of Early... Differences in Airway... Potential Role of the... CD8+ T-Cell Inflammation in... References

 
A smoking-induced inflammatory reaction in the airways and lung parenchyma, comprised mainly of neutrophils and alveolar macrophages, has long been accepted to be the major cause of COPD in smokers. Recent reports have underlined the role of the T lymphocyte as a potentially important factor in the inflammatory process leading to COPD. It has been found that, in the airways and the lung parenchyma, the presence of T cells, predominantly CD8+ T cells, can distinguish between smokers with and without COPD. In addition to T cells, other inflammatory cell types such as neutrophils and macrophages are probably essential in the initial inflammatory process leading to the breakdown of lung tissue, perhaps producing peptides eventually recognized by T cells as antigenic. This would provide an explanation for the T-cell inflammation. Once activated, T cells are present in the lung, and their effector functions would include the attraction and enhancement of the inflammatory function in other inflammatory cells like neutrophils and macrophages. It seems likely that, only when all inflammatory cell types (ie, CD4+, CD8+, neutrophils, and macrophages) are present in the lung, the airways remodeling and parenchymal destruction characteristic of COPD will ensue. If T cells are responsible for the lung injury and progression of COPD, it would resemble a response to an antigenic stimulus originating in the lung. If that were the case, COPD could be considered to be an autoimmune disease triggered by smoking.

Key Words: airways inflammation • antigen presentation • apoptosis • auto-immunity • cigarette smoke • COPD • emphysema • T cell

A smoking-induced inflammatory reaction in the airways and lung parenchyma comprised of neutrophils and alveolar macrophages^{1 2 3 4} has long been accepted to be the major cause of the development of airway abnormalities and emphysema, and consequently COPD, in susceptible smokers. This concept was derived from findings of increased numbers of macrophages and neutrophils in BAL fluid,^{4 5 6} a compartment that may not necessarily reflect events in the lung parenchyma. In recent years, new developments in molecular and cell biology have provided investigators with novel tools to investigate inflammatory processes in the lung. Precise cell phenotyping, cytokine and other mediator production, and activation markers, among several techniques, have allowed for a much improved description of the inflammatory profiles in smokers’ lungs, in addition to improved understanding of the relative kinetics of the infiltration of leukocyte subtypes. This in turn has led to new concepts about the mechanisms underlying the development of COPD. Investigators continue to debate about the predominant inflammatory cell in COPD, often depending on the methods used to assess the inflammation or in the selection of patients, which can vary considerably. Unfortunately, the disparity of results, although potentially enriching, tends to confuse our understanding of inflammation in COPD patients, in part due to the lack of a unifying approach to the interpretation of these findings. In this review, a speculative new unifying explanation for the inflammatory process in smokers and how it leads to COPD is provided.

	The Cellular Inflammatory Infiltrate in the Airways

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The earliest, and constant pathological abnormality in the airway of smokers is the cellular inflammatory infiltrate throughout the wall. Inflammation per se may be responsible for mild airflow limitation.^{7 8 9} Indeed, it has been suggested that inflammation may lead to functional bronchiolar constriction by releasing mediators that may act directly on bronchiolar smooth muscle.¹⁰ The chronicity of inflammation would, in turn, produce other changes such as airways fibrosis, and may increase the smooth muscle mass either directly as a result of inflammation or indirectly as a result of chronically increased muscle tone. These changes, by increasing the thickness of the airway wall, would promote narrowing and airflow limitation.¹¹ Inflammation of the airways also may play an important role in the destruction of the alveolar walls normally attached to the airways, and this decrease in alveolar attachments would contribute further to airflow limitation by deforming and narrowing the airway lumen.¹²

The stimuli for this inflammatory infiltrate are not known precisely, but it is possible that injury to the airways epithelium, which is the first structure encountered by cigarette smoke, promotes and perpetuates inflammation in the airways. Epithelial cells have the potential to initiate airways inflammation through metabolizing arachidonic acid.¹³ For example, one product of this pathway, dihydroxyeicosatetraenoic acid is a potent signal to recruit neutrophils to the airways.¹⁴ Another system implicated in airway inflammatory responses, which possibly is triggered by the loss or alteration of the epithelial surface, is neurogenic inflammation. Stimulation of sensory nerves in the airway epithelium releases tachykinins including substance P and neurokinins A and B.^{15 16 17 18 19} These tachykinins cause the chemotaxis and adhesion of neutrophils,^{20 21} stimulate the release of cytokines, and cause the degranulation of eosinophils.^{22 23}

In animal studies, exposure to cigarette smoke and other irritants promotes neutrophils to appear promptly in the airways. Hulbert and colleagues²⁴ also showed that when the airway mucosa of guinea pigs is injured by the inhalation of cigarette smoke, edema forms within 30 min, and the number of neutrophils in the airway epithelium increased fivefold from control values measured 6 h after injury. Not surprisingly, neutrophils are found abundantly in the walls of smokers’ airways, and the numbers of submucosal neutrophils correlate significantly with the dose of cigarette smoke. However, at least in some reports, the numbers of neutrophils in the airway walls are not different in smokers with or without airflow obstruction.²⁵

These early inflammatory events in smokers might not be specific, and may represent an innate immune response to airway injury. Other irritants also will trigger an inflammatory reaction in the airways. For example, Baile et al²⁶ reported that acid inhalation in dogs caused abnormalities in small airways function that were associate with an accumulation of neutrophils in noncartilaginous airways. Similarly, the inhalation of NO₂ causes rapid increases of airway resistance and airway responsiveness with an influx of neutrophils followed by mononuclear cells.²⁷ SO₂-induced changes also have been described, consisting of a marked neutrophilic infiltration of the airways and an increase in resistance.²⁸ The inhalation of neutrophil elastase also elicits increases in BAL fluid total cell counts and is accompanied by epithelial damage, mucus plugging, and neutrophil and macrophage infiltration into the bronchial mucosa.²⁹ Ozone exposure has been studied extensively in human volunteers and may describe the events occurring in the airways after repeated exposure to a respiratory irritant (eg, NO₂, SO_2, ozone, cigarettes, or gas oil). Acute exposure to ozone leads to an increase in neutrophil and mononuclear cell numbers, increases in the concentration of total protein, interleukin (IL)-6 and IL-8, and reduced glutathione levels in BAL fluid. Furthermore, bronchial biopsy specimens showed a prominent neutrophilic inflammation of the airway.³⁰

Thus, the "early" inflammatory infiltrate that is found in smokers’ airways, and is reflected in tests of pulmonary function, probably represents a nonspecific response of airways to injury in general. A principal difference between the insult from cigarette smoke and those described above, however, may be the chronic inflammatory stimuli produced by the daily inhalation of cigarette smoke. It would seem, therefore, that the majority of smokers would develop a chronic, nonspecific inflammation in the airway and lung parenchyma, but, for unknown reasons, some smokers develop severe abnormalities in airways and emphysema, which eventually become clinical COPD. The remainder of the smokers without COPD will still harbor the nonspecific neutrophilic and macrophage infiltrate but with otherwise normal airways and lung parenchyma, and only "mild" functional changes that never become clinically relevant.

	Biochemical Markers of Early Lung Inflammation in Smokers

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Despite its nonspecific nature, the early inflammatory response to cigarette smoke is probably crucial to the development of subsequent tissue damage and disease in susceptible individuals. Neutrophils and macrophages can potentially produce large quantities of proteases, of which the various elastase enzymes have attracted the most attention as likely causes of loss of elastic recoil and the destruction of the elastic fibers in the lung parenchyma. Indeed, lung specimens from patients with panlobular emphysema have a significantly decreased elastin content. It might, therefore, be anticipated that the levels of elastin degradation products in smokers would be increased in COPD patients and that this may serve as a good index of lung damage from cigarettes. Increased plasma and urine levels of elastin-derived peptides have been reported in COPD patients when compared to those in nonsmokers.^{31 32 33 34} Also, urinary excretion of desmosine, a marker of elastin breakdown, was reported to be higher in subjects with COPD than in nonsmokers.^{35 36} However, the levels of elastin breakdown products also were elevated in smokers without COPD,^{32 37 38 39 40} which suggests that, while active inflammation triggered by chronic cigarette smoke can lead to the destruction of elastic fibers in all smokers, other factors may be at play in those who subsequently develop clinical COPD.

Although elastin breakdown occurs in all smokers, it may be accelerated in those who develop COPD. In support of this hypothesis is the finding that in smokers who experienced a rapid decline in lung function and who were deemed likely to develop COPD, the excretion of desmosine was 36% greater than that in smokers with a slow rate of decline of lung function.⁴¹ This suggests that the balance between destruction and repair that is probably maintained in most smokers favors tissue destruction in those who go on to develop COPD. If this is so, why is elastic fiber breakdown accelerated in the COPD patient? Is the inflammatory process in smokers who develop COPD quantitatively or qualitatively different from that in smokers who do not develop COPD?

	Differences in Airway Inflammation Between Smokers With and Without COPD

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It is reasonable to hypothesize that the inflammatory process in the airways of smokers destined to develop COPD differs from that in individuals who are resistant to the effects of cigarette smoke. This has proved to be difficult to demonstrate, and it remains unclear whether quantitative or qualitative differences in the inflammatory response account for the development of COPD in susceptible subjects. A logical cell to consider first was the neutrophil, which is characteristically present in the airways of smokers, and releases elastase and other proteolytic enzymes with the capacity to cause lung destruction. However, the presence of pulmonary neutrophilia does not seem to differentiate between COPD patients and other smokers. It was demonstrated in 1985⁴² that, although lung neutrophil numbers were increased in smokers, those subjects with emphysema did not have higher numbers of neutrophils in the lung parenchyma than smokers without emphysema. Similarly, Bosken and colleagues²⁵ found no difference in the intensity of the airway neutrophilia between smokers with and without airway obstruction. In contrast, other studies have found an inverse correlation between neutrophilia and the extent of disease. For example, in one report,⁴³ the total number of cells in the lungs correlated positively with the degree of microscopic emphysema, but the number of neutrophils in the lungs of the same patients decreased as degree of emphysema increased. Subsequently, Finkelstein and colleagues,⁴⁴ using immunocytochemistry and morphometry, determined the number of inflammatory cells (ie, T cells, B cells, tissue and alveolar macrophages, and neutrophils) per cubic millimeter of lung tissue. These investigators confirmed that the numbers of neutrophils in the lung decreased significantly as the degree of emphysema increased. In contrast, the degree of lung destruction was closely related to the numbers of T lymphocytes in the alveolar wall (Fig 1 ). Destruction also was associated with the presence of increased numbers of alveolar macrophages. Furthermore, the numbers of T cells and macrophages correlated, suggesting the possibility of an interaction between these cells in the inflammatory process leading to lung tissue damage.

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Correlation between emphysema (expressed as the density of alveolar walls [Vv1 ALV]) and the numbers of neutrophils (PMN), T lymphocytes, and alveolar macrophages per mm3 in the alveolar walls of 6 nonsmokers and 15 smokers. Decreasing alveolar density signifies increasing emphysema. PMN: r = 0.71; p < 0.01. T cells: r = -0.70; p < 0.01. Alveolar macrophages: r = -0.78; p < 0.01. Reprinted with permission from Finkelstein et al.44

Majo et al⁴⁷ studied lungs that were obtained at surgery from the following three groups of subjects: nonsmokers, smokers with no evidence of emphysema or lung function impairment, and smokers with both emphysema and abnormal lung function. Similar to the findings in the airways described above,^{45 46} the only measurable difference between smokers with and without COPD was a substantial increase in the number of T lymphocytes (CD3⁺ cells) and CD8+ T cells per millimeter of alveolar wall (Fig 2 ). Of interest, in smokers with COPD the total number of T cells, CD8+ cells, and CD4+ cells increased with the amount of smoke inhaled, but this did not occur in smokers without COPD.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Inflammatory cell profile in the lungs of nonsmokers (NS), smokers without anatomic emphysema (SNE), and smokers with emphysema (SE). The number of cells is expressed as the mean ± SEM of number of cells per mm of alveolar wall. ANOVA = analysis of variance. Reprinted with permission from Majo et al.47

	Potential Role of the T cells in COPD

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Based on the known physiologic behavior of T cells, the following may clarify the role of inflammation in COPD. Naïve, non-antigen-activated T cells do not stay long in the lung, but, rather, they return to the circulation or die.⁴⁷ A role for T cells in causing a particular inflammatory disease is suspected largely because of the demonstration of increased T-cell numbers in the affected organ. For T cells to "home in" to the lungs (or to any organ) and proliferate, they need, first, to be activated by the recognition of an antigen and, second, to home in to the organ in which the antigen is being produced. Once in the lung, activated T cells could exert their effector functions. The CD4+ (or CD8+) T cell would do so by the production of cytokines in either a Th1 (ie, IL-2 or interferon [IFN]-) or Th2 (ie, IL-4, IL-5, and IL-10) pattern. The presence of large numbers of alveolar macrophages in the lung and the significant correlation between the numbers of CD3+ T cells and macrophages in the lungs of smokers⁴⁴ suggests that a Th1 CD4+ and CD8+ T-cell population is involved in this inflammatory process. CD4+ Th-1 T cells produce IFN-, which is the most potent macrophage-activating cytokine. Cytokines produced by CD8+ T cells can initiate the same reaction. On activation, macrophages exert functions such as the generation of reactive oxygen species (eg, nitric oxide) and acute inflammation through the secretion of short-lived inflammatory mediators such as eicosanoids. In addition, macrophages become more efficient antigen-presenting cells following activation. CD4+-derived and CD8+-derived IFN- stimulate alveolar macrophages to secrete cytokines, including IL-12, which feeds back into the cell lymphocyte line promoting T cells to differentiate into the Th1 subset, thereby promoting CD4+ and CD8+ Th1 cytokines and cytotoxic T-lymphocyte differentiation.⁴⁸

The number of CD4+ T cells in the lungs of smokers increased significantly after approximately 30 years of smoking, as did the CD8+ T cells, suggesting that the CD4+ T cell might be playing a role in the inflammatory process.⁴⁷ CD4+ T cells are required for the priming of CD8+ cytotoxic T-cell responses, for maintaining their memory, and for ensuring survival, suggesting that even low numbers of CD4+ T cells may be essential for the development of the CD8+ T-cell inflammatory infiltrate found in smokers.⁴⁹

Another important effector function of the T lymphocyte is the alteration of their microvascular environment. Under the influence of cytokines secreted by antigen-activated T cells or through contact-dependent signals, microvascular endothelial cells perform several functions that contribute to inflammation.⁴⁸ Vasodilatation increases local blood flow and the delivery of leukocytes to sites of inflammation via prostacyclin and nitric oxide. By the expression of new or increased levels of certain surface proteins, postcapillary venule endothelial cells become adhesive to leukocytes. Also, antigen-activated T cells cause endothelial cells to secrete chemokines such as IL-8 and monocyte chemotactic protein-1, which act on the leukocytes to promote their extravasation. Finally, cytokines or contact-dependent signals from activated T cells cause endothelial cells to undergo shape changes and basement membrane remodeling that favor the leakage of macromolecules and extravasation of cells.

	CD8+ T-Cell Inflammation in Emphysematous Lungs

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One of the important consequences of the effector functions of cytotoxic CD8+ T cells is the apoptosis of target cells, and it would not be surprising that apoptosis plays a role in the destruction of lung tissue in patients with emphysema. Majo et al⁴⁷ have reported that, in smokers with emphysema, both the degree of apoptosis and the number of CD8+ T cells in the alveolar wall increased in parallel with the amount of smoke inhaled (Fig 3 ). This suggests that the proliferation of cytotoxic T cells induced by smoking may participate in the destruction of the lungs by inducing apoptosis of structural cells. Although we did not identify which cells were undergoing apoptosis,⁴⁷ others^{50 51 52} have reported increased numbers of lung structural cells undergoing apoptosis in emphysematous lungs.

View larger version (8K): [in this window] [in a new window] [Download PPT slide]   Figure 3.. Correlation between the numbers of CD8+ T cells and apoptosis in the alveolar wall of smokers with emphysema. Reprinted with permission from Majo et al.47

It is our hypothesis that smoking promotes an initial neutrophilic and macrophage inflammation that by diverse mechanisms (eg, proteases or oxidation) damages lung cells and degrades the interstitium (eg, elastin, collagen, and proteoglycans). Lung injury may lead to structural alterations in self-antigens that create partially cross-reactive neoantigens and to the release of anatomically sequestered antigens^{48 53 54} that would be recognized by autoreactive T cells, thereby inducing their activation and proliferation. Through their effector functions, activated CD8+ T cells, and possibly CD4+ T cells, could damage the lung by promoting further cellular inflammation (ie, macrophages and neutrophils),^{48 53} the direct killing of target cells by perforin-induced necrosis or perforin-induced or Fas-Fal-induced apoptosis^{54 55} and eventually produce the tissue destruction and remodeling seen in the lungs of COPD patients. If T cells alone or together with other inflammatory cells are responsible for the lung injury and progression observed in COPD patients, it would resemble a response to an antigenic stimulus originating in the lung and induced by cigarette smoking. If that were the case, COPD could be considered an autoimmune disease that is triggered by smoking.⁴⁷

In summary, it would be surprising if the etiology and pathogenesis of a chronic and complex disease such as COPD could be explained totally by the action of one type of cell (ie, the neutrophil) and the imbalance of proteases and antiproteases that increased numbers and activation of neutrophils would produce in the lungs of smokers. From an inflammatory-immunologic point of view, it would be more likely that after years of low-grade injury of the many tissue components of the lung, some smokers mount an acquired immunologic reaction to antigenic products of the lung destruction that are produced by the constant exposure to cigarette smoke. While there is no proof for this hypothesis, we have many clues that it might be valid. Available data shows that T cells infiltrate the lungs of smokers with COPD, but not those of healthy smokers. Many years ago, neutrophils were found in the BAL fluid of smokers and, since then, many investigators have pursued the single role of this cell type in the pathogenesis of emphysema. We now have better evidence with which to implicate T cells and to discern how these cells may collaborate with the neutrophil and macrophages by increasing their numbers and efficiency as effector cells in the process of lung destruction. We believe that the investigation of this "new paradigm" for the pathogenesis of this disorder may eventually lead to the understanding of the mechanisms of disease in smokers and, importantly, to the discovery of effective therapies to prevent and treat COPD.

	Footnotes

 
Abbreviations: IFN = interferon; IL = interleukin

	References

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