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Los Angeles, CA
Dr. Baydur is Professor of Clinical Medicine, Division of Pulmonary and Critical Care Medicine, Keck School of Medicine, University of Southern California.
Correspondence to: Ahmet Baydur, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Keck School of Medicine, University of Southern California, 2025 Zonal Ave, GNH 11–900, Los Angeles, CA 90033; e-mail: baydur{at}usc.edu
In recent years, efforts have been aimed at defining the airway changes associated with COPD. Polymorphonuclear leukocytes play a major role in airway inflammation. New information on the mechanisms of polymorphonuclear leukocyte recruitment and other actions in airway and parenchymal dysfunction has included observations about a role for mononuclear cell-mediated inflammation in COPD patients. Such cells infiltrate the bronchial submucosa in increased numbers in patients with COPD. In addition, neutrophil chemotaxis into the airways is evidence that chemokines and chemokine receptors play a role in the inflammatory response.12 Chemotaxis is stimulated by smoking, and yet airway inflammation continues even after smoking cessation. Many molecules induce chemotactic activity for neutrophils, including leukotrienes (LTs). These molecules are now known to comprise the main ingredients of the slow-reacting substance of anaphylaxis, a mediator of hypersensitivity reactions.
Continued research has increased understanding of the varied classes and functions in the LT family. LTs may be released from both blood-borne and tissue-residing cells. LTs collectively stimulate the contraction of vascular and nonvascular smooth muscles, enhance vascular permeability, and control the attraction and activation of leukocytes.3 Their actions are usually in conjunction with other mediators and modulators of different events, such as vasodilating prostaglandins (PGs), lipoxins, interleukins, and histamine. Levels of many of these compounds can be analyzed in bronchial washing fluid, sputum concentrate, and exhaled breath condensate (EBC). The EBC of asthmatic patients and healthy subjects contains detectable levels of LTB4, LTC4, LTD4, LTE4, and LTF4.45 Stable patients with COPD, COPD exacerbations, and moderate or severe asthma exhibit increased concentrations of LTB4 in EBC,467 suggesting that LTB4 may be involved in exacerbations of COPD as well as in those of asthma, and may contribute to neutrophil recruitment. Other eicosanoids are also potent mediators of vasoactivity, plasma exudation, mucus secretion, bronchoactivity, cough, and recruitment of inflammatory cells. For example, the levels of PGs such as PGE2 and PGF2
in EBC are markedly increased in patients with COPD, but not in patients with asthma.89 By contrast, patients with asthma exhibit increased concentrations of thromboxane B2, while patients with COPD and healthy subjects do not.6 The techniques of EBC analysis are simple to perform and can be repeated over the course of the illness to monitor the patient’s response to therapy. They reflect the degree of oxidative stress and help to determine the degree of reversibility of airway obstruction. Although exhaled and bronchial nitric oxide (NO) has been used the most, other mediators such as LTs may play increasing roles in the diagnosis and management of airway disease.
Making a distinction between patients with COPD and smokers with chronic asthma who have persistent airflow limitations remains a difficult task. Data from the underlying inflammatory pattern can help to distinguish the two conditions. In the current issue of CHEST (see page 1553), Kostikas and colleagues undertook this challenge by assessing levels of LTB4, a cysteinyl LT, in the EBC and sputum supernatant of COPD patients with reversible and nonreversible airway obstruction after bronchodilation, and compare them with matched smoking asthmatic patients and healthy individuals who smoked to clarify the in vivo role of this mediator. All of the subjects were men. The authors hypothesized that COPD patients with reversible airway obstruction might have levels of LTB4 similar to those of asthmatic patients who smoked, possibly through some common pathophysiologic mechanism. They also assessed sputum differential counts and correlations with lung function. Finally, they validated measurements of LTB4 in EBC and induced sputum supernatant to determine whether there was a correlation between the levels of this mediator in these two specimens, in order to test whether these two techniques provide comparable measurements in the assessment of airway inflammation. The authors found that, compared to LTB4 levels in the EBC of control subjects, LTB4 levels in the EBC of COPD and asthmatic patients were increased by about threefold. The values of LTB4 were similar in COPD patients with airway obstruction reversibility and asthmatic patients, and were 35% higher in COPD patients without airway obstruction reversibility. Similar results were observed with levels found in the sputum supernatant. LTB4 levels also correlated with the reversibility of airway obstruction in all of the COPD patients, but not with the degree of lung function impairment. The authors concluded that patients with asthma and reversible COPD exhibit higher LTB4 values, in contrast to patients with nonreversible COPD and healthy control subjects. They attributed this difference to the presence of reversibility of airway obstruction, reflecting a common underlying inflammatory process.
These findings reflect the results of recent reports that have described overlapping features of asthma and COPD, namely, airway remodeling and asthma. The Dutch hypothesis suggests that, in some patients, COPD and asthma are not distinct entities, and that similar pathogenetic mechanisms may be involved in the pathogenesis of asthma and COPD.10 The histologic and immunohistologic findings in patients with these diagnoses are sometimes difficult to distinguish, although there are differences in the pattern of inflammation, the affected structures, and the site at which these changes occur.11 The differences are most apparent when nonsmoking patients with asthma and smoking patients with COPD are compared. As airway obstruction becomes more severe and reversible, the patterns of inflammation become more similar, mainly due to increases in the number of neutrophils in both asthma and COPD patients. One would expect that such a development be reflected by increased levels of LTs in EBC and sputum supernatant, as was the case in the study of Kostikas and colleagues.
These findings have implications for the management of patients with asthma and COPD. Selective inhibitors of LT biosynthesis and action attenuate immunologically induced inflammation, implicating endogenous LTs as significant mediators of inflammation. Included among these inhibitory substances are mouse antibody antagonists of interleukin-8 (now known as CXCL8) and LTB4 receptor that may inhibit in vitro neutrophil chemotaxis.12 When used in combination, sputum-induced chemotaxis was reduced by almost half. While therapy with inhaled corticosteroids, alone and in combination with long-acting bronchodilators, results in a dose-dependent reduction in exhaled NO in patients with asthma,1314 the evaluation of LT antagonists is problematic as they have no bronchodilator properties or the immunomodulatory properties of corticosteroids. LT antagonists such as pranlukast, montelukast, and zafirlukast have been shown1516 to block the increase or to reduce the production of exhaled NO in patients. Similar effects by such agents on exhaled LT concentrations have not yet been demonstrated, but there is no reason to doubt that this would be the case.
There are still several issues that need to be resolved regarding the assessment of antichemotactic therapy, particularly in patients with COPD. As stated previously, a number of chemotactic factors other than LTs have been identified in different body fluids and tissues, including CXCL8 and polymeric 1-antitrypsin.1718 The most important of these chemokines in COPD patients need to be identified to guide the manufacture and testing of appropriate antichemotactic compounds. There may be methodologic problems associated with the assays or immunoenzymatic methods used to identify the chemotactic factors. There are also differences in the concentrations of chemokines depending on the site at which they are sampled (ie, sputum, BAL fluid, and EBC). Exacerbations of COPD may be associated with different chemotactic factors than those associated with the stable state. Likewise, whether the patient was a former or current smoker also affects the types and concentrations of chemokines that will be found in the sputum or BAL fluid.192021 While Kostikas and colleagues showed that the EBC levels of LTB4 were 25 to 30 times greater in concentration than those in the sputum supernatant, they also demonstrated a close correlation between the concentrations in the two media in both COPD and asthmatic patients (r 
0.8; p < 0.0001), regardless of the disease activity. This finding supports the view that the sampling of at least one of the media tested would provide a reliable degree of chemokine activity.
Because other cell types besides neutrophils (eg, macrophages, lymphocytes, mast cells, and eosinophils) participate in the production of airway inflammation, the blockage or amelioration only of the neutrophil-mediated component of the inflammation may not be sufficient to reverse the course of COPD. Ultimately, if the goal is to prevent fibrotic remodeling, as well as to control inflammation, other more specific mediators, perhaps used in combination, would have to be identified for blockage. Examples of substances that contribute to airway remodeling and fibrosis include tissue growth factor2223 and vascular endothelial growth factor. Vascular endothelial growth factor levels can be reduced by the administration of pranlukast in steroid-untreated asthmatic patients.24 For now, the detection and assay of chemokine levels in EBC and sputum supernatants are useful markers for airway neutrophilic inflammation but do not necessarily serve as guidelines for specific therapies directed against the progression of airway disease.
References
1-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema. Am J Respir Cell Mol Biol 2002;26,723-730
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