COPD: Is Chemotaxis the Key?

Abstract

Over the last years, many studies were aimed at better redefining the airway inflammatory changes that are associated with COPD, the diagnostic umbrella comprising emphysema, small airways disease, and chronic bronchitis (CB). The reappraisal of inflammation of the airways as a fundamental part of the disease was possible by capitalizing, on one side, on the different tools that are available for evaluating airway inflammation from more to less invasive or noninvasive (eg, BAL or sputum) and, on the other side, on the recent progresses in immunology and leukocyte biology.Looking back at the results of all these studies, they were somehow surprising. Neutrophils have been known for a long time as the major component of sputum in CB and COPD patients,1Chodosh S Examination of sputum cells.N Engl J Med. 1970; 282: 854-857Crossref PubMed Scopus (45) Google Scholar and consistently their role in intraluminal inflammation has been confirmed, but new and important information has been added on the mechanisms of polymorphonuclear leukocyte recruitment and on their activities in the derangement of the airways and lung parenchyma. Moreover, what was really new and exciting was the observation of a role for mononuclear cell-mediated inflammation also in COPD patients. Lymphocytes and monocytes/macrophages are found in increased numbers and in the activated state in the bronchial submucosa of CB and COPD patients.2Saetta M Di Stefano A Maestrelli P et al.Activated T-lymphocytes, and macrophages. in bronchial mucosa of subjects with chronic bronchitis.Am Rev Respir Dis. 1993; 147: 301-306Crossref PubMed Scopus (330) Google Scholar3Di Stefano A Turato G Maestrelli P et al.Up-regulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis.Am J Respir Crit Care Med. 1994; 149: 803-810Crossref PubMed Scopus (219) Google Scholar It is a picture that somehow resembles that found in the bronchi of asthmatic patients, but at variance with the situation in asthma patients, in COPD patients the causative agents and the characteristics (eg, T helper-1 vs T helper-2 cytokine profile) of this reaction are still unclear.4Jeffery PK Structural and inflammatory changes in COPD: a comparison with asthma.Thorax. 1998; 53: 129-136Crossref PubMed Scopus (302) Google Scholar Moreover, the interaction between the mononuclear and the polymorphonuclear part of airway inflammation is just starting to be addressed, with evidence of the role of chemokines and chemokine receptors.5Di Stefano A Capelli A Lusuardi M et al.Decreased T lymphocyte infiltration in bronchial biopsies of subjects with severe chronic obstructive pulmonary disease.Clin Exp Allergy. 2001; 31: 893-902Crossref PubMed Scopus (72) Google Scholar6Saetta M Mariani M Panina-Bordignon P et al.Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2002; 165: 1404-1409Crossref PubMed Scopus (320) Google ScholarBeginning with these observations, the research focused on the possible molecular mechanisms causing airway inflammation, trying to identify the possible targets for new treatment approaches. So what is the key to airway inflammation in COPD patients? Many researchers think that neutrophil chemotaxis is the key. As a follow-up to this concept, the hypothesis that by inhibiting, or reducing, the neutrophil influx into the airways one should be able to reduce the burden of airway inflammation and, thus, to change the natural history of the disease, has arisen.Chemotaxis is a biological phenomenon whereby a cell type migrates through barriers (eg, vessel walls or epithelial layers) and tissues toward a site of inflammation or infection. Thus, it represents a useful biological phenomenon since it allows for the allocation of resources (ie, cells and cell products) in a short time to the place where they are needed. The cells migrating to the site of chemotaxis will initiate and maintain the inflammatory processes, which may switch up self-maintaining circuits and become chronic and irreversible, causing tissue derangement and organ failure. In the case of COPD, although cigarette smoke is the cause of the disease in most patients and smoke is able to induce neutrophil chemotaxis,7Blue ML Janoff A Possible mechanisms of emphysema in cigarette smokers: release of elastase from human polymorphonuclear leukocytes by cigarette smoke condensate in vitro.Am Rev Respir Dis. 1978; 117: 317-325PubMed Google Scholar8Sato E Koyama S Takamizawa A et al.Smoke extract stimulates lung fibroblasts to release neutrophil and monocyte chemotactic activities.Am J Physiol. 1999; 277: L1149-L1157PubMed Google Scholar one of the characteristics is the continuing maintenance of the airway inflammatory picture after smoking cessation.Chemotaxis is also a complex and multistep process in which, under a variety of stimuli, different cell types produce either the chemotactic factors or the factors that induce their production, other cells migrate through margination, deformation, and rolling adhesion mediated by adhesion molecules, and the mediators of chemotaxis and their receptors have an interplay. As an example, a long list of molecules, each of them produced by different cell types, are able to exert a chemotactic activity for neutrophils: classic chemoattractants such as C5a, leukotriene (LT) B4, platelet-activating factor, and formyl-methionyl-leucyl-phenylalanine; chemokines such as interleukin (IL)-8, growth-related oncogene (GRO)-α, GRO-β, and GRO-γ; and other recently recognized factors.9Holland SM Gallin JL Neutrophils Crystal.in: West RG Weibel JB The lung scientific foundations. 2nd ed. Lippincott-Raven, Philadelphia, PA1997: 877-890Google Scholar10Pan ZZ Parkyn L Ray A et al.Inducible lung-specific expression of RANTES: preferential recruitment of neutrophils.Am J Physiol. 2000; 279: L658-L666PubMed Google Scholar11Parmar JS Mahadeva R Reed BJ et al.Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema.Am J Respir Cell Mol Biol. 2002; 26: 723-730Crossref PubMed Scopus (135) Google ScholarIn this issue of CHEST (see page 1240), Beeh and colleagues, starting from the observation that IL-8 and LTB4 are identified as neutrophil chemotactic factors in the sputa of COPD patients, demonstrate that a mouse antibody antagonist of IL-8 and an antagonist of LTB4 receptor may inhibit in vitro neutrophil chemotaxis. Similarly, an LT synthesis inhibitor has been shown to be ready for further clinical studies, and other compounds are being tested.12Gompertz S Stockley RA A randomized, placebo-controlled trial of a leukotriene synthesis inhibitor in patients with COPD.Chest. 2002; 122: 289-294Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar13Barnes PJ Chronic obstructive pulmonary disease.N Engl J Med. 2000; 343: 269-280Crossref PubMed Scopus (1202) Google Scholar14Pauwels RA Buist S Calverley PMA et al.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; 163: 1256-1276Crossref PubMed Scopus (4307) Google Scholar This evidence means that if chemotaxis is the key factor in the airway inflammation of patients with COPD, there are compounds that can block it, thus opening new avenues for the treatment of this deadly disease.Together with antichemotactic drugs, many new compounds or classes of compounds are presently in development for the treatment of COPD, such as antioxidants, protease inhibitors, adhesion molecule inhibitors, and new anti-inflammatory drugs.13Barnes PJ Chronic obstructive pulmonary disease.N Engl J Med. 2000; 343: 269-280Crossref PubMed Scopus (1202) Google Scholar14Pauwels RA Buist S Calverley PMA et al.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; 163: 1256-1276Crossref PubMed Scopus (4307) Google Scholar All of these new approaches have their rationale in cellular and molecular mechanisms of the inflammatory components in COPD that are taken as targets for the proposed treatment, but there are still a number of problems to be solved. For the antichemotactic drugs, the first problem is to identify the important mediators of chemotaxis that drive neutrophils into the airways of COPD patients. Neutrophilic chemotactic factors such as, IL-8, LTB4, and GRO-α have been identified in COPD patients at different levels, in BAL,15Riise GC Ahlstedt S Larsson S et al.Bronchial inflammation in chronic bronchitis assessed by measurements of cell products in bronchial lavage fluid.Thorax. 1995; 50: 360-365Crossref PubMed Scopus (142) Google Scholar16Pesci A Balbi B Majori M et al.Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease.Eur Respir J. 1998; 12: 380-386Crossref PubMed Scopus (259) Google Scholar17Balbi B Majori M Bertacco S et al.Inhaled corticosteroids in stable COPD patients: do they have effects on cells and molecular mediators of airway inflammation?.Chest. 2000; 117: 1633-1637Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar18Tanino M Betsuyaku T Takeyabu K et al.Increased levels of interleukin-8 in BAL fluid from smokers susceptible to pulmonary emphysema.Thorax. 2002; 57: 405-411Crossref PubMed Scopus (123) Google Scholar sputum,19Keatings VM Collins PD Scott DM et al.Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma.Am J Respir Crit Care Med. 1996; 153: 530-534Crossref PubMed Scopus (1218) Google Scholar20Mikami M Llewellyn-Jones CG Bayley D et al.The chemotactic activity of sputum from patients with bronchiectasis.Am J Respir Crit Care Med. 1998; 157: 723-728Crossref PubMed Scopus (76) Google Scholar21Traves SL Culpitt SV Russell REK et al.Increased levels of the chemokines GROα and MCP-1 in sputum samples from patients with COPD.Thorax. 2002; 57: 590-595Crossref PubMed Scopus (298) Google Scholar serum,22Seggev JS Thornton Jr, WH Edes TE Serum leukotriene B4 levels in patients with obstructive pulmonary disease.Chest. 1991; 99: 289-291Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar and lung tissue.23De Boer WI Sont JK van Schadewijk A et al.Monocyte chemoattractant protein 1, interleukin-8, and chronic airways inflammation in COPD.J Pathol. 2000; 190: 619-626Crossref PubMed Scopus (255) Google Scholar There is a need to clearly identify the chemotactic factors that, among many others, may be more important in COPD patients, and/or are more easily inhibited in their functional activity. As an example, Beeh and colleagues observed that the pretreatment of neutrophils with the combination of both of the antichemotactic drugs (ie, anti-IL-8 and anti-LTB4 receptor) reduced the sputum-induced chemotaxis by roughly 45%, which was less than the combined effect of either drug alone, thus suggesting the presence in the sputa of other, yet unidentified, neutrophil chemoattractants.Chemotaxis may be quantitatively assayed in vitro using the chemotaxis chamber24Boyden Jr, SE The chemotactic effects of mixtures of antibody and antigen on polymorphonuclear leukocytes.J Exp Med. 1962; 115: 453-466Crossref PubMed Scopus (2004) Google Scholar or chemotactic factors may be identified by immunoenzymatic methods. In both cases, methodologic problems that are caused by the presence of the natural inhibitors of some chemotactic factors25Marshall LJ Perks B Ferkol T et al.IL-8 released constitutively by primary bronchial epithelial cells in culture forms an inactive complex with secretory component.J Immunol. 2001; 167: 2816-2823Crossref PubMed Scopus (45) Google Scholar or by the possible confounding effects of dithiothreitol on sputum sol assays26Pignatti P Delmastro M Perfetti L et al.Is dithiothreitol affecting cells and soluble mediators during sputum processing? A modified methodology to process sputum.J Allergy Clin Immunol. 2002; 110: 667-668Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar27Kelly MM Leigh R Horsewood P et al.Induced sputum: validity of fluid-phase IL-5 measurement.J Allergy Clin Immunol. 2000; 105: 1162-1168Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar may occur. In addition, it is possible that at different sites (eg, larger vs smaller airways) the “cocktail” of chemotactic factors varies. The different proportions of the various chemotactic factors that are detected would then be due to the methodology used to obtain solutes from the airways (eg, sputum, sampling more proximal airways, or BAL, sampling also the lower respiratory tract). Exacerbations of COPD, or subtypes of them (eg, bacterial), may be associated with a set of chemotactic signals that is different from that driving neutrophilic inflammation during the stable state, a difference that can be hypothesized also for the other COPD patient groups such as current smokers vs former or never-smokers.17Balbi B Majori M Bertacco S et al.Inhaled corticosteroids in stable COPD patients: do they have effects on cells and molecular mediators of airway inflammation?.Chest. 2000; 117: 1633-1637Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar28Rutgers SR Postma DS ten Hacken NH et al.Ongoing airway inflammation in patients with COPD who do not currently smoke.Thorax. 2000; 55: 12-18Crossref PubMed Scopus (286) Google Scholar29Lusuardi M Capelli A Cerutti CG et al.Airways inflammation in subjects with chronic bronchitis who have never smoked.Thorax. 1994; 489: 1211-1216Crossref Scopus (30) Google Scholar Severe and mild-to-moderate stages of the disease are associated with different cellular inflammatory bronchial infiltrates30Di Stefano A Capelli A Lusuardi M et al.Severity of airflow limitation is associated with severity of airway inflammation in smokers.Am J Respir Crit Care Med. 1998; 158: 1277-1285Crossref PubMed Scopus (461) Google Scholar and also may be characterized by distinct sets of chemotactic factors. The genetic background of patients is probably important, as the same agent (ie, cigarette smoke) could cause different molecular responses in patient subpopulations sharing particular alleles for one or more chemotactic factors.After identifying and antagonizing the relevant neutrophil chemotactic factors, and certainly IL-8 and LTB4 are good candidates, one should ask to what extent the airway inflammation in COPD patients would be reduced. Together with variable bronchospasm and hyperrreactivity, the features of COPD causing airflow limitation comprise a substantial reduction in the caliber and number of small airways, the loss of alveolar attachments causing air trapping, exaggerated mucus production, and the presence of airway inflammatory infiltrates.4Jeffery PK Structural and inflammatory changes in COPD: a comparison with asthma.Thorax. 1998; 53: 129-136Crossref PubMed Scopus (302) Google Scholar Neutrophils and their products contribute to all these features, but other cell types (eg, macrophages, lymphocytes, or eosinophils) are surely also involved in the genesis of airway inflammation. At least some activities of neutrophils in COPD could be surrogated by other cell types, such as macrophages.31Hautamaki RD Kobayashi DK Senior RM et al.Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice.Science. 1997; 277: 2002-2004Crossref PubMed Scopus (1233) Google Scholar Thus, the suppression only of the neutrophil-dependent part of inflammation, even if possible, may not be sufficient to cure COPD while it could have also serious side effects on bacterial infection susceptibility.Since one of the targets of the antichemotactic strategies seems to be IL-8 or its receptor, it should be remembered that the chemokine system is redundant, with many molecules sharing overlapping effects and acting through the same surface receptors,32Mantovani A The chemokine system: redundancy for robust outputs.Immunol Today. 1999; 20: 254-257Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar and it may be difficult to inhibit in vivo chemotaxis significantly by blocking just one chemokine or receptor. Lastly, it has been demonstrated that similar activities claimed for the new antichemotactic drugs are exerted, directly or indirectly, by old drugs that are used worldwide, such as theophylline.33Culpitt SV de Matos C Russell RE et al.Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2002; 165: 1371-1376Crossref PubMed Scopus (155) Google ScholarIn conclusion, the antichemotaxis approach is probably not ready for prime time in the treatment of COPD. Despite all of the above-mentioned limitations, it represents a very good working hypothesis, introducing for the first time the concept of an etiologic treatment that would counteract the noxious effects of the neutrophilic inflammatory burden in the airways of COPD patients. The best reward for the hard work of many research groups will be in unveiling the molecular pathways of COPD airway inflammation. Over the last years, many studies were aimed at better redefining the airway inflammatory changes that are associated with COPD, the diagnostic umbrella comprising emphysema, small airways disease, and chronic bronchitis (CB). The reappraisal of inflammation of the airways as a fundamental part of the disease was possible by capitalizing, on one side, on the different tools that are available for evaluating airway inflammation from more to less invasive or noninvasive (eg, BAL or sputum) and, on the other side, on the recent progresses in immunology and leukocyte biology. Looking back at the results of all these studies, they were somehow surprising. Neutrophils have been known for a long time as the major component of sputum in CB and COPD patients,1Chodosh S Examination of sputum cells.N Engl J Med. 1970; 282: 854-857Crossref PubMed Scopus (45) Google Scholar and consistently their role in intraluminal inflammation has been confirmed, but new and important information has been added on the mechanisms of polymorphonuclear leukocyte recruitment and on their activities in the derangement of the airways and lung parenchyma. Moreover, what was really new and exciting was the observation of a role for mononuclear cell-mediated inflammation also in COPD patients. Lymphocytes and monocytes/macrophages are found in increased numbers and in the activated state in the bronchial submucosa of CB and COPD patients.2Saetta M Di Stefano A Maestrelli P et al.Activated T-lymphocytes, and macrophages. in bronchial mucosa of subjects with chronic bronchitis.Am Rev Respir Dis. 1993; 147: 301-306Crossref PubMed Scopus (330) Google Scholar3Di Stefano A Turato G Maestrelli P et al.Up-regulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis.Am J Respir Crit Care Med. 1994; 149: 803-810Crossref PubMed Scopus (219) Google Scholar It is a picture that somehow resembles that found in the bronchi of asthmatic patients, but at variance with the situation in asthma patients, in COPD patients the causative agents and the characteristics (eg, T helper-1 vs T helper-2 cytokine profile) of this reaction are still unclear.4Jeffery PK Structural and inflammatory changes in COPD: a comparison with asthma.Thorax. 1998; 53: 129-136Crossref PubMed Scopus (302) Google Scholar Moreover, the interaction between the mononuclear and the polymorphonuclear part of airway inflammation is just starting to be addressed, with evidence of the role of chemokines and chemokine receptors.5Di Stefano A Capelli A Lusuardi M et al.Decreased T lymphocyte infiltration in bronchial biopsies of subjects with severe chronic obstructive pulmonary disease.Clin Exp Allergy. 2001; 31: 893-902Crossref PubMed Scopus (72) Google Scholar6Saetta M Mariani M Panina-Bordignon P et al.Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2002; 165: 1404-1409Crossref PubMed Scopus (320) Google Scholar Beginning with these observations, the research focused on the possible molecular mechanisms causing airway inflammation, trying to identify the possible targets for new treatment approaches. So what is the key to airway inflammation in COPD patients? Many researchers think that neutrophil chemotaxis is the key. As a follow-up to this concept, the hypothesis that by inhibiting, or reducing, the neutrophil influx into the airways one should be able to reduce the burden of airway inflammation and, thus, to change the natural history of the disease, has arisen. Chemotaxis is a biological phenomenon whereby a cell type migrates through barriers (eg, vessel walls or epithelial layers) and tissues toward a site of inflammation or infection. Thus, it represents a useful biological phenomenon since it allows for the allocation of resources (ie, cells and cell products) in a short time to the place where they are needed. The cells migrating to the site of chemotaxis will initiate and maintain the inflammatory processes, which may switch up self-maintaining circuits and become chronic and irreversible, causing tissue derangement and organ failure. In the case of COPD, although cigarette smoke is the cause of the disease in most patients and smoke is able to induce neutrophil chemotaxis,7Blue ML Janoff A Possible mechanisms of emphysema in cigarette smokers: release of elastase from human polymorphonuclear leukocytes by cigarette smoke condensate in vitro.Am Rev Respir Dis. 1978; 117: 317-325PubMed Google Scholar8Sato E Koyama S Takamizawa A et al.Smoke extract stimulates lung fibroblasts to release neutrophil and monocyte chemotactic activities.Am J Physiol. 1999; 277: L1149-L1157PubMed Google Scholar one of the characteristics is the continuing maintenance of the airway inflammatory picture after smoking cessation. Chemotaxis is also a complex and multistep process in which, under a variety of stimuli, different cell types produce either the chemotactic factors or the factors that induce their production, other cells migrate through margination, deformation, and rolling adhesion mediated by adhesion molecules, and the mediators of chemotaxis and their receptors have an interplay. As an example, a long list of molecules, each of them produced by different cell types, are able to exert a chemotactic activity for neutrophils: classic chemoattractants such as C5a, leukotriene (LT) B4, platelet-activating factor, and formyl-methionyl-leucyl-phenylalanine; chemokines such as interleukin (IL)-8, growth-related oncogene (GRO)-α, GRO-β, and GRO-γ; and other recently recognized factors.9Holland SM Gallin JL Neutrophils Crystal.in: West RG Weibel JB The lung scientific foundations. 2nd ed. Lippincott-Raven, Philadelphia, PA1997: 877-890Google Scholar10Pan ZZ Parkyn L Ray A et al.Inducible lung-specific expression of RANTES: preferential recruitment of neutrophils.Am J Physiol. 2000; 279: L658-L666PubMed Google Scholar11Parmar JS Mahadeva R Reed BJ et al.Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema.Am J Respir Cell Mol Biol. 2002; 26: 723-730Crossref PubMed Scopus (135) Google Scholar In this issue of CHEST (see page 1240), Beeh and colleagues, starting from the observation that IL-8 and LTB4 are identified as neutrophil chemotactic factors in the sputa of COPD patients, demonstrate that a mouse antibody antagonist of IL-8 and an antagonist of LTB4 receptor may inhibit in vitro neutrophil chemotaxis. Similarly, an LT synthesis inhibitor has been shown to be ready for further clinical studies, and other compounds are being tested.12Gompertz S Stockley RA A randomized, placebo-controlled trial of a leukotriene synthesis inhibitor in patients with COPD.Chest. 2002; 122: 289-294Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar13Barnes PJ Chronic obstructive pulmonary disease.N Engl J Med. 2000; 343: 269-280Crossref PubMed Scopus (1202) Google Scholar14Pauwels RA Buist S Calverley PMA et al.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; 163: 1256-1276Crossref PubMed Scopus (4307) Google Scholar This evidence means that if chemotaxis is the key factor in the airway inflammation of patients with COPD, there are compounds that can block it, thus opening new avenues for the treatment of this deadly disease. Together with antichemotactic drugs, many new compounds or classes of compounds are presently in development for the treatment of COPD, such as antioxidants, protease inhibitors, adhesion molecule inhibitors, and new anti-inflammatory drugs.13Barnes PJ Chronic obstructive pulmonary disease.N Engl J Med. 2000; 343: 269-280Crossref PubMed Scopus (1202) Google Scholar14Pauwels RA Buist S Calverley PMA et al.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; 163: 1256-1276Crossref PubMed Scopus (4307) Google Scholar All of these new approaches have their rationale in cellular and molecular mechanisms of the inflammatory components in COPD that are taken as targets for the proposed treatment, but there are still a number of problems to be solved. For the antichemotactic drugs, the first problem is to identify the important mediators of chemotaxis that drive neutrophils into the airways of COPD patients. Neutrophilic chemotactic factors such as, IL-8, LTB4, and GRO-α have been identified in COPD patients at different levels, in BAL,15Riise GC Ahlstedt S Larsson S et al.Bronchial inflammation in chronic bronchitis assessed by measurements of cell products in bronchial lavage fluid.Thorax. 1995; 50: 360-365Crossref PubMed Scopus (142) Google Scholar16Pesci A Balbi B Majori M et al.Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease.Eur Respir J. 1998; 12: 380-386Crossref PubMed Scopus (259) Google Scholar17Balbi B Majori M Bertacco S et al.Inhaled corticosteroids in stable COPD patients: do they have effects on cells and molecular mediators of airway inflammation?.Chest. 2000; 117: 1633-1637Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar18Tanino M Betsuyaku T Takeyabu K et al.Increased levels of interleukin-8 in BAL fluid from smokers susceptible to pulmonary emphysema.Thorax. 2002; 57: 405-411Crossref PubMed Scopus (123) Google Scholar sputum,19Keatings VM Collins PD Scott DM et al.Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma.Am J Respir Crit Care Med. 1996; 153: 530-534Crossref PubMed Scopus (1218) Google Scholar20Mikami M Llewellyn-Jones CG Bayley D et al.The chemotactic activity of sputum from patients with bronchiectasis.Am J Respir Crit Care Med. 1998; 157: 723-728Crossref PubMed Scopus (76) Google Scholar21Traves SL Culpitt SV Russell REK et al.Increased levels of the chemokines GROα and MCP-1 in sputum samples from patients with COPD.Thorax. 2002; 57: 590-595Crossref PubMed Scopus (298) Google Scholar serum,22Seggev JS Thornton Jr, WH Edes TE Serum leukotriene B4 levels in patients with obstructive pulmonary disease.Chest. 1991; 99: 289-291Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar and lung tissue.23De Boer WI Sont JK van Schadewijk A et al.Monocyte chemoattractant protein 1, interleukin-8, and chronic airways inflammation in COPD.J Pathol. 2000; 190: 619-626Crossref PubMed Scopus (255) Google Scholar There is a need to clearly identify the chemotactic factors that, among many others, may be more important in COPD patients, and/or are more easily inhibited in their functional activity. As an example, Beeh and colleagues observed that the pretreatment of neutrophils with the combination of both of the antichemotactic drugs (ie, anti-IL-8 and anti-LTB4 receptor) reduced the sputum-induced chemotaxis by roughly 45%, which was less than the combined effect of either drug alone, thus suggesting the presence in the sputa of other, yet unidentified, neutrophil chemoattractants. Chemotaxis may be quantitatively assayed in vitro using the chemotaxis chamber24Boyden Jr, SE The chemotactic effects of mixtures of antibody and antigen on polymorphonuclear leukocytes.J Exp Med. 1962; 115: 453-466Crossref PubMed Scopus (2004) Google Scholar or chemotactic factors may be identified by immunoenzymatic methods. In both cases, methodologic problems that are caused by the presence of the natural inhibitors of some chemotactic factors25Marshall LJ Perks B Ferkol T et al.IL-8 released constitutively by primary bronchial epithelial cells in culture forms an inactive complex with secretory component.J Immunol. 2001; 167: 2816-2823Crossref PubMed Scopus (45) Google Scholar or by the possible confounding effects of dithiothreitol on sputum sol assays26Pignatti P Delmastro M Perfetti L et al.Is dithiothreitol affecting cells and soluble mediators during sputum processing? A modified methodology to process sputum.J Allergy Clin Immunol. 2002; 110: 667-668Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar27Kelly MM Leigh R Horsewood P et al.Induced sputum: validity of fluid-phase IL-5 measurement.J Allergy Clin Immunol. 2000; 105: 1162-1168Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar may occur. In addition, it is possible that at different sites (eg, larger vs smaller airways) the “cocktail” of chemotactic factors varies. The different proportions of the various chemotactic factors that are detected would then be due to the methodology used to obtain solutes from the airways (eg, sputum, sampling more proximal airways, or BAL, sampling also the lower respiratory tract). Exacerbations of COPD, or subtypes of them (eg, bacterial), may be associated with a set of chemotactic signals that is different from that driving neutrophilic inflammation during the stable state, a difference that can be hypothesized also for the other COPD patient groups such as current smokers vs former or never-smokers.17Balbi B Majori M Bertacco S et al.Inhaled corticosteroids in stable COPD patients: do they have effects on cells and molecular mediators of airway inflammation?.Chest. 2000; 117: 1633-1637Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar28Rutgers SR Postma DS ten Hacken NH et al.Ongoing airway inflammation in patients with COPD who do not currently smoke.Thorax. 2000; 55: 12-18Crossref PubMed Scopus (286) Google Scholar29Lusuardi M Capelli A Cerutti CG et al.Airways inflammation in subjects with chronic bronchitis who have never smoked.Thorax. 1994; 489: 1211-1216Crossref Scopus (30) Google Scholar Severe and mild-to-moderate stages of the disease are associated with different cellular inflammatory bronchial infiltrates30Di Stefano A Capelli A Lusuardi M et al.Severity of airflow limitation is associated with severity of airway inflammation in smokers.Am J Respir Crit Care Med. 1998; 158: 1277-1285Crossref PubMed Scopus (461) Google Scholar and also may be characterized by distinct sets of chemotactic factors. The genetic background of patients is probably important, as the same agent (ie, cigarette smoke) could cause different molecular responses in patient subpopulations sharing particular alleles for one or more chemotactic factors. After identifying and antagonizing the relevant neutrophil chemotactic factors, and certainly IL-8 and LTB4 are good candidates, one should ask to what extent the airway inflammation in COPD patients would be reduced. Together with variable bronchospasm and hyperrreactivity, the features of COPD causing airflow limitation comprise a substantial reduction in the caliber and number of small airways, the loss of alveolar attachments causing air trapping, exaggerated mucus production, and the presence of airway inflammatory infiltrates.4Jeffery PK Structural and inflammatory changes in COPD: a comparison with asthma.Thorax. 1998; 53: 129-136Crossref PubMed Scopus (302) Google Scholar Neutrophils and their products contribute to all these features, but other cell types (eg, macrophages, lymphocytes, or eosinophils) are surely also involved in the genesis of airway inflammation. At least some activities of neutrophils in COPD could be surrogated by other cell types, such as macrophages.31Hautamaki RD Kobayashi DK Senior RM et al.Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice.Science. 1997; 277: 2002-2004Crossref PubMed Scopus (1233) Google Scholar Thus, the suppression only of the neutrophil-dependent part of inflammation, even if possible, may not be sufficient to cure COPD while it could have also serious side effects on bacterial infection susceptibility. Since one of the targets of the antichemotactic strategies seems to be IL-8 or its receptor, it should be remembered that the chemokine system is redundant, with many molecules sharing overlapping effects and acting through the same surface receptors,32Mantovani A The chemokine system: redundancy for robust outputs.Immunol Today. 1999; 20: 254-257Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar and it may be difficult to inhibit in vivo chemotaxis significantly by blocking just one chemokine or receptor. Lastly, it has been demonstrated that similar activities claimed for the new antichemotactic drugs are exerted, directly or indirectly, by old drugs that are used worldwide, such as theophylline.33Culpitt SV de Matos C Russell RE et al.Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2002; 165: 1371-1376Crossref PubMed Scopus (155) Google Scholar In conclusion, the antichemotaxis approach is probably not ready for prime time in the treatment of COPD. Despite all of the above-mentioned limitations, it represents a very good working hypothesis, introducing for the first time the concept of an etiologic treatment that would counteract the noxious effects of the neutrophilic inflammatory burden in the airways of COPD patients. The best reward for the hard work of many research groups will be in unveiling the molecular pathways of COPD airway inflammation.