Inflammatory mechanisms in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation affecting predominantly the lung parenchyma and peripheral airways that results in largely irreversible and progressive airflow limitation. This inflammation is characterized by increased numbers of alveolar macrophages, neutrophils, T lymphocytes (predominantly TC1, TH1, and TH17 cells), and innate lymphoid cells recruited from the circulation. These cells and structural cells, including epithelial and endothelial cells and fibroblasts, secrete a variety of proinflammatory mediators, including cytokines, chemokines, growth factors, and lipid mediators. Although most patients with COPD have a predominantly neutrophilic inflammation, some have an increase in eosinophil counts, which might be orchestrated by TH2 cells and type 2 innate lymphoid cells though release of IL-33 from epithelial cells. These patients might be more responsive to corticosteroids and bronchodilators. Oxidative stress plays a key role in driving COPD-related inflammation, even in ex-smokers, and might result in activation of the proinflammatory transcription factor nuclear factor κB (NF-κB), impaired antiprotease defenses, DNA damage, cellular senescence, autoantibody generation, and corticosteroid resistance though inactivation of histone deacetylase 2. Systemic inflammation is also found in patients with COPD and can worsen comorbidities, such as cardiovascular diseases, diabetes, and osteoporosis. Accelerated aging in the lungs of patients with COPD can also generate inflammatory protein release from senescent cells in the lung. In the future, it will be important to recognize phenotypes of patients with optimal responses to more specific therapies, and development of biomarkers that identify the therapeutic phenotypes will be important. Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation affecting predominantly the lung parenchyma and peripheral airways that results in largely irreversible and progressive airflow limitation. This inflammation is characterized by increased numbers of alveolar macrophages, neutrophils, T lymphocytes (predominantly TC1, TH1, and TH17 cells), and innate lymphoid cells recruited from the circulation. These cells and structural cells, including epithelial and endothelial cells and fibroblasts, secrete a variety of proinflammatory mediators, including cytokines, chemokines, growth factors, and lipid mediators. Although most patients with COPD have a predominantly neutrophilic inflammation, some have an increase in eosinophil counts, which might be orchestrated by TH2 cells and type 2 innate lymphoid cells though release of IL-33 from epithelial cells. These patients might be more responsive to corticosteroids and bronchodilators. Oxidative stress plays a key role in driving COPD-related inflammation, even in ex-smokers, and might result in activation of the proinflammatory transcription factor nuclear factor κB (NF-κB), impaired antiprotease defenses, DNA damage, cellular senescence, autoantibody generation, and corticosteroid resistance though inactivation of histone deacetylase 2. Systemic inflammation is also found in patients with COPD and can worsen comorbidities, such as cardiovascular diseases, diabetes, and osteoporosis. Accelerated aging in the lungs of patients with COPD can also generate inflammatory protein release from senescent cells in the lung. In the future, it will be important to recognize phenotypes of patients with optimal responses to more specific therapies, and development of biomarkers that identify the therapeutic phenotypes will be important. GlossaryBIOMASS SMOKEIndoor air pollution source resulting from burning of tobacco, wood, or other plant fuels. Burning of biomass results in polyaromatic hydrocarbon particulates that can be metabolized into oxidant species. Traditional biomass (wood, coal, charcoal, dung, and crop wastes) burned in open fires and traditional stoves are used by almost half the world's population and contribute to more than 1 million COPD-related deaths annually.CYSTEINYL LEUKOTRIENESInflammatory mediators produced from arachidonic acid by 5-lipoxygenase in mast cells, eosinophils, and other inflammatory cells. Cysteinyl leukotrienes include leukotriene (LT) C4, LTD4, and LTE4.DEFENSINSA distinct family of antimicrobial peptides produced by epithelial cells on mucosal surfaces, as well as by neutrophils, natural killer cells, and cytotoxic T lymphocytes. Defensins have direct antimicrobial activity, as well as the ability to activate inflammatory responses.ELASTINA connective tissue protein similar to collagen that helps form a 3-dimensional basket-like structure around the alveoli and airways, allowing the lung to expand in all directions without developing excessive tissue recoil.EXHALED BREATH CONDENSATESA noninvasive technique for measuring airway inflammation obtained by cooling exhaled air. Exhaled breath condensate samples are thought to reflect contents of the airway lining fluid.HISTONEWater-soluble proteins rich in the basic amino acids lysine and arginine that complex with DNA in the nucleosomes of chromatin.IL-10A cytokine produced primarily by mononuclear phagocytic cells, as well as CD25+CD4+ regulatory T cells and TH1 and TH2 lymphocytes. IL-10 has many biologic functions aimed at maintaining homeostatic control of immune reactions, including inhibition of antigen-presenting cells, decreased MHC class II expression, decreased CD80 (T-cell costimulator) expression, inhibition of TH1 and TH2 cytokine production, and inhibition of IgE production and eosinophil activation.INDOOR AIR POLLUTIONIn addition to tobacco smoke, additional indoor pollutant sources include cooking and combustion, building materials, air conditioning, consumer products, heating, biologic agents, and particle resuspension. Specific products of indoor pollution include carbon monoxide, carbon dioxide, nitrogen dioxide, volatile organic compounds (eg, aldehydes), radon, lead, organic dusts, and microbial agents.NLRP3 INFLAMMASOMEAlso referred to as the NALP3 inflammasome, an enzyme complex that functions to activate the potent proinflammatory molecules IL-1, IL-18, and IL-33. Mutations in NLRP3 result in the cryopyrin-associated periodic syndromes, such as Muckle-Wells syndrome, which involve inappropriate production of active IL-1β.γδ T CELLSAbundant in epithelial tissues, these T cells have a clonally distributed receptor composed of heterodimers of γ and δ chains. These receptors do not recognize MHC-associated peptide antigens and are not MHC restricted. γδ T cells comprise only 5% of all T cells. The receptors for γδ T cells have limited diversity.The Editors wish to acknowledge Daniel Searing, MD, for preparing this glossary. Indoor air pollution source resulting from burning of tobacco, wood, or other plant fuels. Burning of biomass results in polyaromatic hydrocarbon particulates that can be metabolized into oxidant species. Traditional biomass (wood, coal, charcoal, dung, and crop wastes) burned in open fires and traditional stoves are used by almost half the world's population and contribute to more than 1 million COPD-related deaths annually. Inflammatory mediators produced from arachidonic acid by 5-lipoxygenase in mast cells, eosinophils, and other inflammatory cells. Cysteinyl leukotrienes include leukotriene (LT) C4, LTD4, and LTE4. A distinct family of antimicrobial peptides produced by epithelial cells on mucosal surfaces, as well as by neutrophils, natural killer cells, and cytotoxic T lymphocytes. Defensins have direct antimicrobial activity, as well as the ability to activate inflammatory responses. A connective tissue protein similar to collagen that helps form a 3-dimensional basket-like structure around the alveoli and airways, allowing the lung to expand in all directions without developing excessive tissue recoil. A noninvasive technique for measuring airway inflammation obtained by cooling exhaled air. Exhaled breath condensate samples are thought to reflect contents of the airway lining fluid. Water-soluble proteins rich in the basic amino acids lysine and arginine that complex with DNA in the nucleosomes of chromatin. A cytokine produced primarily by mononuclear phagocytic cells, as well as CD25+CD4+ regulatory T cells and TH1 and TH2 lymphocytes. IL-10 has many biologic functions aimed at maintaining homeostatic control of immune reactions, including inhibition of antigen-presenting cells, decreased MHC class II expression, decreased CD80 (T-cell costimulator) expression, inhibition of TH1 and TH2 cytokine production, and inhibition of IgE production and eosinophil activation. In addition to tobacco smoke, additional indoor pollutant sources include cooking and combustion, building materials, air conditioning, consumer products, heating, biologic agents, and particle resuspension. Specific products of indoor pollution include carbon monoxide, carbon dioxide, nitrogen dioxide, volatile organic compounds (eg, aldehydes), radon, lead, organic dusts, and microbial agents. Also referred to as the NALP3 inflammasome, an enzyme complex that functions to activate the potent proinflammatory molecules IL-1, IL-18, and IL-33. Mutations in NLRP3 result in the cryopyrin-associated periodic syndromes, such as Muckle-Wells syndrome, which involve inappropriate production of active IL-1β. Abundant in epithelial tissues, these T cells have a clonally distributed receptor composed of heterodimers of γ and δ chains. These receptors do not recognize MHC-associated peptide antigens and are not MHC restricted. γδ T cells comprise only 5% of all T cells. The receptors for γδ T cells have limited diversity. The Editors wish to acknowledge Daniel Searing, MD, for preparing this glossary. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. Chronic obstructive pulmonary disease (COPD) is a major global epidemic that is increasing throughout the world as populations age and survive previous causes of death.1Barnes P.J. Burney P.G.J. Silverman E.K. Celli B.R. Vestbo J. Wedzicha J.A. et al.Chronic obstructive pulmonary disease.Nat Rev Dis Primers. 2015; 1: 15076Crossref PubMed Scopus (84) Google Scholar COPD is now the fourth-ranked cause of death worldwide and predicted to become the fifth-ranked cause of disability, affecting approximately 10% of persons older than 45 years.2Lozano R. Naghavi M. Foreman K. Lim S. Shibuya K. Aboyans V. et al.Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380: 2095-2128Abstract Full Text Full Text PDF PubMed Scopus (7341) Google Scholar In developed countries COPD now affects female and male subjects equally, reflecting the equal prevalence of smoking. It is now recognized that there are different clinical phenotypes of COPD, with some patients having predominantly small-airway disease and others having mainly emphysema. Other differences include age of onset, the frequency of exacerbations, and association with other diseases, such as chronic cardiovascular and metabolic diseases (comorbidities). Several attempts have been made to segregate patients with COPD into different clusters based on clinical and radiologic characteristics, but it has been difficult to identify these phenotypes in different populations, and there has been no link to underlying disease mechanisms (endotypes).3Castaldi P.J. Dy J. Ross J. Chang Y. Washko G.R. Curran-Everett D. et al.Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema.Thorax. 2014; 69: 415-422Crossref PubMed Scopus (83) Google Scholar, 4Burgel P.R. Paillasseur J.L. Caillaud D. Tillie-Leblond I. Chanez P. Escamilla R. et al.Clinical COPD phenotypes: a novel approach using principal component and cluster analyses.Eur Respir J. 2010; 36: 531-539Crossref PubMed Scopus (214) Google Scholar COPD is associated with chronic inflammation of the airways and lung parenchyma, which increases further during acute exacerbations and is also associated with systemic inflammation.5Barnes P.J. Cellular and molecular mechanisms of chronic obstructive pulmonary disease.Clin Chest Med. 2014; 35: 71-86Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar Although the nature of this inflammation in lungs from patients with COPD has been well described, it is still uncertain how this relates to clinical outcomes, disease progression, and response to different therapies, and more research is needed to understand this better. Longitudinal studies of populations with COPD over many years have demonstrated that only about 50% of patients given a diagnosis of COPD have an accelerated decrease in lung function, whereas the remainder have a normal age-related decrease but start from a lower value, presumably because of impaired lung development.6Lange P. Celli B. Agusti A. Boje Jensen G. Divo M. Faner R. et al.Lung-function trajectories leading to chronic obstructive pulmonary disease.N Engl J Med. 2015; 373: 111-122Crossref PubMed Scopus (189) Google Scholar This implies that only half of patients with “COPD” have inflammation, whereas those with normal decreases in lung function presumably do not, although in most studies no distinction is made because the trajectory of lung function is unknown. More research is urgently needed to understand different patterns of lung inflammation in patients with COPD and how these relate to clinical outcomes, response to therapy, and prognosis. In particular, it is necessary to understand how inflammation changes in response to different environmental stimuli and how it changes over time in the same patient. COPD of different causes can differ in terms of inflammation, but the COPD associated with indoor air pollution appears to have a very similar pattern of inflammation to that seen in patients with smoking-related COPD, suggesting that the respiratory tract might respond to different risk factors in the same way.7Iyer N. Brashier B. Madas S. Londhe J. Salvi S. Barnes P.J. Physiological and inflammatory phenotypic comparisons between non-smoking and smoking COPD.Eur Resp J. 2013; 42: 3042Google Scholar This review discusses the nature of inflammation in patients with COPD and the underlying molecular mechanisms that can identify new targets for more effective anti-inflammatory therapy in the future.8Barnes P.J. New anti-inflammatory treatments for chronic obstructive pulmonary disease.Nat Rev Drug Discov. 2013; 12: 543-559Crossref PubMed Scopus (223) Google Scholar The progressive airflow limitation in patients with COPD results from 2 major pathological processes: remodeling and narrowing of the small airways and destruction of the lung parenchyma with consequent loss of the alveolar attachments of these airways as a result of emphysema. These pathological changes appear to be the consequence of chronic inflammation in the lung periphery, the intensity of which increases as the disease progresses.9Hogg J.C. Chu F. Utokaparch S. Woods R. Elliott W.M. Buzatu L. et al.The nature of small-airway obstruction in chronic obstructive pulmonary disease.N Engl J Med. 2004; 350: 2645-2653Crossref PubMed Scopus (2470) Google Scholar Even in patients with mild disease, there is obstruction and loss of the peripheral airways.10McDonough J.E. Yuan R. Suzuki M. Seyednejad N. Elliott W.M. Sanchez P.G. et al.Small-airway obstruction and emphysema in chronic obstructive pulmonary disease.N Engl J Med. 2011; 365: 1567-1575Crossref PubMed Google Scholar Analysis of serial computed tomographic scans suggests that small-airway obstruction usually precedes the development of emphysema,11Galban C.J. Han M.K. Boes J.L. Chughtai K.A. Meyer C.R. Johnson T.D. et al.Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression.Nat Med. 2012; 18: 1711-1715Crossref PubMed Scopus (317) Google Scholar but the mechanisms for this are not clear. Small-airway obstruction and loss of alveolar attachments result in airway closure, and air trapping on expiration that is worsened by exercise and dynamic hyperinflation might account for exertional dyspnea, the major symptom of COPD, even in patients with mild disease.12Ofir D. Laveneziana P. Webb K.A. Lam Y.M. O'Donnell D.E. Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage I chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2008; 177: 622-629Crossref PubMed Scopus (238) Google Scholar, 13O'Donnell D.E. Laveneziana P. Webb K. Neder J.A. Chronic obstructive pulmonary disease: clinical integrative physiology.Clin Chest Med. 2014; 35: 51-69Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar It is presumed that the peripheral location of inflammation in patients with COPD reflects the sites of deposition of inhaled irritant particles, such as cigarette and wood smoke. Indeed, in patients with COPD associated with household air pollution (biomass smoke) in developing countries, small-airway disease is predominant, whereas in cigarette smokers small airway disease and emphysema often coexist.14Perez-Padilla R. Schilmann A. Riojas-Rodriguez H. Respiratory health effects of indoor air pollution.Int J Tuberc Lung Dis. 2010; 14: 1079-1086PubMed Google Scholar The pattern of inhalation of irritants can also determine localization because wood smoke is usually inhaled tidally, whereas cigarette smoke is often inhaled deeply with a breath hold. This can be seen particularly in smokers of cannabis (marijuana) cigarettes, who can have marked emphysema.15Joshi M. Joshi A. Bartter T. Marijuana and lung diseases.Curr Opin Pulm Med. 2014; 20: 173-179Crossref PubMed Scopus (56) Google Scholar In patients with COPD, there is a characteristic pattern of inflammation with increased numbers of neutrophils in the airway lumen and increased numbers of macrophages, T lymphocytes, and B lymphocytes.9Hogg J.C. Chu F. Utokaparch S. Woods R. Elliott W.M. Buzatu L. et al.The nature of small-airway obstruction in chronic obstructive pulmonary disease.N Engl J Med. 2004; 350: 2645-2653Crossref PubMed Scopus (2470) Google Scholar, 16Barnes P.J. Immunology of asthma and chronic obstructive pulmonary disease.Nat Immunol Rev. 2008; 8: 183-192Crossref PubMed Scopus (867) Google Scholar, 17Brusselle G.G. Joos G.F. Bracke K.R. New insights into the immunology of chronic obstructive pulmonary disease.Lancet. 2011; 378: 1015-1026Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar The inflammatory response in patients with COPD involves both innate and adaptive immune responses, which are linked through activation of dendritic cells.18Givi M.E. Redegeld F.A. Folkerts G. Mortaz E. Dendritic cells in pathogenesis of COPD.Curr Pharm Des. 2012; 18: 2329-2335Google Scholar A similar pattern of inflammation and mediator expression is found in smokers without airflow limitation, but in patients with COPD, this inflammation is amplified and even further increased during acute exacerbations or precipitated by bacterial or viral infection (Fig 1). The molecular basis for the amplification of inflammation is not yet fully understood but might be, at least in part, determined by genetic and epigenetic factors. The molecular mechanisms of amplification might determine which smokers are susceptible to the development of airway obstruction. Cigarette smoke and other irritants inhaled into the respiratory tract might activate surface macrophages and airway epithelial cells to release multiple chemotactic mediators, particularly chemokines, which attract circulating neutrophils, monocytes, and lymphocytes into the lungs. This inflammation persists even when smoking is stopped, suggesting that there are self-perpetuating mechanisms, although these have not yet been elucidated.19Gamble E. Grootendorst D.C. Hattotuwa K. O'Shaughnessy T. Ram F.S. Qiu Y. et al.Airway mucosal inflammation in COPD is similar in smokers and ex-smokers: a pooled analysis.Eur Respir J. 2007; 30: 467-471Crossref PubMed Scopus (102) Google Scholar It is possible that long-lived memory T cells, bacterial colonization, or autoimmunity might drive the persistent inflammation seen in patients with COPD. The inflammation seen in the lungs of patients with COPD involves both innate immunity (neutrophils, macrophages, eosinophils, mast cells, natural killer cells, γδ T cells, innate lymphoid cells, and dendritic cells) and adaptive immunity (T and B lymphocytes), but also, there is activation of structural cells, including airway and alveolar epithelial cells, endothelial cells, and fibroblasts. Epithelial cells are activated by cigarette smoke and other inhaled irritants, such as biomass fuel smoke, to produce inflammatory mediators, including TNF-α, IL-1β, IL-6, GM-CSF, and CXCL8 (IL-8).20Gao W. Li L. Wang Y. Zhang S. Adcock I.M. Barnes P.J. et al.Bronchial epithelial cells: The key effector cells in the pathogenesis of chronic obstructive pulmonary disease?.Respirology. 2015; 20: 722-729Crossref PubMed Scopus (60) Google Scholar Epithelial cells in the small airways express TGF-β, which then induces local fibrosis. Vascular endothelial growth factor (VEGF) appears to be necessary to maintain alveolar cell integrity, and blockade of VEGF receptors in rats induces apoptosis of alveolar cells and an emphysema-like pathology.14Perez-Padilla R. Schilmann A. Riojas-Rodriguez H. Respiratory health effects of indoor air pollution.Int J Tuberc Lung Dis. 2010; 14: 1079-1086PubMed Google Scholar A reduction in peripheral lung VEGF concentrations is found in smokers and patients with COPD, but levels of another growth factor, hepatocyte growth factor, are increased in smokers and therefore might protect against the effect of reduced VEGF levels on alveolar integrity. However, in patients with COPD, both VEGF and hepatocyte growth factor levels are reduced, which might contribute to development of emphysema.21Kanazawa H. Tochino Y. Asai K. Hirata K. Simultaneous assessment of hepatocyte growth factor and vascular endothelial growth factor in epithelial lining fluid from patients with COPD.Chest. 2014; 146: 1159-1165Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Airway epithelial cells are also important in defense of the airways, with mucus production from goblet cells and secretion of antioxidants, antiproteases, and defensins/cathelicidins. Cigarette smoke and other noxious agents might impair these responses of the airway epithelium, increasing susceptibility to infection. The airway epithelium in patients with chronic bronchitis and COPD often shows squamous metaplasia, which can result from increased proliferation of basal airway epithelial cells, but the nature of the growth factors involved in epithelial cell proliferation, the cell cycle, and differentiation in patients with COPD are not yet certain. Epithelial growth factor receptors (EGFRs) show increased expression in airway epithelial cells of patients with COPD and might contribute to basal cell proliferation, resulting in squamous metaplasia and an increased risk of bronchial carcinoma.22de Boer W.I. Hau C.M. van Schadewijk A. Stolk J. van Krieken J.H. Hiemstra P.S. Expression of epidermal growth factors and their receptors in the bronchial epithelium of subjects with chronic obstructive pulmonary disease.Am J Clin Pathol. 2006; 125: 184-192Crossref PubMed Google Scholar Club (Clara) cells can act as progenitor cells in the peripheral airways and might be susceptible to damage from inhaled irritants. Conditional depletion of club cells in mice leads to squamous cell metaplasia and peribronchiolar fibrosis, similar to the pathology of COPD.23Perl A.K. Riethmacher D. Whitsett J.A. Conditional depletion of airway progenitor cells induces peribronchiolar fibrosis.Am J Respir Crit Care Med. 2011; 183: 511-521Crossref PubMed Scopus (46) Google Scholar Club cell secretory protein is deficient in patients with COPD.24Gamez A.S. Gras D. Petit A. Knabe L. Molinari N. Vachier I. et al.Supplementing defect in Club Cell Secretory Protein attenuates airway inflammation in COPD.Chest. 2015; 147: 1467-1476Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Mucus hyperplasia is a feature of many patients with COPD and is a response to chronic airway irritation by cigarette smoke and other pollutants. EGFRs play an important role on mucus hyperplasia and secretion and can be activated by neutrophilic inflammation through neutrophil elastase secretion, which releases TGF-α (Fig 2).25Burgel P.R. Nadel J.A. Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium.Thorax. 2004; 59: 992-996Crossref PubMed Scopus (172) Google Scholar Oxidant stress is also able to activate EGFRs and induce mucus hypersecretion.26Shao M.X. Nakanaga T. Nadel J.A. Cigarette smoke Induces MUC5AC mucin overproduction via tumor necrosis factor-a converting enzyme in human airway epithelial (NCI-H292) cells.Am J Physiol Lung Cell Mol Physiol. 2004; 287: L420-L427Crossref PubMed Scopus (0) Google Scholar An EGFR inhibitor is effective in blocking LPS- and TNF-α–induced expression of MUC5AC in human airway epithelial cells and inhibiting LPS-induced mucus secretion and hyperplasia in rats exposed to cigarette smoke.27Takezawa K. Ogawa T. Shimizu S. Shimizu T. Epidermal growth factor receptor inhibitor AG1478 inhibits mucus hypersecretion in airway epithelium.Am J Rhinol Allergy. 2016; 30: 1-6Google Scholar However, an EGFR inhibitor (BIBW2948) was ineffective in reducing mucin gene expression in patients with COPD and was tolerated poorly.28Woodruff P.G. Wolff M. Hohlfeld J.M. Krug N. Dransfield M.T. Sutherland E.R. et al.Safety and efficacy of an inhaled epidermal growth factor receptor inhibitor (BIBW 2948 BS) in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2010; 181: 438-445Crossref PubMed Scopus (0) Google Scholar Macrophages play a key role in orchestrating chronic inflammation in patients with COPD (Fig 3).29Barnes P.J. Macrophages as orchestrators of COPD.COPD. 2004; 1: 59-70Crossref PubMed Scopus (0) Google Scholar Macrophage numbers are markedly increased (5- to 10-fold) in the airways, lung parenchyma, bronchoalveolar lavage (BAL) fluid, and sputum of patients with COPD. Macrophages are localized to sites of alveolar wall destruction in patients with emphysema, and there is a correlation between macrophage numbers in the parenchyma and the severity of emphysema. Macrophages can be activated by cigarette smoke extract to release inflammatory mediators, including TNF-α, CXCL1, CXCL8, CCL2 (monocyte chemoattractant protein 1), leukotriene (LT) B4, and reactive oxygen species (ROS). Alveolar macrophages also secrete elastolytic enzymes, including matrix metalloproteinases (MMPs) 2, 9, and 12; cathepsins K, L, and S; and neutrophil elastase taken up from neutrophils.30Russell R.E. Thorley A. Culpitt S.V. Dodd S. Donnelly L.E. Demattos C. et al.Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases.Am J Physiol Lung Cell Mol Physiol. 2002; 283: L867-L873Crossref PubMed Google Scholar Alveolar macrophages from patients with COPD secrete more inflammatory proteins and have a greater elastolytic activity at baseline than those from normal smokers and this is further increased by exposure to cigarette smoke. Macrophages demonstrate this difference, even when maintained in culture for 3 days, and therefore appear to be intrinsically different from the macrophages of normal smokers and nonsmoking healthy control subjects. There are different phenotypes of macrophages that can be differentially activated and with different responses. The murine M1 or “classically activated” macrophages are proinflammatory, whereas M2 or “alternatively activated” macrophages are more anti-inflammatory, release IL-10, and show marked phagocytic activity.31Gordon S. Pluddemann A. Tissue macrophage heterogeneity: issues and prospects.Semin Immunopathol. 2013; 35: 533-540Crossref PubMed Scopus (0) Google Scholar However, these distinctions are less clear in human macrophages, and the surface markers of these phenotypes are less distinct. In general, it is likely that M1-like macrophages predominate in patients with COPD, but further studies are needed.32Chana K.K. Fenwick P.S. Nicholson A.G. Barnes P.J. Donnelly L.E. Identification of a distinct glucocorticosteroid-insensitive pulmonary macrophage phenotype in patients with chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2014; 133: 207-216Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar MMP-9 is the predominant elastolytic enzyme secreted by alveolar macrophages from patients with COPD. Most of the inflammatory proteins upregulated in macrophages from patients with COPD are regulated by the transcription factor NF-κB, which is activated in alveolar macrophages of patients with COPD, particularly during exacerbations.33Caramori G. Romagnoli M. Casolari P. Bellettato C. Casoni G. Boschetto P. et al.Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations.Thorax. 2003; 58: 348-351Crossref PubMed Scopus (162) Google Scholar The increased numbers of macrophages in the lungs of smokers and patients with COPD is due to increased recruitment of monocytes from the circulation in response to the monocyte-selective chemokines CCL2 and CXCL1, levels of which are increased in the sputum and BAL fluid of patients with COPD.34Traves S.L. Culpitt S. Russell R.E.K. Barnes P.J. Donnelly L.E. Elevated levels of the chemokines GRO-a and MCP-1 in sputum samples from COPD patients.Thorax. 2002; 57: 590-595Crossref PubMed Scopus (0) Google Scholar