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The Influence of Cigarette Smoking on Viral InfectionsCigarette Smoke, Viral Infections, and COPD: Translating Bench Science to Impact COPD Pathogenesis and Acute Exacerbations of COPD Clinically FREE TO VIEW

Carla M. T. Bauer, PhD; Mathieu C. Morissette, PhD; Martin R. Stämpfli, PhD
Author and Funding Information

From the Pharma Research and Early Development (Dr Bauer), Inflammation Discovery and Translational Area, Hoffmann-La Roche Inc, Nutley, NJ; and Departments of Pathology and Molecular Medicine and Medicine (Drs Morissette and Stämpfli), McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.

Correspondence to: Martin R. Stämpfli, PhD, Departments of Pathology and Molecular Medicine and Medicine, McMaster Immunology Research Centre, McMaster University, Michael DeGroote Centre for Learning and Discovery, Room 4080, 1280 Main St W, Hamilton, ON, L8S 4K2, Canada; e-mail: stampfli@mcmaster.ca


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(1):196-206. doi:10.1378/chest.12-0930
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COPD is a complex syndrome that poses a serious health threat to >1.1 billion smokers worldwide. The stable disease is punctuated by episodes of acute exacerbation, which are predominantly the result of viral and bacterial infections. Despite their devastating health impact, mechanisms underlying disease exacerbations remain poorly understood. Mounting evidence suggests that cigarette smoke profoundly affects the immune system, compromising the host’s ability to mount appropriate immune and inflammatory responses against microbial agents. This review highlights recent advances in our understanding of the impact of cigarette smoke on type 1 interferon and IL-1 signaling cascades. The immune defects caused by cigarette smoke on these two key pathways contribute to the seemingly contradictory nature of cigarette smoke as both a damaging and a proinflammatory factor as well as an immunosuppressive factor. Understanding the impact of cigarette smoke on the immune system may unravel novel targets for therapies that could affect acute exacerbations and COPD pathogenesis.

Figures in this Article

The detrimental impact of cigarette smoking on human health is well established1: Tobacco use is a risk factor for six of the eight leading causes of death in the world.2 Despite these alarming statistics, as many as one-half of the world’s 1 billion smokers will eventually die of smoking-related diseases.3 Cigarette smoking is a major risk factor for lung cancer and cardiovascular diseases, and it directly correlates with the development of COPD, a chronic lung disorder characterized by irreversible and progressive airway obstruction.4 Although emphasis has been placed on reducing smoking prevalence, a greater understanding of the mechanisms that contribute to COPD pathogenesis and disease exacerbation are equally relevant given the burden this disorder places on health-care systems,5 and the addictive nature6 and persistence7 of the cigarette smoking habit. Emerging data in both preclinical and clinical studies suggest opposing effects of cigarette smoke on key antimicrobial signaling cascades (ie, IL-1 and type 1 interferon [IFN]). The importance of these pathways to effective antiviral responses and the maintenance of lung homeostasis are the central focus of the current review.

COPD is a collective term used to describe a range of chronic lung disorders characterized by progressive and largely irreversible airflow limitation.4 Although it is well established that genetic and environmental factors contribute to the development of COPD,8,9 the disease is found almost exclusively in smokers in the industrialized world,4 and in less-developed nations, it has been attributed to the inhalation of emissions from domestic burning of biomass fuels.9,10 It is widely accepted that compromised airway function in COPD is, at least in part, a consequence of persistent airway inflammation that results in the destruction of lung architecture,11 but mechanisms underlying these inflammatory processes are still the subject of active investigation. Moreover, it is not well understood how this chronic inflammatory state affects lung immune homeostasis and, of particular relevance to this review, immune inflammatory processes elicited by viral agents.

Lung infections contribute to the pathogenesis of COPD mainly through exacerbation of the stable disease and through colonization and chronic infection of the lower respiratory tract. Acute exacerbations of COPD (AECOPD) are caused predominantly by viral and bacterial infections,12 while a minor contribution is also made by air pollution and other environmental factors.9 Respiratory viral infections in particular cause as many as 40% to 60% of all exacerbations.13,14 Even though rhinoviruses and respiratory syncytial virus are responsible for the largest fraction of those exacerbations, seasonal influenza has been shown to be a significant cause of acute episodes.15 Although the current review focuses on viral-induced exacerbations, nontypable Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae are the most commonly isolated bacteria in the lungs of patients with COPD.16 Given that microbial infections are the main etiologic factor of AECOPD and contribute to disease progression,17 understanding the consequences of cigarette smoking to lung antimicrobial responses will undoubtedly provide insight for the development of treatment modalities to limit AECOPD and attenuate disease progression.

Inflammatory Cellular Makeup of the COPD Lung

The inflammatory response that ensues within the lungs of patients with COPD appears to be an amplification of the normal inflammatory response to chronic irritants, such as cigarette smoke4 (Fig 1). Because the epithelium provides the first cellular barrier to inhaled irritants, these cells, through the production of inflammatory mediators, likely initiate the chemotaxis and accumulation of a specific pattern of inflammatory cells, including neutrophils, macrophages, and lymphocytes. Lung inflammation is further amplified by oxidative stress and proteases, which ultimately lead to the classic pathologic changes observed in COPD, specifically, chronic bronchitis, emphysema, and small airways disease. Of particular relevance to host defense, cigarette smoke has been shown to compromise the integrity of the respiratory epithelium,18 providing pathogens with a point of entry into the tissue (Fig 1). Furthermore, cigarette smoke has been shown to impair cilia beat frequency and reduce mucociliary clearance,19,20 both of which are integral to effective antimicrobial responses.

Figure Jump LinkFigure 1. The three major consequences of chronic cigarette smoke exposure. Chronic inflammation, progressive destruction of the lung, and an increased susceptibility to infections contribute to the impaired lung and immune system homeostasis that are all recognized features of COPD.Grahic Jump Location

Neutrophils are a major cell type recruited to the COPD lung in response to IL-8, which is believed to be secreted by the epithelium. Although neutrophils have been shown to be integral for the control of bacterial and viral infections of the lung,21,22 they also are a source of neutrophil elastase, matrix metalloproteinases, and cathepsins, all of which have been shown to enable tissue damage and mucous hypersecretion. Brown et al23 showed a significant reduction in the proportion of sputum neutrophils undergoing spontaneous apoptosis in healthy smokers and individuals with COPD compared with nonsmokers, suggesting that their continual presence within the lung is important for perpetuating the inflammatory response.

Alveolar macrophages play an equally important role in the defense against inhaled constituents as a result of their unique location in the alveolar space.24 Numbers of alveolar macrophages are increased fivefold to tenfold in the airways, lung parenchyma, BAL fluid, and sputum of smokers and patients with COPD.25 Furthermore, a correlation exists between macrophage numbers in the airways and COPD severity.26 Macrophages isolated from patients with COPD have been shown to express increased levels of matrix metalloproteinase 9 following ex vivo stimulation compared with alveolar macrophages isolated from control subjects, suggesting that they also play a role in promoting tissue destruction.27 Because macrophages are known to ingest apoptotic cells,28 the defective phagocytic capacity reported of alveolar macrophages in patients with COPD may also contribute to the increased number of neutrophils in the airways of those patients.29

Finally, among other immune inflammatory cells to be implicated in COPD pathogenesis, CD8+ T cells have also been shown to be increased in the lung parenchyma and peripheral and central airways of patients with COPD.30,31 Furthermore, the numbers of CD8+ T lymphocytes correlate with the degree of airflow limitation in smokers. Upon activation, cytotoxic CD8+ T cells release a number of mediators, including perforin and granzyme, that are important for activating cell death cascades. Although critically involved in the host response against viral infections, it has been proposed that activation of the corresponding pathways in these cells may promote tissue damage and perpetuate the aberrant immune response observed in COPD.32

Paradoxically, from our overview of the cellularity of the COPD lung, one might argue that the lung environment is primed to respond to microbial insult; all of the cell types (neutrophils, macrophages, and cytotoxic T cells) found in abundance in the smoke-exposed lung have also been shown to play fundamental roles in antimicrobial defense. The fact remains that patients with COPD experience exacerbations as a result of microbial infections; thus, the remainder of this review focuses on how the smoke-primed lung environment contributes not only to COPD pathogenesis but also leads to dysregulated antimicrobial inflammatory responses.

Cigarette Smoke and the Antiviral Response

A complex and multilayered defense system protects the lungs against potentially harmful environmental agents33-35 through a combination of physical barriers and innate and adaptive immune mechanisms. Maintaining a homeostatic state in the lung is critical because excessive inflammatory processes may comprise airflow and gas exchange. Although it is widely accepted that smokers have a greater risk of lower respiratory tract illness due to microbial agents, it is presently unclear whether this is caused by increased susceptibility to infectious agents, delayed pathogen clearance, or exaggerated antimicrobial inflammatory responses. Underlying the altered responsiveness to viral and bacterial pathogens is likely the direct effect of cigarette smoke on both immune homeostasis and host defense mechanisms.36-38

The innate immune system is equipped with an array of molecular sensors that have evolved to detect conserved structures from pathogens or from danger signals that are released in response to endogenous insults. Germline-encoded pathogen recognition receptors and their recognition of pathogen-associated molecular patterns or danger-associated molecular patterns (DAMPs) enable the innate immune system to discriminate between different types of pathogens and danger signals to elaborate an appropriate immune response.39,40 Three major families of pathogen recognition receptors have been identified: the Toll-like receptors (TLRs), the retinoic acid-inducible gene I (RIG-I)-like receptors, and the NOD-like receptors (NLRs).

Double-stranded RNA (dsRNA), a by-product of viral infection, is a pathogen-associated molecular pattern that is recognized by the innate immune system through TLRs responsible for sensing the production and accumulation of viral nucleic acids. Of the four mammalian TLRs responsible for the identification of nucleic acids, TLR-3 recognizes the replication intermediate dsRNA of most, if not all, viruses.41 Upon stimulation of TLR-3, distinctive intracellular pathways are activated, including TRIF (Toll-IL-1 receptor domain-containing adaptor protein inducing IFN-β).42 This adaptor molecule initiates a signaling cascade that results in the nuclear translocation of interferon regulatory factor (IRF) 3 and nuclear factor κB (NF-κB). Alternatively, the cytoplasmic RIG-I-like receptors have also been shown to bind dsRNA and cause the activation of IRF-3 and NF-κB.43 During virus infection, stimulation of TLR-3 and RIG-I leads to IRF-3 phosphorylation, homodimerization, and translocation into the nucleus where it associates with other transcription factors like NF-κB to form a complex that binds to the IFN-stimulated response element in the IFN-β promoter.44,45 Ultimately, the production of an antiviral state, the cellular environment that restricts viral replication and spread, is elicited through the production of IFN-stimulated genes (ISGs).

The hypothesis that cigarette smoke may impair host defense strategies emerged in the 1980s when cigarette smoke was shown to affect the production of type 1 IFN (Fig 2). As increasing puffs of cigarette smoke were delivered to cultures of cells that were stimulated in vitro with the viral dsRNA analog polyinosinic:polycytidylic acid, an impaired type 1 IFN response was observed.46 We confirmed more recently that Beas-2B epithelial cells and human embryonic lung fibroblasts exposed to increasing concentrations of smoke-conditioned medium (SCM) showed impaired type 1 IFN production in response to polyinosinic:polycytidylic acid.47 Furthermore, cigarette smoke suppressed not only the immediate early phase but also the inductive phase of the type 1 IFN response in a dose-dependent fashion, compromising the induction of an antiviral state and suppressing production of IFNs and several ISGs. Interestingly, the effects elicited by SCM were reversible and almost entirely abrogated in the presence of glutathione, an antioxidant. HuangFu et al48 further demonstrated that a cigarette smoke condensate stimulated specific serine phosphorylation-dependent ubiquitination and degradation of the IFNAR1 (IFN-α, IFN-β, and IFN-ω receptor 1) subunit of the type 1 IFN receptor, which led to attenuation of IFN signaling and a subsequent decrease in the resistance to viral infection. In line with our observations that glutathione, a tripeptide known to protect cells from oxidants,49 reversed the effects of SCM on type 1 IFN responses, HuangFu et al48 showed that the inhibitor of reactive oxygen species N-acetylcysteine noticeably reduced the cigarette smoke condensate-mediated IFNAR1 phosphorylation. Taken together, these in vitro studies provide compelling evidence that cigarette smoke is very likely affecting several aspects of the IFN response in patients who have been exposed to chronic cigarette smoke (Fig 2); remarkably, both in vitro studies discussed demonstrated that these effects were reversible, a point that would be of interest to consider in ex-smokers with COPD.

Figure Jump LinkFigure 2. The interplay between the cellular and molecular mechanisms triggered by cigarette smoke and viral infections, which ultimately lead to impaired type 1 interferon responses and exaggerated inflammatory responses. CXCL = C-X-C motif chemokine; GSH = glutathione; IFN = interferon; IFNRA1 = interferon receptor α-1; IL-1R1 = IL-1 receptor, type 1; IL-18R = IL-18 receptor; IRF = interferon regulatory factor; ISRE = interferon-stimulated response element; NAC = N-acetyl-L-cysteine; MCP-1 = monocyte chemotactic protein-1; NF-κB = nuclear factor κB; PAMP = pathogen-associated molecular pattern; PRR = pathogen recognition receptor.Grahic Jump Location

Studies in experimental animals by Gualano et al50 showed transient increases in viral titers in cigarette smoke-exposed influenza-infected mice compared with control mice, and all mice cleared the virus by day 10, regardless of smoke exposure. Although these data suggest compromised antiviral host responses, type 1 IFN was not assessed. Studies pursued by us51,52 as well as by Kang et al53 did not show increased viral titers in cigarette smoke-exposed influenza-infected animals. Similarly, we did not observe impaired type 1 IFN responses in smoke-exposed mice.52 The incongruities observed in viral loads between research groups are interesting in that although increased rhinovirus loads in patients with COPD in nasal lavage samples have been demonstrated by Mallia et al,54 the differences only reached significance on day 6 postinfection and did not reach significance on any other day in either the BAL or the sputum samples assessed compared with control subjects (discussed in further detail later in this article). Collectively, these data do not clarify whether viral load is in fact causing problems for patients with an exacerbation of COPD and will require additional follow-up.

To further implicate defective IFN responses in smokers (Fig 2), a recent study published by Jaspers et al55 demonstrated that the expression of ISG, IRF-7, was significantly decreased in influenza-infected and IFN-β-stimulated ex vivo-differentiated nasal epithelial cells derived from smokers compared with control subjects. To strengthen their ex vivo observation, they showed that nasal inoculation of smoking and nonsmoking healthy volunteers with a live-attenuated influenza virus resulted in reduced IRF-7 transcripts in healthy smokers compared with control subjects. These data, along with the data presented by Mallia et al54 and the aforementioned in vitro studies, lend support to the notion that impaired type 1 IFN responses may render smokers more susceptible to respiratory virus infection. Although, the conclusions drawn from the human studies still require further investigation, pursuing mechanistic studies in smoke-exposed mice may be difficult because the inflammatory makeup of the lung environment may very well be masking any IFN deficiencies. The possibility that the inflammatory status of the lung is concealing deficiencies in type 1 IFN will be increasingly clear throughout the remainder of this review, where we examine the components driving cigarette smoke-induced inflammation and specifically what role they may play in antiviral host responses.

Modeling Virus-Induced AECOPD Clinically

Experimental infection of well-defined patient populations with relevant viruses is an important tool to further our understanding of the effects of cigarette smoking on viral infections and their importance to the pathogenesis of COPD. Of interest is the study by Mallia et al54 that demonstrated that experimental rhinovirus infection in patients with COPD (not asymptomatic smokers) could induce the symptomatic, physiologic, and inflammatory features that have been previously reported in naturally occurring exacerbations of the disease.14,56-58 They were able to demonstrate that rhinovirus infection was associated with increased neutrophilic inflammation and deficient production of the type 1 IFN IFN-β in patients with COPD.54 These findings are of particular interest given the established importance of type 1 IFNs to antiviral host defense because IFNs are vital to the containment of viral infections. In line with preclinical observations in cigarette smoke exposure and influenza infection mouse models, rhinovirus infection was shown to be associated with an exacerbated inflammatory response. Although the study by Mallia et al54 addresses an important and highly relevant question in COPD research, mechanisms underlying decreased IFN responses and excessive inflammation were not assessed. Another limitation of the study was that a nonsmoking control group was not included in the analysis, which complicates the comparison with animal models (discussed in the next section) that used smoke-exposed and control experimental groups. Even though rhinovirus challenge models provide important indications of mechanisms driving exacerbations, these studies need to be expanded to other clinically relevant viruses. To date, the use of complementary approaches, such as experimentation in defined cell culture systems or animal models, have provided mechanistic insight to support the notion that cigarette smoke first dampens type 1 IFN responses and second, causes exaggerated inflammatory responses to viral infections.

Cigarette Smoke Exacerbates Inflammatory Processes Elicited by Viral Agents

As discussed previously, patients with COPD have been shown to develop exacerbated inflammatory responses to rhinovirus challenge compared with control subjects.54 Increased sputum neutrophils and sputum neutrophil elastase were observed in patients with COPD over the course of infection compared with control subjects. In addition, BAL measurements revealed that patients with COPD had greater neutrophils compared with control subjects. Although no differences were observed between patients with COPD and control subjects on the level of BAL lymphocytes, significantly greater numbers of lymphocytes were detected in patients with COPD over baseline, whereas no differences were noted over baseline in control subjects.

Similar to the clinical observations, it is well established that cigarette smoke exacerbates the inflammatory response to infectious agents in animal models.50-53,59-63 Although studies have examined the consequences of cigarette smoke exposure to viral agents50-53,60 and bacteria,59,61-63 we focus our subsequent discussion on the impact of cigarette smoking on antiviral responses. Most animal studies reported to date have used influenza virus as the pathogen of choice to examine the consequences of cigarette smoke to antiviral host defense. The reason for which influenza viruses have preferentially been used is the historical lack of animal models to examine the other infectious agents implicated in AECOPD, specifically rhinovirus and respiratory syncytial virus. With the development of the transgenic mouse expressing the mouse-human chimeric receptor for rhinovirus in the lung,64 studies examining the impact of cigarette smoke exposure on rhinovirus infection would be topical, especially given the recent clinical data reported in patients with COPD and rhinovirus.54 An outstanding question remains: Does this preclinical model translate well to what has already been shown clinically and would this provide a better opportunity to understand the mechanisms driving rhinovirus-induced exacerbations in patients with COPD?

We reported that cigarette smoke exacerbated the inflammatory response to a mouse-adapted H1N1 influenza A virus 5 days postinfection in a C57BL/6 mouse model.51,60 Similar findings with influenza viruses driving exaggerated inflammatory responses in smoke-exposed animals have also been reported from two other research groups.50,53 Gualano et al50 observed increased inflammation in smoke-exposed influenza-infected BALB/c mice. Similarly, Kang et al53 demonstrated that influenza infection of cigarette smoke-exposed C57BL/6 mice had increased BAL cellularity at days 6, 9, and 12 postinfection compared with control mice. That a similar theme of exaggerated inflammation has been observed in multiple models across research groups poses the question of what drives this increased inflammatory response, especially given that no consensus was reached on differences in viral loads observed in smoke-exposed and control influenza-infected mice (as discussed previously). Nonetheless, it is plausible that inflammatory processes elicited by cigarette smoke may predispose to exacerbated inflammatory processes in response to viral agents. Thus, we begin by discussing mechanisms of cigarette smoke-induced inflammation and subsequently review their relevance to the exacerbated responses elicited by viral infections.

Cytokines and chemokines play a fundamental role in orchestrating chronic inflammation. Many studies have examined a long list of inflammatory mediators both during stable COPD and during episodes of acute exacerbation.65 Somewhat astoundingly, >50 cytokines and chemokines have been reported. These include proinflammatory mediators, such as tumor necrosis factor-α57,66; IL-1β67,68; IL-656,69; and, more recently, IL-18.70,71 A range of different chemoattractants, such as monocyte chemotactic protein-1/CCL2,72,73 keratinocyte chemoattractant/CXCL-1, IL-8,66,72,73 and neutrophil chemoattractants, have also been examined. The expression of inflammatory mediators induced in smoke-exposed mice is similarly complex.74 Although it is well established that cigarette smoke exposure of experimental animals does not replicate the complexity of COPD, it provides a valid model to study mechanisms of cigarette smoke-induced inflammation and airspace enlargement.

Of particular relevance to cigarette smoke-induced inflammation are IL-1β and IL-18 (Fig 2). IL-1β, in particular, mediates a wide range of reactions, including fever, hypotension, and release of other cytokines such as IL-6, which is required to sustain immune responses.75 Animal studies performed by Castro et al76 demonstrated that inhibition of IL-1β reduced pulmonary inflammation as a result of long-term cigarette smoke exposure. Furthermore, Doz et al77 demonstrated in an acute model of smoke exposure that inflammation was dependent on TLR-4/IL-1 receptor, type 1 (IL-1R1) signaling. Similarly, studies assessing the role of IL-18 and IL-18 receptor signaling concluded that these cascades play critical roles in the pathogenesis of cigarette smoke-induced inflammation in preclinical animal models.78 Moreover, studies overexpressing IL-1β and IL-18 have implicated these cytokines in the pathologies associated with COPD.79,80 Although these studies demonstrated a role for IL-1β and IL-18 in promoting smoke-induced inflammation and pathogenesis, a role for the inflammasome was not considered.

More recently, studies using caspase inhibitors have proposed a role for the inflammasome,79 a molecular complex consisting of an NLR, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and caspase-1, which promote the activation of IL-1β and IL-18. Given the potential novel role for IL-1 to promote smoke-induced inflammation through an inflammasome complex, we examined the roles of IL-1α and IL-1β signaling of the IL-1R1.51 We demonstrated in a cohort of patients with COPD that IL-1α is not only expressed during stable COPD but also increases in a correlative fashion with IL-1β during disease exacerbation. Importantly, IL-1β had been previously suggested to correlate with clinical aspects of disease severity in patients with COPD68 and was shown more recently to be expressed at greater levels in the epithelium of smoking patients compared with healthy, nonsmoking control subjects.81 In a preclinical smoke exposure model, we demonstrated with blocking antibodies that cigarette smoke-induced neutrophilia was IL-1α-dependent but independent of IL-1β.60 These data were corroborated by another study recently published by Pauwels et al82 that demonstrated that smoke-induced neutrophilia was not only attenuated with IL-1α blockade but also diminished with administration of an anti-IL-1β antibody. Although both studies conclusively demonstrated that deficiencies in inflammasome components caspase-160,82 and NLRP382 did not affect cigarette smoke-induced inflammation, we found that the expression of IL-1R1 on structural cells (epithelial cells) was necessary and sufficient to elicit smoke-induced neutrophilia.60 These findings further highlight the role of the respiratory epithelium in promoting cigarette smoke-induced inflammation.

The notion that IL-1α/IL-1R1 signaling was critical to smoke-induced inflammation is interesting in light of recent work demonstrating that macrophages respond to DAMPs released from necrotic cells by releasing IL-1α,83 which, in turn, triggers neutrophilic cellular infiltration through the activation of IL-1R1 on parenchymal cells. As a consequence, neutrophil-recruiting chemokines are produced, and neutrophils are subsequently recruited to the site of inflammation. Given that neutrophilia and pathologic tissue damage, including necrosis, are key hallmarks of COPD, it is plausible that IL-1α plays a mechanistic role in the initiation of an inflammatory response in COPD. Interestingly, we have previously shown that alveolar macrophages cultured ex vivo from smoke-exposed animals produce significantly more IL-1α compared with control animals.84 Whether the source of IL-1α, which is driving neutrophilic inflammation in smoke-exposed mice, is entirely macrophage derived or is a consequence of intracellular stores of IL-1 being released from necrotic cells is not yet known.

Although our preclinical studies suggest a more prominent role for IL-1α in driving neutrophilic inflammation, recent works by Eltom et al,85 and Lucattelli et al86 suggest a potential role for DAMPs, such as extracellular sources of adenosine triphosphate (ATP), in driving neutrophilic inflammation. This is of particular interest since ATP has been shown to be increased in the lungs of patients with COPD.87 Excess levels of ATP are proposed to activate the purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7) receptor, which, in turn, activates both the inflammasome and caspase-1. The study by Eltom et al85 demonstrated in P2X7-deficient mice that cigarette smoke failed to increase airway neutrophilia, caspase-1 activity, and IL-1β compared with the relevant wild-type control mice. Although the authors elegantly demonstrated that a P2X7 inhibitor could block cigarette-smoke induced inflammation, they did not assess whether a P2X7 deficiency altered IL-1α levels. Importantly, the study by Lucattelli et al86 demonstrated further that emphysema was attenuated in P2X7-deficient animals compared with control animals. Of particular interest was the finding that P2X7 receptor expression was essential on immune cells in chimeric mouse experiments because they demonstrated that an immune cell deficiency in P2X7 attenuated lung inflammation and emphysema in smoke-exposed mice. Interestingly, HMGB-1 (high-mobility group protein 1), another DAMP molecule, has been shown to be elevated in COPD airways88 and could also be explored along with other DAMPs for their potential in mediating the mechanisms of IL-1α/IL-1R1 neutrophilic inflammation. Furthermore, although accumulating evidence suggests that the sterile inflammatory response is playing a role in cigarette smoke-induced inflammation, a more in-depth analysis of these pathways is warranted because these mechanisms may provide a rationale for the design of novel pharmacotherapies.

Smoke-Induced Inflammation, IL-1, and Dysregulated Antiviral Responses

Given that cigarette smoke is altering the inflammatory and, consequently, the homeostatic state of the lung (as discussed previously), it is plausible that this status contributes to exaggerated inflammatory responses in the case of a respiratory infection. Indeed, Kang et al53 demonstrated that a dysregulated inflammatory response to viral stimulus in smoke-exposed animals was driven by IL-18Rα; TLR-3; and, to some extent, RNA-dependent protein kinase signaling. More recently, we showed that the IL-1α/IL-1R1-dependent activation of the airway epithelium is key for driving exacerbated inflammation following H1N1 influenza A virus infection of smoke-exposed mice.60 Using precision-cut lung slices generated and cultured ex vivo from smoke-exposed animals, we demonstrated that resident lung cells were primed to respond to viral insult. Furthermore, when we were able to attenuate smoke-induced inflammation (using gene-deficient IL-1R1 mice and anti-IL-1α blocking antibodies), we were also able to attenuate components of the exaggerated inflammatory response observed in smoke-exposed mice compared with the relevant control mice.

In light of our work and that of others demonstrating that IL-1 plays a fundamental role in promoting both acute and chronic neutrophilia in preclinical mouse models, further studies are required to effectively assess whether mechanisms driving smoke-induced inflammation may also play important roles in promoting exaggerated inflammatory responses to infectious insults. Of particular interest is the potential role for ATP in driving exaggerated responses to microbial agents, especially given that ATP signaling of the P2X7 receptor has been shown to contribute to smoke-induced inflammation.85,86 In particular, the potential of IL-1β in driving exaggerated inflammatory responses to influenza virus infection in smoke-exposed animals also warrants further analysis. The recent development that IL-1 signaling plays an important role in both cigarette smoke-induced inflammation and exaggerated antiinfluenza responses in smoke-exposed mice is clinically very timely, given that therapies targeting IL-1, namely anakinra, are approved for reducing the signs and symptoms of rheumatoid arthritis.

Extending Beyond the Preclinical Mouse Model To Impact COPD and AECOPD Clinically

Although it is well understood that smokers have a longer duration of cough89 as a result of respiratory tract infections, the ability to understand the mechanisms driving this response in mice is not entirely possible. In spite of the fact that the majority of preclinical work done to date has focused largely on mouse models of cigarette smoke exposure in combination with various viral challenges, aspects of COPD, such as cough, will need to be examined in more-appropriate models. For example, cough responses have been examined in cigarette smoke-exposed guinea pigs,90 but to our knowledge, the combination of cigarette smoke and infectious agents, such as influenza virus, have not been pursued. Whether the clinical observation that virus infection causes a longer duration of cough can be replicated in a guinea pig model warrants the effort required to establish such models, especially given that little is known regarding the mechanisms driving cough. Furthermore, such models will be useful to test interventions preclinically for their potential ability to not only affect inflammatory outcomes but also alleviate the symptomology that is associated with COPD and exacerbations thereof.

Although human infection models are in their infancy in COPD research, these studies hold great promise for the effective translation of information derived from preclinical animal models for the design of novel therapies that may effectively impact both COPD pathogenesis and AECOPD. The challenge to effectively begin to understand the inflammatory signatures of viral and bacterial exacerbation of COPD will be to develop additional human models that probe the similarities and differences observed in the etiologic cause of an exacerbation and whether personalized treatment strategies will be required, depending on the infectious entity rendering a patient with COPD ill and hospitalized. Of equal importance is the validation and development of preclinical models to effectively examine mechanisms driving disease pathogenesis and the associated exacerbations. Ultimately, an integrated approach of clinical and basic research will be required because realistically, only a limited number of mechanisms will be dissected and uncovered from patient samples. Clinical research uncovers potential pathways of interest generally through correlation with disease indices, whereas animal models provide an opportunity to investigate specific facets of the disease and study them in isolation from other confounding factors (ie, comorbidities of disease). Access to tissues samples that are ethically not accessible clinically, to transgenic (knock-in and knock-out) mouse strains, and to unique experimental intervention tools will enable us to dissect the mechanisms underlying disease pathogenesis and progression. The mindful selection of relevant animal models (eg, outbred mouse strains, guinea pigs, rats) and the interpretation and extrapolation of preclinical data will be of utmost importance to comprehensively assess the pathways underlying COPD. The interpretation of these data in the context of experimental human challenge models will help to ensure that we may successfully translate preclinical findings to affect the pathogenesis of COPD and AECOPD clinically.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

AECOPD

acute exacerbations of COPD

ATP

adenosine triphosphate

DAMP

danger-associated molecular pattern

dsRNA

double-stranded RNA

IFN

interferon

IL-1R1

IL-1 receptor, type 1

IRF-3

interferon regulatory factor 3

ISG

interferon-stimulated gene

NF-κB

nuclear factor κB

NLR

NOD-like receptor

P2X7

purinergic receptor P2X ligand-gated ion channel 7

RIG-I

retinoic acid-inducible gene I

SCM

smoke-conditioned medium

TLR

Toll-like receptor

US Department of Health and Human ServicesUS Department of Health and Human Services. How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office of Smoking and Health; 2010.
 
World Health Organization.Mpower: a Policy Package to Reverse the Tobacco Epidemic. Geneva, Switzerland: World Health Organization; 2008.
 
Alwan A. Progress continues—nearly 3.8 billion people are now covered by an effective tobacco control measure. In:WHO Report on the Global Tobacco Epidemic. Geneva, Switzerland: World Health Organization; 2011:7.
 
Global Initiative for Chronic Obstructive Lung Disease. Management and prevention of COPD, 2011. Global Initiative for Chronic Obstructive Lung Disease website.http://www.goldcopd.org/. Accessed December 14, 2011.
 
Foster TS, Miller JD, Marton JP, Caloyeras JP, Russell MW, Menzin J. Assessment of the economic burden of COPD in the US: a review and synthesis of the literature. COPD. 2006;3(4):211-218. [CrossRef] [PubMed]
 
Benowitz NL. Drug therapy. Pharmacologic aspects of cigarette smoking and nicotine addiction. N Engl J Med. 1988;319(20):1318-1330. [CrossRef] [PubMed]
 
Centers for Disease Control and Prevention (CDC)Centers for Disease Control and Prevention (CDC). Vital signs: current cigarette smoking among adults aged ≥18 years—United States, 2005-2010. MMWR Morb Mortal Wkly Rep. 2011;60(35):1207-1212. [PubMed]
 
Kalsheker N, Chappell S. The new genetics and chronic obstructive pulmonary disease. COPD. 2008;5(4):257-264. [CrossRef] [PubMed]
 
Laumbach RJ, Kipen HM. Respiratory health effects of air pollution: update on biomass smoke and traffic pollution. J Allergy Clin Immunol. 2012;129(1):3-11. [CrossRef] [PubMed]
 
Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers. Lancet. 2009;374(9691):733-743. [CrossRef] [PubMed]
 
Górska K, Maskey-Warzechowska M, Krenke R. Airway inflammation in chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2010;16(2):89-96. [CrossRef] [PubMed]
 
Wedzicha JA. Airway infection accelerates decline of lung function in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(10 pt 1):1757-1758. [PubMed]
 
Tan WC, Xiang X, Qiu D, Ng TP, Lam SF, Hegele RG. Epidemiology of respiratory viruses in patients hospitalized with near-fatal asthma, acute exacerbations of asthma, or chronic obstructive pulmonary disease. Am J Med. 2003;115(4):272-277. [CrossRef] [PubMed]
 
Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med. 2006;173(10):1114-1121. [CrossRef] [PubMed]
 
Fuhrman C, Roche N, Vergnenègre A, Zureik M, Chouaid C, Delmas MC. Hospital admissions related to acute exacerbations of chronic obstructive pulmonary disease in France, 1998-2007. Respir Med. 2011;105(4):595-601. [CrossRef] [PubMed]
 
Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med. 2008;359(22):2355-2365. [CrossRef] [PubMed]
 
Kanner RE, Anthonisen NR, Connett JELung Health Study Research GroupKanner RE.Anthonisen NR.Connett JE. Lung Health Study Research Group. Lower respiratory illnesses promote FEV(1) decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am J Respir Crit Care Med. 2001;164(3):358-364. [PubMed]
 
Gangl K, Reininger R, Bernhard D, et al. Cigarette smoke facilitates allergen penetration across respiratory epithelium. Allergy. 2009;64(3):398-405. [CrossRef] [PubMed]
 
Burns AR, Hosford SP, Dunn LA, Walker DC, Hogg JC. Respiratory epithelial permeability after cigarette smoke exposure in guinea pigs. J Appl Physiol. 1989;66(5):2109-2116. [PubMed]
 
Foster WM. Mucociliary transport and cough in humans. Pulm Pharmacol Ther. 2002;15(3):277-282. [CrossRef] [PubMed]
 
Laws TR, Davey MS, Titball RW, Lukaszewski R. Neutrophils are important in early control of lung infection byYersinia pestisMicrobes Infect. 2010;12(4):331-335. [CrossRef] [PubMed]
 
Tate MD, Deng YM, Jones JE, Anderson GP, Brooks AG, Reading PC. Neutrophils ameliorate lung injury and the development of severe disease during influenza infection. J Immunol. 2009;183(11):7441-7450. [CrossRef] [PubMed]
 
Brown V, Elborn JS, Bradley J, Ennis M. Dysregulated apoptosis and NFkappaB expression in COPD subjects. Respir Res. 2009;10(:24-. [CrossRef] [PubMed]
 
Fels AO, Cohn ZA. The alveolar macrophage. J Appl Physiol. 1986;60(2):353-369. [PubMed]
 
Finkelstein R, Fraser RS, Ghezzo H, Cosio MG. Alveolar inflammation and its relation to emphysema in smokers. Am J Respir Crit Care Med. 1995;152(5 pt 1):1666-1672. [PubMed]
 
Di 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(4):1277-1285. [PubMed]
 
Russell RE, Culpitt SV, DeMatos C, et al. Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2002;26(5):602-609. [PubMed]
 
Janeway CAJ, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease.5th ed. New York, NY: Garland Publishing, 2001.
 
Hodge S, Hodge G, Scicchitano R, Reynolds PN, Holmes M. Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunol Cell Biol. 2003;81(4):289-296. [CrossRef] [PubMed]
 
O’Shaughnessy TC, Ansari TW, Barnes NC, Jeffery PK. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8+ T lymphocytes with FEV1. Am J Respir Crit Care Med. 1997;155(3):852-857. [PubMed]
 
Saetta M, Baraldo S, Corbino L, et al. CD8+ve cells in the lungs of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;160(2):711-717. [PubMed]
 
Tzortzaki EG, Siafakas NM. A hypothesis for the initiation of COPD. Eur Respir J. 2009;34(2):310-315. [CrossRef] [PubMed]
 
Tamura S, Kurata T. Defense mechanisms against influenza virus infection in the respiratory tract mucosa. Jpn J Infect Dis. 2004;57(6):236-247. [PubMed]
 
Reynolds HY. Modulating airway defenses against microbes. Curr Opin Pulm Med. 2002;8(3):154-165. [CrossRef] [PubMed]
 
Holt PG, Strickland DH, Wikström ME, Jahnsen FL. Regulation of immunological homeostasis in the respiratory tract. Nat Rev Immunol. 2008;8(2):142-152. [CrossRef] [PubMed]
 
Stämpfli MR, Anderson GP. How cigarette smoke skews immune responses to promote infection, lung disease and cancer. Nat Rev Immunol. 2009;9(5):377-384. [CrossRef] [PubMed]
 
Taylor JD. COPD and the response of the lung to tobacco smoke exposure. Pulm Pharmacol Ther. 2010;23(5):376-383. [CrossRef] [PubMed]
 
Brusselle GG, Joos GF, Bracke KR. New insights into the immunology of chronic obstructive pulmonary disease. Lancet. 2011;378(9795):1015-1026. [CrossRef] [PubMed]
 
Broz P, Monack DM. Molecular mechanisms of inflammasome activation during microbial infections. Immunol Rev. 2011;243(1):174-190. [CrossRef] [PubMed]
 
Barber GN. Cytoplasmic DNA innate immune pathways. Immunol Rev. 2011;243(1):99-108. [CrossRef] [PubMed]
 
Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of theDrosophilaToll protein signals activation of adaptive immunity. Nature. 1997;388(6640):394-397. [CrossRef] [PubMed]
 
Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol. 2005;17(1):1-14. [CrossRef] [PubMed]
 
Yoneyama M, Kikuchi M, Natsukawa T, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. 2004;5(7):730-737. [CrossRef] [PubMed]
 
Yoneyama M, Suhara W, Fukuhara Y, Fukuda M, Nishida E, Fujita T. Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300. EMBO J. 1998;17(4):1087-1095. [CrossRef] [PubMed]
 
Wathelet MG, Lin CH, Parekh BS, Ronco LV, Howley PM, Maniatis T. Virus infection induces the assembly of coordinately activated transcription factors on the IFN-β enhancer in vivo. Mol Cell. 1998;1(4):507-518. [CrossRef] [PubMed]
 
Sonnenfeld G, Hudgens RW. Effect of sidestream and mainstream smoke exposure on in vitro interferon-alpha/beta production by L-929 cells. Cancer Res. 1986;46(6):2779-2783. [PubMed]
 
Bauer CM, Dewitte-Orr SJ, Hornby KR, et al. Cigarette smoke suppresses type I interferon-mediated antiviral immunity in lung fibroblast and epithelial cells. J Interferon Cytokine Res. 2008;28(3):167-179. [CrossRef] [PubMed]
 
HuangFu WC, Liu J, Harty RN, Fuchs SY. Cigarette smoking products suppress anti-viral effects of type I interferon via phosphorylation-dependent downregulation of its receptor. FEBS Lett. 2008;582(21-22):3206-3210. [CrossRef] [PubMed]
 
Rahman I, MacNee W. Lung glutathione and oxidative stress: implications in cigarette smoke-induced airway disease. Am J Physiol. 1999;277(6 pt 1):L1067-L1088. [PubMed]
 
Gualano RC, Hansen MJ, Vlahos R, et al. Cigarette smoke worsens lung inflammation and impairs resolution of influenza infection in mice. Respir Res. 2008;9(:53-. [CrossRef] [PubMed]
 
Bauer CM, Zavitz CC, Botelho FM, et al. Treating viral exacerbations of chronic obstructive pulmonary disease: insights from a mouse model of cigarette smoke and H1N1 influenza infection. PLoS One. 2010;5(10):e13251-. [CrossRef] [PubMed]
 
Robbins CS, Bauer CM, Vujicic N, et al. Cigarette smoke impacts immune inflammatory responses to influenza in mice. Am J Respir Crit Care Med. 2006;174(12):1342-1351. [CrossRef] [PubMed]
 
Kang MJ, Lee CG, Lee JY, et al. Cigarette smoke selectively enhances viral PAMP- and virus-induced pulmonary innate immune and remodeling responses in mice. J Clin Invest. 2008;118(8):2771-2784. [PubMed]
 
Mallia P, Message SD, Gielen V, et al. Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation. Am J Respir Crit Care Med. 2011;183(6):734-742. [CrossRef] [PubMed]
 
Jaspers I, Horvath KM, Zhang W, Brighton LE, Carson JL, Noah TL. Reduced expression of IRF7 in nasal epithelial cells from smokers after infection with influenza. Am J Respir Cell Mol Biol. 2010;43(3):368-375. [CrossRef] [PubMed]
 
Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax. 2000;55(2):114-120. [CrossRef] [PubMed]
 
Aaron SD, Angel JB, Lunau M, et al. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163(2):349-355. [PubMed]
 
Hurst JR, Perera WR, Wilkinson TM, Donaldson GC, Wedzicha JA. Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173(1):71-78. [CrossRef] [PubMed]
 
Drannik AG, Pouladi MA, Robbins CS, Goncharova SI, Kianpour S, Stämpfli MR. Impact of cigarette smoke on clearance and inflammation afterPseudomonas aeruginosainfection. Am J Respir Crit Care Med. 2004;170(11):1164-1171. [CrossRef] [PubMed]
 
Botelho FM, Bauer CM, Finch D, et al. IL-1alpha/IL-1R1 expression in chronic obstructive pulmonary disease and mechanistic relevance to smoke-induced neutrophilia in mice. PLoS One. 2011;6(12):e28457-. [CrossRef] [PubMed]
 
Gaschler GJ, Skrtic M, Zavitz CC, et al. Bacteria challenge in smoke-exposed mice exacerbates inflammation and skews the inflammatory profile. Am J Respir Crit Care Med. 2009;179(8):666-675. [CrossRef] [PubMed]
 
Harvey CJ, Thimmulappa RK, Sethi S, et al. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Sci Transl Med. 2011;3(78):78ra32-. [CrossRef] [PubMed]
 
Phipps JC, Aronoff DM, Curtis JL, Goel D, O’Brien E, Mancuso P. Cigarette smoke exposure impairs pulmonary bacterial clearance and alveolar macrophage complement-mediated phagocytosis of Streptococcus pneumoniae. Infect Immun. 2010;78(3):1214-1220. [CrossRef] [PubMed]
 
Bartlett NW, Walton RP, Edwards MR, et al. Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation. Nat Med. 2008;14(2):199-204. [CrossRef] [PubMed]
 
Barnes PJ. The cytokine network in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2009;41(6):631-638. [CrossRef] [PubMed]
 
Keatings VM, Collins PD, Scott DM, Barnes PJ. 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(2):530-534. [PubMed]
 
Kuschner WG, D’Alessandro A, Wong H, Blanc PD. Dose-dependent cigarette smoking-related inflammatory responses in healthy adults. Eur Respir J. 1996;9(10):1989-1994. [CrossRef] [PubMed]
 
Sapey E, Ahmad A, Bayley D, et al. Imbalances between interleukin-1 and tumor necrosis factor agonists and antagonists in stable COPD. J Clin Immunol. 2009;29(4):508-516. [CrossRef] [PubMed]
 
Bucchioni E, Kharitonov SA, Allegra L, Barnes PJ. High levels of interleukin-6 in the exhaled breath condensate of patients with COPD. Respir Med. 2003;97(12):1299-1302. [CrossRef] [PubMed]
 
Imaoka H, Hoshino T, Takei S, et al. Interleukin-18 production and pulmonary function in COPD. Eur Respir J. 2008;31(2):287-297. [CrossRef] [PubMed]
 
Rovina N, Dima E, Gerassimou C, Kollintza A, Gratziou C, Roussos C. Interleukin-18 in induced sputum: association with lung function in chronic obstructive pulmonary disease. Respir Med. 2009;103(7):1056-1062. [CrossRef] [PubMed]
 
de Boer WI, Sont JK, van Schadewijk A, Stolk J, van Krieken JH, Hiemstra PS. Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD. J Pathol. 2000;190(5):619-626. [CrossRef] [PubMed]
 
Traves SL, Culpitt SV, Russell RE, Barnes PJ, Donnelly LE. Increased levels of the chemokines GROalpha and MCP-1 in sputum samples from patients with COPD. Thorax. 2002;57(7):590-595. [CrossRef] [PubMed]
 
Botelho FM, Gaschler GJ, Kianpour S, et al. Innate immune processes are sufficient for driving cigarette smoke-induced inflammation in mice. Am J Respir Cell Mol Biol. 2010;42(4):394-403. [CrossRef] [PubMed]
 
Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. 1996;87(6):2095-2147. [PubMed]
 
Castro P, Legora-Machado A, Cardilo-Reis L, et al. Inhibition of interleukin-1beta reduces mouse lung inflammation induced by exposure to cigarette smoke. Eur J Pharmacol. 2004;498(1-3):279-286. [CrossRef] [PubMed]
 
Doz E, Noulin N, Boichot E, et al. Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent. J Immunol. 2008;180(2):1169-1178. [PubMed]
 
Kang MJ, Homer RJ, Gallo A, et al. IL-18 is induced and IL-18 receptor alpha plays a critical role in the pathogenesis of cigarette smoke-induced pulmonary emphysema and inflammation. J Immunol. 2007;178(3):1948-1959. [PubMed]
 
Churg A, Zhou S, Wang X, Wang R, Wright JL. The role of interleukin-1beta in murine cigarette smoke-induced emphysema and small airway remodeling. Am J Respir Cell Mol Biol. 2009;40(4):482-490. [CrossRef] [PubMed]
 
Hoshino T, Kato S, Oka N, et al. Pulmonary inflammation and emphysema: role of the cytokines IL-18 and IL-13. Am J Respir Crit Care Med. 2007;176(1):49-62. [CrossRef] [PubMed]
 
Herfs M, Hubert P, Poirrier AL, et al. Proinflammatory cytokines induce bronchial hyperplasia and squamous metaplasia in smokers: implications for chronic obstructive pulmonary disease therapy. Am J Respir Cell Mol Biol. 2012;47(1):67-79. [CrossRef] [PubMed]
 
Pauwels NS, Bracke KR, Dupont LL, et al. Role of IL-1α and the Nlrp3/caspase-1/IL-1β axis in cigarette smoke-induced pulmonary inflammation and COPD. Eur Respir J. 2011;38(5):1019-1028. [CrossRef] [PubMed]
 
Kono H, Karmarkar D, Iwakura Y, Rock KL. Identification of the cellular sensor that stimulates the inflammatory response to sterile cell death. J Immunol. 2010;184(8):4470-4478. [CrossRef] [PubMed]
 
Gaschler GJ, Zavitz CC, Bauer CM, et al. Cigarette smoke exposure attenuates cytokine production by mouse alveolar macrophages. Am J Respir Cell Mol Biol. 2008;38(2):218-226. [CrossRef] [PubMed]
 
Eltom S, Stevenson CS, Rastrick J, et al. P2X7 receptor and caspase 1 activation are central to airway inflammation observed after exposure to tobacco smoke. PLoS One. 2011;6(9):e24097-. [CrossRef] [PubMed]
 
Lucattelli M, Cicko S, Müller T, et al. P2X7 receptor signaling in the pathogenesis of smoke-induced lung inflammation and emphysema. Am J Respir Cell Mol Biol. 2011;44(3):423-429. [CrossRef] [PubMed]
 
Lommatzsch M, Cicko S, Müller T, et al. Extracellular adenosine triphosphate and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181(9):928-934. [CrossRef] [PubMed]
 
Ferhani N, Letuve S, Kozhich A, et al. Expression of high-mobility group box 1 and of receptor for advanced glycation end products in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181(9):917-927. [CrossRef] [PubMed]
 
Aronson MD, Weiss ST, Ben RL, Komaroff AL. Association between cigarette smoking and acute respiratory tract illness in young adults. JAMA. 1982;248(2):181-183. [CrossRef] [PubMed]
 
Lee LY, Gu Q, Lin YS. Effect of smoking on cough reflex sensitivity: basic and preclinical studies. Lung. 2010;188(suppl 1):S23-S27. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. The three major consequences of chronic cigarette smoke exposure. Chronic inflammation, progressive destruction of the lung, and an increased susceptibility to infections contribute to the impaired lung and immune system homeostasis that are all recognized features of COPD.Grahic Jump Location
Figure Jump LinkFigure 2. The interplay between the cellular and molecular mechanisms triggered by cigarette smoke and viral infections, which ultimately lead to impaired type 1 interferon responses and exaggerated inflammatory responses. CXCL = C-X-C motif chemokine; GSH = glutathione; IFN = interferon; IFNRA1 = interferon receptor α-1; IL-1R1 = IL-1 receptor, type 1; IL-18R = IL-18 receptor; IRF = interferon regulatory factor; ISRE = interferon-stimulated response element; NAC = N-acetyl-L-cysteine; MCP-1 = monocyte chemotactic protein-1; NF-κB = nuclear factor κB; PAMP = pathogen-associated molecular pattern; PRR = pathogen recognition receptor.Grahic Jump Location

Tables

References

US Department of Health and Human ServicesUS Department of Health and Human Services. How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office of Smoking and Health; 2010.
 
World Health Organization.Mpower: a Policy Package to Reverse the Tobacco Epidemic. Geneva, Switzerland: World Health Organization; 2008.
 
Alwan A. Progress continues—nearly 3.8 billion people are now covered by an effective tobacco control measure. In:WHO Report on the Global Tobacco Epidemic. Geneva, Switzerland: World Health Organization; 2011:7.
 
Global Initiative for Chronic Obstructive Lung Disease. Management and prevention of COPD, 2011. Global Initiative for Chronic Obstructive Lung Disease website.http://www.goldcopd.org/. Accessed December 14, 2011.
 
Foster TS, Miller JD, Marton JP, Caloyeras JP, Russell MW, Menzin J. Assessment of the economic burden of COPD in the US: a review and synthesis of the literature. COPD. 2006;3(4):211-218. [CrossRef] [PubMed]
 
Benowitz NL. Drug therapy. Pharmacologic aspects of cigarette smoking and nicotine addiction. N Engl J Med. 1988;319(20):1318-1330. [CrossRef] [PubMed]
 
Centers for Disease Control and Prevention (CDC)Centers for Disease Control and Prevention (CDC). Vital signs: current cigarette smoking among adults aged ≥18 years—United States, 2005-2010. MMWR Morb Mortal Wkly Rep. 2011;60(35):1207-1212. [PubMed]
 
Kalsheker N, Chappell S. The new genetics and chronic obstructive pulmonary disease. COPD. 2008;5(4):257-264. [CrossRef] [PubMed]
 
Laumbach RJ, Kipen HM. Respiratory health effects of air pollution: update on biomass smoke and traffic pollution. J Allergy Clin Immunol. 2012;129(1):3-11. [CrossRef] [PubMed]
 
Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers. Lancet. 2009;374(9691):733-743. [CrossRef] [PubMed]
 
Górska K, Maskey-Warzechowska M, Krenke R. Airway inflammation in chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2010;16(2):89-96. [CrossRef] [PubMed]
 
Wedzicha JA. Airway infection accelerates decline of lung function in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(10 pt 1):1757-1758. [PubMed]
 
Tan WC, Xiang X, Qiu D, Ng TP, Lam SF, Hegele RG. Epidemiology of respiratory viruses in patients hospitalized with near-fatal asthma, acute exacerbations of asthma, or chronic obstructive pulmonary disease. Am J Med. 2003;115(4):272-277. [CrossRef] [PubMed]
 
Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med. 2006;173(10):1114-1121. [CrossRef] [PubMed]
 
Fuhrman C, Roche N, Vergnenègre A, Zureik M, Chouaid C, Delmas MC. Hospital admissions related to acute exacerbations of chronic obstructive pulmonary disease in France, 1998-2007. Respir Med. 2011;105(4):595-601. [CrossRef] [PubMed]
 
Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med. 2008;359(22):2355-2365. [CrossRef] [PubMed]
 
Kanner RE, Anthonisen NR, Connett JELung Health Study Research GroupKanner RE.Anthonisen NR.Connett JE. Lung Health Study Research Group. Lower respiratory illnesses promote FEV(1) decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am J Respir Crit Care Med. 2001;164(3):358-364. [PubMed]
 
Gangl K, Reininger R, Bernhard D, et al. Cigarette smoke facilitates allergen penetration across respiratory epithelium. Allergy. 2009;64(3):398-405. [CrossRef] [PubMed]
 
Burns AR, Hosford SP, Dunn LA, Walker DC, Hogg JC. Respiratory epithelial permeability after cigarette smoke exposure in guinea pigs. J Appl Physiol. 1989;66(5):2109-2116. [PubMed]
 
Foster WM. Mucociliary transport and cough in humans. Pulm Pharmacol Ther. 2002;15(3):277-282. [CrossRef] [PubMed]
 
Laws TR, Davey MS, Titball RW, Lukaszewski R. Neutrophils are important in early control of lung infection byYersinia pestisMicrobes Infect. 2010;12(4):331-335. [CrossRef] [PubMed]
 
Tate MD, Deng YM, Jones JE, Anderson GP, Brooks AG, Reading PC. Neutrophils ameliorate lung injury and the development of severe disease during influenza infection. J Immunol. 2009;183(11):7441-7450. [CrossRef] [PubMed]
 
Brown V, Elborn JS, Bradley J, Ennis M. Dysregulated apoptosis and NFkappaB expression in COPD subjects. Respir Res. 2009;10(:24-. [CrossRef] [PubMed]
 
Fels AO, Cohn ZA. The alveolar macrophage. J Appl Physiol. 1986;60(2):353-369. [PubMed]
 
Finkelstein R, Fraser RS, Ghezzo H, Cosio MG. Alveolar inflammation and its relation to emphysema in smokers. Am J Respir Crit Care Med. 1995;152(5 pt 1):1666-1672. [PubMed]
 
Di 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(4):1277-1285. [PubMed]
 
Russell RE, Culpitt SV, DeMatos C, et al. Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2002;26(5):602-609. [PubMed]
 
Janeway CAJ, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease.5th ed. New York, NY: Garland Publishing, 2001.
 
Hodge S, Hodge G, Scicchitano R, Reynolds PN, Holmes M. Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunol Cell Biol. 2003;81(4):289-296. [CrossRef] [PubMed]
 
O’Shaughnessy TC, Ansari TW, Barnes NC, Jeffery PK. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8+ T lymphocytes with FEV1. Am J Respir Crit Care Med. 1997;155(3):852-857. [PubMed]
 
Saetta M, Baraldo S, Corbino L, et al. CD8+ve cells in the lungs of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;160(2):711-717. [PubMed]
 
Tzortzaki EG, Siafakas NM. A hypothesis for the initiation of COPD. Eur Respir J. 2009;34(2):310-315. [CrossRef] [PubMed]
 
Tamura S, Kurata T. Defense mechanisms against influenza virus infection in the respiratory tract mucosa. Jpn J Infect Dis. 2004;57(6):236-247. [PubMed]
 
Reynolds HY. Modulating airway defenses against microbes. Curr Opin Pulm Med. 2002;8(3):154-165. [CrossRef] [PubMed]
 
Holt PG, Strickland DH, Wikström ME, Jahnsen FL. Regulation of immunological homeostasis in the respiratory tract. Nat Rev Immunol. 2008;8(2):142-152. [CrossRef] [PubMed]
 
Stämpfli MR, Anderson GP. How cigarette smoke skews immune responses to promote infection, lung disease and cancer. Nat Rev Immunol. 2009;9(5):377-384. [CrossRef] [PubMed]
 
Taylor JD. COPD and the response of the lung to tobacco smoke exposure. Pulm Pharmacol Ther. 2010;23(5):376-383. [CrossRef] [PubMed]
 
Brusselle GG, Joos GF, Bracke KR. New insights into the immunology of chronic obstructive pulmonary disease. Lancet. 2011;378(9795):1015-1026. [CrossRef] [PubMed]
 
Broz P, Monack DM. Molecular mechanisms of inflammasome activation during microbial infections. Immunol Rev. 2011;243(1):174-190. [CrossRef] [PubMed]
 
Barber GN. Cytoplasmic DNA innate immune pathways. Immunol Rev. 2011;243(1):99-108. [CrossRef] [PubMed]
 
Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of theDrosophilaToll protein signals activation of adaptive immunity. Nature. 1997;388(6640):394-397. [CrossRef] [PubMed]
 
Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol. 2005;17(1):1-14. [CrossRef] [PubMed]
 
Yoneyama M, Kikuchi M, Natsukawa T, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. 2004;5(7):730-737. [CrossRef] [PubMed]
 
Yoneyama M, Suhara W, Fukuhara Y, Fukuda M, Nishida E, Fujita T. Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300. EMBO J. 1998;17(4):1087-1095. [CrossRef] [PubMed]
 
Wathelet MG, Lin CH, Parekh BS, Ronco LV, Howley PM, Maniatis T. Virus infection induces the assembly of coordinately activated transcription factors on the IFN-β enhancer in vivo. Mol Cell. 1998;1(4):507-518. [CrossRef] [PubMed]
 
Sonnenfeld G, Hudgens RW. Effect of sidestream and mainstream smoke exposure on in vitro interferon-alpha/beta production by L-929 cells. Cancer Res. 1986;46(6):2779-2783. [PubMed]
 
Bauer CM, Dewitte-Orr SJ, Hornby KR, et al. Cigarette smoke suppresses type I interferon-mediated antiviral immunity in lung fibroblast and epithelial cells. J Interferon Cytokine Res. 2008;28(3):167-179. [CrossRef] [PubMed]
 
HuangFu WC, Liu J, Harty RN, Fuchs SY. Cigarette smoking products suppress anti-viral effects of type I interferon via phosphorylation-dependent downregulation of its receptor. FEBS Lett. 2008;582(21-22):3206-3210. [CrossRef] [PubMed]
 
Rahman I, MacNee W. Lung glutathione and oxidative stress: implications in cigarette smoke-induced airway disease. Am J Physiol. 1999;277(6 pt 1):L1067-L1088. [PubMed]
 
Gualano RC, Hansen MJ, Vlahos R, et al. Cigarette smoke worsens lung inflammation and impairs resolution of influenza infection in mice. Respir Res. 2008;9(:53-. [CrossRef] [PubMed]
 
Bauer CM, Zavitz CC, Botelho FM, et al. Treating viral exacerbations of chronic obstructive pulmonary disease: insights from a mouse model of cigarette smoke and H1N1 influenza infection. PLoS One. 2010;5(10):e13251-. [CrossRef] [PubMed]
 
Robbins CS, Bauer CM, Vujicic N, et al. Cigarette smoke impacts immune inflammatory responses to influenza in mice. Am J Respir Crit Care Med. 2006;174(12):1342-1351. [CrossRef] [PubMed]
 
Kang MJ, Lee CG, Lee JY, et al. Cigarette smoke selectively enhances viral PAMP- and virus-induced pulmonary innate immune and remodeling responses in mice. J Clin Invest. 2008;118(8):2771-2784. [PubMed]
 
Mallia P, Message SD, Gielen V, et al. Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation. Am J Respir Crit Care Med. 2011;183(6):734-742. [CrossRef] [PubMed]
 
Jaspers I, Horvath KM, Zhang W, Brighton LE, Carson JL, Noah TL. Reduced expression of IRF7 in nasal epithelial cells from smokers after infection with influenza. Am J Respir Cell Mol Biol. 2010;43(3):368-375. [CrossRef] [PubMed]
 
Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax. 2000;55(2):114-120. [CrossRef] [PubMed]
 
Aaron SD, Angel JB, Lunau M, et al. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163(2):349-355. [PubMed]
 
Hurst JR, Perera WR, Wilkinson TM, Donaldson GC, Wedzicha JA. Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173(1):71-78. [CrossRef] [PubMed]
 
Drannik AG, Pouladi MA, Robbins CS, Goncharova SI, Kianpour S, Stämpfli MR. Impact of cigarette smoke on clearance and inflammation afterPseudomonas aeruginosainfection. Am J Respir Crit Care Med. 2004;170(11):1164-1171. [CrossRef] [PubMed]
 
Botelho FM, Bauer CM, Finch D, et al. IL-1alpha/IL-1R1 expression in chronic obstructive pulmonary disease and mechanistic relevance to smoke-induced neutrophilia in mice. PLoS One. 2011;6(12):e28457-. [CrossRef] [PubMed]
 
Gaschler GJ, Skrtic M, Zavitz CC, et al. Bacteria challenge in smoke-exposed mice exacerbates inflammation and skews the inflammatory profile. Am J Respir Crit Care Med. 2009;179(8):666-675. [CrossRef] [PubMed]
 
Harvey CJ, Thimmulappa RK, Sethi S, et al. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Sci Transl Med. 2011;3(78):78ra32-. [CrossRef] [PubMed]
 
Phipps JC, Aronoff DM, Curtis JL, Goel D, O’Brien E, Mancuso P. Cigarette smoke exposure impairs pulmonary bacterial clearance and alveolar macrophage complement-mediated phagocytosis of Streptococcus pneumoniae. Infect Immun. 2010;78(3):1214-1220. [CrossRef] [PubMed]
 
Bartlett NW, Walton RP, Edwards MR, et al. Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation. Nat Med. 2008;14(2):199-204. [CrossRef] [PubMed]
 
Barnes PJ. The cytokine network in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2009;41(6):631-638. [CrossRef] [PubMed]
 
Keatings VM, Collins PD, Scott DM, Barnes PJ. 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(2):530-534. [PubMed]
 
Kuschner WG, D’Alessandro A, Wong H, Blanc PD. Dose-dependent cigarette smoking-related inflammatory responses in healthy adults. Eur Respir J. 1996;9(10):1989-1994. [CrossRef] [PubMed]
 
Sapey E, Ahmad A, Bayley D, et al. Imbalances between interleukin-1 and tumor necrosis factor agonists and antagonists in stable COPD. J Clin Immunol. 2009;29(4):508-516. [CrossRef] [PubMed]
 
Bucchioni E, Kharitonov SA, Allegra L, Barnes PJ. High levels of interleukin-6 in the exhaled breath condensate of patients with COPD. Respir Med. 2003;97(12):1299-1302. [CrossRef] [PubMed]
 
Imaoka H, Hoshino T, Takei S, et al. Interleukin-18 production and pulmonary function in COPD. Eur Respir J. 2008;31(2):287-297. [CrossRef] [PubMed]
 
Rovina N, Dima E, Gerassimou C, Kollintza A, Gratziou C, Roussos C. Interleukin-18 in induced sputum: association with lung function in chronic obstructive pulmonary disease. Respir Med. 2009;103(7):1056-1062. [CrossRef] [PubMed]
 
de Boer WI, Sont JK, van Schadewijk A, Stolk J, van Krieken JH, Hiemstra PS. Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD. J Pathol. 2000;190(5):619-626. [CrossRef] [PubMed]
 
Traves SL, Culpitt SV, Russell RE, Barnes PJ, Donnelly LE. Increased levels of the chemokines GROalpha and MCP-1 in sputum samples from patients with COPD. Thorax. 2002;57(7):590-595. [CrossRef] [PubMed]
 
Botelho FM, Gaschler GJ, Kianpour S, et al. Innate immune processes are sufficient for driving cigarette smoke-induced inflammation in mice. Am J Respir Cell Mol Biol. 2010;42(4):394-403. [CrossRef] [PubMed]
 
Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. 1996;87(6):2095-2147. [PubMed]
 
Castro P, Legora-Machado A, Cardilo-Reis L, et al. Inhibition of interleukin-1beta reduces mouse lung inflammation induced by exposure to cigarette smoke. Eur J Pharmacol. 2004;498(1-3):279-286. [CrossRef] [PubMed]
 
Doz E, Noulin N, Boichot E, et al. Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent. J Immunol. 2008;180(2):1169-1178. [PubMed]
 
Kang MJ, Homer RJ, Gallo A, et al. IL-18 is induced and IL-18 receptor alpha plays a critical role in the pathogenesis of cigarette smoke-induced pulmonary emphysema and inflammation. J Immunol. 2007;178(3):1948-1959. [PubMed]
 
Churg A, Zhou S, Wang X, Wang R, Wright JL. The role of interleukin-1beta in murine cigarette smoke-induced emphysema and small airway remodeling. Am J Respir Cell Mol Biol. 2009;40(4):482-490. [CrossRef] [PubMed]
 
Hoshino T, Kato S, Oka N, et al. Pulmonary inflammation and emphysema: role of the cytokines IL-18 and IL-13. Am J Respir Crit Care Med. 2007;176(1):49-62. [CrossRef] [PubMed]
 
Herfs M, Hubert P, Poirrier AL, et al. Proinflammatory cytokines induce bronchial hyperplasia and squamous metaplasia in smokers: implications for chronic obstructive pulmonary disease therapy. Am J Respir Cell Mol Biol. 2012;47(1):67-79. [CrossRef] [PubMed]
 
Pauwels NS, Bracke KR, Dupont LL, et al. Role of IL-1α and the Nlrp3/caspase-1/IL-1β axis in cigarette smoke-induced pulmonary inflammation and COPD. Eur Respir J. 2011;38(5):1019-1028. [CrossRef] [PubMed]
 
Kono H, Karmarkar D, Iwakura Y, Rock KL. Identification of the cellular sensor that stimulates the inflammatory response to sterile cell death. J Immunol. 2010;184(8):4470-4478. [CrossRef] [PubMed]
 
Gaschler GJ, Zavitz CC, Bauer CM, et al. Cigarette smoke exposure attenuates cytokine production by mouse alveolar macrophages. Am J Respir Cell Mol Biol. 2008;38(2):218-226. [CrossRef] [PubMed]
 
Eltom S, Stevenson CS, Rastrick J, et al. P2X7 receptor and caspase 1 activation are central to airway inflammation observed after exposure to tobacco smoke. PLoS One. 2011;6(9):e24097-. [CrossRef] [PubMed]
 
Lucattelli M, Cicko S, Müller T, et al. P2X7 receptor signaling in the pathogenesis of smoke-induced lung inflammation and emphysema. Am J Respir Cell Mol Biol. 2011;44(3):423-429. [CrossRef] [PubMed]
 
Lommatzsch M, Cicko S, Müller T, et al. Extracellular adenosine triphosphate and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181(9):928-934. [CrossRef] [PubMed]
 
Ferhani N, Letuve S, Kozhich A, et al. Expression of high-mobility group box 1 and of receptor for advanced glycation end products in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181(9):917-927. [CrossRef] [PubMed]
 
Aronson MD, Weiss ST, Ben RL, Komaroff AL. Association between cigarette smoking and acute respiratory tract illness in young adults. JAMA. 1982;248(2):181-183. [CrossRef] [PubMed]
 
Lee LY, Gu Q, Lin YS. Effect of smoking on cough reflex sensitivity: basic and preclinical studies. Lung. 2010;188(suppl 1):S23-S27. [CrossRef] [PubMed]
 
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