American Journal of Respiratory and Critical Care Medicine

Patients with chronic obstructive pulmonary disease (COPD) often suffer other concomitant disorders, such as cardiovascular diseases and metabolic disorders, that influence significantly (and independently of lung function) their health status and prognosis. Thus, COPD is not a single organ condition, and disturbances of a complex network of interorgan connected responses occur and modulate the natural history of the disease. Here, we propose a novel hypothesis that considers a vascularly connected network with (1) the lungs as the main external sensor of the system and a major source of “danger signals”; (2) the endothelium as an internal sensor of the system (also a potential target tissue); and (3) two key responding elements, bone marrow and adipose tissue, which produce both inflammatory and repair signals. According to the model, the development of COPD, and associated multimorbidities (here we focus on cardiovascular disease as an important example), depend on the manner in which the vascular connected network responds, adapts, or fails to adapt (dictated by the genetic and epigenetic background of the individual) to the inhalation of particles and gases, mainly in cigarette smoke. The caveats and limitations of the hypothesis, as well as the experimental and clinical research needed to test and explore the proposed model, are also briefly discussed.

Chronic obstructive pulmonary disease (COPD) is a major public health problem because of its high prevalence, rising incidence, and associated socioeconomic costs (1). COPD is thought to be caused by the inhalation of particles and gases, most frequently found in cigarette smoke, which in genetically susceptible individuals (2) results in an enhanced and persistent inflammatory response in the lungs and also systemically (1). Like other chronic noncommunicable diseases (3), COPD is not a single-organ condition and is often associated with multimorbidity, including cardiovascular disease (CVD), metabolic syndrome, skeletal muscle dysfunction and osteoporosis, among others (4). The acceptance of such interorgan connectivity leads to the appreciation that toxic inhaled agents that directly affect the lungs are also likely to exert effects (direct or indirect) on more distant organs. These, in turn, might modulate the lung’s own response (be it acute or chronic) to the initiating injury.

We propose here that the lungs, bone marrow, and adipose tissue form a previously unrecognized network, interconnected by vasculature and with significant implications for the pathobiology of COPD and, potentially, other chronic noncommunicable diseases that frequently coexist with COPD. In this pulmonary perspective we (1) describe the proposed model and provide the evidence to support it; (2) explore its potential implications for a better understanding and treatment of COPD and associated multimorbidity, focusing on CVD in patients with COPD as an important example (5); and (3) discuss the caveats and limitations of the hypothesis and the experimental and clinical research needed to test it. We hope that this may stimulate the scientific community to explore the proposed model further, because a thorough understanding of the links between the lungs and distant organs/systems can potentially identify novel biomarkers and new targets to treat more effectively this complex condition.

As illustrated in Figure 1, we propose that the lungs, bone marrow, and adipose tissue are major components of a vascular interconnected network that channels biological signals and facilitates their interaction. We suggest that the lung parenchyma and the systemic endothelium act as the main external and internal sensors of the system, respectively, whereas the bone marrow and the adipose tissue are two important responding elements (Figure 1). According to the hypothesis, the development of COPD and associated multimorbidity depends on the manner in which the interacting network responds, adapts, or fails to adapt (as modulated by the genetic and epigenetic background of the individual [6]) to the initial pulmonary injury caused by the inhalation of those toxic gases and particles found mainly in cigarette smoke.

The Lung Parenchyma: An External Sensor of the System

Besides their vital gas exchange function, the lungs act as a selective and protective interface between the internal and external environments. Bronchial and alveolar cells, as well as other tissue-resident cells such as alveolar macrophages (7), are capable of sensing a variety of environmental factors (including viruses, bacteria, particles, and gases, among others), as well as internal “danger signals” (8), and orchestrate an inflammatory response through the release of inflammatory mediators that can act both locally and at a distance. As such, they act as a first, rapid defensive line, recruiting inflammatory effector cells to the lung parenchyma. Such a recruitment process, however, requires the transport of signaling molecules by the systemic circulation to the bone marrow. There (and we suggest below in adipose tissue also), a delayed and more specific response is induced that involves the maturation of mesenchymal stem cells (MSCs), which home back to the lungs for the purpose of restoration of normal lung structure and function.

Systemic Endothelium: An Internal Sensor of the System

Because the endothelial lining is continuous throughout the body, it acts as the internal interface and as a sensor between circulating blood and the body’s cell/tissue milieu. Endothelial cells can also sense and respond to a variety of stimuli including, among others, the following: growth factors, coagulant and anticoagulant proteins, inflammatory cytokines, low-density lipoproteins, endothelin-1, nitrous oxide, oxidative stress, and mechanical forces (shear stress) (9). Endothelial dysfunction plays a major role in the development of vascular disease, both in the systemic (10) and pulmonary circulations (11). Interestingly, COPD is also associated with impaired endothelial function of systemic and pulmonary arteries (12).

The Bone Marrow: An Obvious Responding Element of the System

The bone marrow is a key responding element of the proposed model because it is the source of inflammatory cells that home back to the lungs in response to injury (13). Adult bone marrow contains pluripotent stem cells that have the capacity for self-renewal and give rise to hematopoietic and MSC lineages. In vitro, it has been shown that MSCs can differentiate into bronchial epithelial cells and type I and type II alveolar epithelial cells (14). In vivo, cells of bone marrow origin have been identified in the adult human lung after hematopoietic stem cell transplantation, suggesting that they might play a role in lung tissue repair (15). Bone marrow–derived precursor cells also play a role in angiogenesis, as well as in repair and remodeling of the vessel wall (16). The mechanism(s) by which bone marrow–derived progenitor cells are selectively recruited and differentiate in specific tissues is, as yet, unclear, although recruitment is enhanced by tissue injury, suggesting that the process might be regulated by inflammatory cytokines and other circulating signals.

Adipose Tissue: A Less Obvious Responding Element of the System

We propose that adipose tissue is a less obvious, yet also important, responding element of the network because it is not only a key source of signaling molecules (adipokines) but also a source of stem cells that can participate in tissue repair. Adipokines can have proinflammatory (leptin) and antiinflammatory (adiponectin) effects and, in addition, influence bone marrow functionality (17). For example, leptin is the product of the obese gene (ob), primarily expressed in adipose tissue, but also found in many other tissues, including the lungs. It exerts pleiotropic effects by binding and activating specific leptin receptors in the hypothalamus and other organs, has direct and indirect effects in metabolically active tissues, and regulates several neuroendocrine axes (18). Other identified adipokines that promote inflammation include resistin, retinol-binding protein-4, lipocalin-2, IL-18, angiopoietin-like protein-2, CC-chemokine ligand-5, tumor necrosis factor (TNF), IL-6, and nicotinamide phosphoribosyltransferase (19). The production of most proinflammatory adipokines is up-regulated in obese individuals, in whom they promote insulin resistance, type 2 diabetes mellitus, atherosclerosis, and ischemic heart disease (19). In contrast, adiponectin exerts significant antiinflammatory effects (20). It is synthesized almost exclusively by adipocytes of lean individuals and its expression is significantly reduced in obese subjects (21). Adiponectin exerts its function through its receptors AdipoR1 and AdipoR2, the former being expressed ubiquitously, particularly in skeletal muscle, whereas the latter is most abundantly expressed in liver (22). Finally, adipose tissue represents an abundant and accessible source of adult stem cells capable of differentiating along multiple lineage pathways (23).

The Circulating Signals: The System’s Messengers

The two main sensors of the proposed model (lung parenchyma and systemic endothelium) communicate with the two suggested responder elements (bone marrow and adipose tissue) through a number of biological signals that circulate within the vasculature and include pro- and antiinflammatory and repair signals, as well as microparticles (24).

Many chronic diseases, including COPD, are characterized by low-grade systemic inflammation with elevated serum levels of interleukins, such as IL-6 and IL-8; TNF-α; and acute-phase proteins (C-reactive protein and fibrinogen) (25). Systemic inflammation has been suggested as a key mechanism linking the pulmonary and extrapulmonary manifestations of COPD (26). However, some key conceptual considerations are often less appreciated: (1) the term “inflammation” is imprecisely interpreted and includes a complex network in which a myriad of different cells and molecules participate. To address this complexity, network analysis is required and the term “inflammome” has been proposed to describe this approach (27); and (2) inflammation is a key physiological response (without which all of us would die quickly) and it is designed to be self-limiting (28). It is the uncontrolled persistence of this physiological response that has the potential to damage tissues and develop into a pathological entity.

On the other hand, circulating signals also include microparticles with the capacity to induce changes at distant sites. Microparticles are membrane-bound vesicles with a diameter of less than 1.0 μm that are shed by a number of cells including platelets, endothelial cells, monocytes, granulocytes, erythrocytes, and tumor cells. Microparticles are composed of a phospholipid bilayer that contains most of the membrane-associated proteins of the cells from which they originate and encircles cytosolic components, such as enzymes, transcription factors, mRNA, and microRNA derived from their parent cells (Figure 2). The formation of microparticles is a regulated process in response to cell activation, apoptosis, or physical stress. Microparticle surface proteins allow identification of the cells from which they originate, as well as the mechanism of their formation. In this respect microparticles may serve as biological markers of cell damage or dysfunction (Figure 2). For example, circulating microparticles derived from endothelial cells are increased in acute coronary syndromes and other CVDs (29). Increased levels of circulating endothelial microparticles of apoptotic origin have also been shown to be present in smokers and patients with COPD, the number of circulating microparticles being correlated with the severity of emphysema (30, 31). These findings implicate the involvement of endothelial cell apoptosis in the pathogenesis of emphysema. Circulating microparticles participate in a cell-to-cell communication network because they may activate receptors on target cells and can transfer their content to recipient cells (29). Circulating endothelial microparticles are also capable of producing endothelial dysfunction by altering the intracellular production of vasorelaxing molecules (32) and promoting the recruitment of inflammatory cells (33). As such, increased levels of circulating microparticles originating from apoptotic endothelial cells in emphysema may produce endothelial injury in systemic vessels, potentially explaining the association between COPD and CVD. In this respect it is interesting to note that circulating endothelial microparticles increase during COPD exacerbations (34), perhaps contributing to the increased incidence of cardiovascular events that occur after such episodes (35).

We submit that the model proposed herein provides a framework to develop a novel and testable hypothesis, the results of which might help us to understand better the pathogenesis of the pulmonary and extrapulmonary abnormalities that occur in COPD. To support the proposal, we discuss below the evidence relating COPD (and CVD, one of the most prevalent comorbid diseases in these patients) with the bone marrow, the adipose tissue, and systemic inflammation (Table 1).


Arrow Number (in Figure 1)Interactive Mechanism(s)/Molecule(s) Involved
 Disruption of lung endothelial integrity (TNF-α) (82, 83)
 Increase in ICAM-1 expression on endothelial cells and neutrophil-mediated lung injury (TGF-β1) (82, 83)
 Endothelial destabilization and vessel regression (Angpt-2) (84)
 Inhibition of VEGFR2 causes apoptosis and emphysema (85)
 Inhibition of apoptosis and protection of the pulmonary microvasculature. Stabilization of endothelial cell junctions and protects from plasma leakage(Angpt-1) (86, 87)
 Protects of cardiac allograft arteriosclerosis (Angpt1) (88)
 Inhibition of EPC differentiation, survival, and function (CRP) (89)
 Promotes sprouting and vascular remodeling sensitizing endothelial cells to cytokines. Reduces endothelial cell contacts and regulates the endothelial cell inflammatory responses (Angpt2) (84, 90)
 Mobilization of bone marrow endothelial progenitor cells by hypoxia and/or ischemia (EPO, SDF-1, VEGF) (87, 9193)
 Stabilization of vessels by maximizing the interactions between endothelial cells and their surrounding support cells and matrix (Angpt1) (94)
 Mobilization of endothelial and hematopoietic progenitor cells. Increase vasculogenesis (VEGF and Angpt1) (95)
 Activation of the sympathetic nervous system (96)
 Vascular smooth muscle cell proliferation (97)
 Induction of endothelial and matrix proliferation (98)
 Stimulation of vascular remodeling (endothelin-1, TGF) (99)
 Stimulation of osteoblastic differentiation and hydroxyapatite production by calcifying vascular cells (100)
 Induction of caveolin-1 expression in endothelial cells (101)
 Reduction in paraoxonase-1 activity (102)
 Increase in P-selectin expression on platelets (103)
 Promotion of ADP-induced platelet aggregation (104)
 Generation of active tissue factor (105, 106)
 Expression of plasminogen activator inhibitor-1 in endothelial cells (107)
 Generation of reactive oxygen species (108)
 Induction of hypertrophy of cardiomyocytes (109)
 Activation of hematopoietic and embryonic cells to promote myocyte growth (110, 111)
 Modification of composition and structure of the extracellular matrix of cardiac tissue (112, 113)
 Modification of processes of apoptosis and autophagy (114, 115)
 Negative inotropic effects on cardiac myocytes (116)
 Inhibition of endothelial production of proinflammatory cytokines and chemokines (117, 118)
 Inhibition of foam cell formation from macrophages (119)
 Stimulation of IL-10 and IL-1 receptor antagonist by macrophages (117)
 Activation of endothelial NO synthase (120)
 Activation of AMP-activated protein kinase signaling (121)
 Increased expression of prostaglandin I2 (122)
 Inverse association between adiponectin and left ventricular mass (123)
 Positive relationship with N-terminal prohormone of brain natriuretic peptide (124)
 Antihypertrophic effects in cardiomyocytes (125)
 Protection against angiotensin II–induced cardiac fibrosis; protection of heart from detrimental remodeling after myocardial infarction (126)
 Release of fibrocytes into circulation (SDF-1) (127)
 Recruitment of neutrophils into the lung during COPD exacerbations (CXCL5) (128)
 Increase in cytokines in COPD and anemic chronic disease are associated with reduced number of bone marrow–derived progenitor cells (TNF-α, IL-6) (36, 129)
 Survival and function improvement of endothelial progenitor cells (IL-10) (130)
 Insulin regulation in obesity (TNF-α; IL-6, CRP) (131)
 Stimulation of myeloid differentiation; enhanced recruitment of EPCs into intimal lesions (leptin) (132, 133)
 Increase in the number of circulating EPCs (adiponectin) (134, 135)
6Proinflammatory (leptin)
 Increased leptin expression in bronchial epithelial cells and alveolar macrophages in peripheral lung of patients with COPD (61)
 Overexpression of leptin in the submucosa of proximal airways of patients with COPD (65)
 Leptin may be involved in the regulation of infiltration and survival of inflammatory cells in the submucosa of patients with COPD (65)
 Leptin is significantly correlated with inflammatory markers in induced sputum (136)
 Leptin increases cell proliferation and decreases TGF-β release in 16HBE cell line (65)
 TGF-β decreases and fluticasone propionate increases leptin receptor expression in16HBE cell line (65)
 Leptin inhibits PDGF-airway smooth muscle migration and proliferation and IL-13–induced eotaxin production (137)
 Leptin induces cell proliferation in SQ-5 cells by increasing MAP kinase activity (138)
 Involvement in postnatal lung development (139142)
 Leptin as stimulus of ventilation (143)
 Leptin involvement in acute exacerbations
 Polymorphisms in the OB-R gene decreases susceptibility to loss of lung function (144)
Antiinflammatory (adiponectin)
 Serum adiponectin concentrations are significantly related to increased bronchial hyperreactivity and an accelerated decline in lung function (145)
 Adiponectin-deficient mice demonstrate abnormal alveolarization (145)
 Association between serum adiponectin and lung function in young adults and patients with COPD (67)

Definition of abbreviations: COPD = chronic obstructive pulmonary disease; CRP = C-reactive protein; EPC = endothelial progenitor cell; EPO = erythropoietin; ICAM-1 = intercellular adhesion molecule-1; MAP = mitogen-activated protein; NO = nitric oxide; PDGF = platelet-derived growth factor; SDF-1 = stromal cell–derived factor-1; TGF-β1 = transforming growth factor-β1; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial cell growth factor; VEGFR2 = vascular endothelial cell growth factor receptor-2.

*For further explanations, see Figure 1 and text.

COPD and the Bone Marrow

Indirect evidence suggests that the bone marrow may be malfunctioning in COPD. Compared with control subjects, patients with COPD have decreased numbers of circulating hematopoietic and angiogenic progenitor cells, and this appears to be associated with the severity of their airflow limitation, the presence of arterial hypoxemia, and their exercise capacity (36). Similarly, in patients with chronic respiratory failure, reduced levels of circulating proangiogenic hematopoietic progenitor cells are associated with increased levels of apoptosis of these cells (37). The mechanism(s) underlying these observations are unclear, but they are likely to impair the lung’s capacity to repair and maintain its normal structure and function (38).

CVD and the Bone Marrow

Bone marrow–derived progenitor cells expressing CD34 and CD133 on their surface may engraft into injured vessels and differentiate into true endothelial cells (39). Circulating levels of these so-called endothelial progenitor cells are reduced in patients with CVD risk factors and are associated with endothelial dysfunction of systemic arteries (40). In patients with heart failure, diabetes, and other vascular diseases, higher levels of circulating endothelial progenitor cells are associated with reduced vascular complications (40).

On the other hand, pulmonary vascular remodeling, including loss of cell junctions, endothelial denudation, intimal hyperplasia, and muscularization of small pulmonary arteries, can occur in heavy smokers with normal lung function as well as in patients with COPD (41, 42). Of note, the presence of pulmonary hypertension is not associated with a greater derangement of vessel structure (43). Experimental studies in COPD models indicate that pulmonary vascular changes precede the development of emphysema (44), but little is known about the dynamics of endothelial repair in COPD. Using progenitor cell antibodies, immune-positive cells have been identified, both in denuded areas of the endothelium and within the intimal layer of pulmonary arteries from patients with COPD (42), suggesting that they might contribute to endothelial repair (45).

COPD and Adipose Tissue

Abnormalities in body weight and composition occur often in patients with COPD. Obesity (i.e., a body mass index [BMI] > 30 kg/m2) has been reported in 18–54% of patients with COPD, particularly in those with milder disease (4648), whereas cachexia (BMI < 21 kg/m2) occurs in about 20–40% of patients, particularly in those with severe airflow limitation (4951). Both conditions may significantly impact the pathogenesis and natural history of COPD. On the one hand, persistent systemic inflammation seems particularly prevalent among obese patients with COPD (27), likely in relation to increased abdominal (visceral) fat mass (52), the proinflammatory capacity of which is considerably greater than that of subcutaneous fat (53). Interestingly, excessive visceral fat mass is also reported in nonobese patients with COPD (54). We acknowledge that low BMI is associated with increased mortality risk (55) and a more rapid decline of lung function (56), such that the link between adiposity/cachexia, adipokines, and COPD is complex and still not well understood. However, data have shown that (1) there is differential clustering of comorbidity profiles in obese and lean patients with COPD (57); (2) low leptin-to-fat ratios occur in males and females with COPD and low BMI (58); and, finally, (3) BMI and sex are the strongest determinants for both leptin and adiponectin levels in patients with COPD (59).

Adipokines can have substantial respiratory effects (60) (Table 1). Smoking increases the expression of the leptin receptor system in the lungs (61). Leptin signaling–deficient mice show an imbalance in innate and adaptive immune cells recruited to the lung after chronic smoke exposure, which can be restored after exogenous leptin administration (62). Leptin also has effects on postnatal lung development (63) and the regulation of ventilation (64). In patients with COPD, there is increased leptin expression in bronchial epithelial cells and alveolar macrophages (61), and this correlates with the expression of activated T lymphocytes and the absence of apoptotic T cells (65). Interestingly, patients with COPD carrying polymorphisms in the Ob-R gene are less susceptible to lung function loss (66). On the other hand, adiponectin has significant antiinflammatory effects in the lungs in experimental animals (Table 1). In humans, data are still unclear because some (67), but not all, investigators (58) report an association between serum adiponectin and lung function in COPD. Finally, it is of note that fat-derived mesenchymal cells constitute a potentially important source of exogenous stem cells to repair lung injury (68). Although data in humans are still scarce, adipose-derived stem cells implanted into tracheal defects in rats differentiated into a pseudo-stratified columnar epithelium with well-differentiated ciliated and goblet cells and neovascularization (69).

CVD and Adipose Tissue

Proinflammatory adipokines exert numerous and varied effects on the cardiovascular system. Besides leptin (Table 1) others include (1) resistin, which promotes the expression of proinflammatory adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and pentraxin-3, on vascular endothelial cells, thereby enhancing leukocyte adhesion; (2) ANGPTL2, which activates inflammatory responses by endothelial cells, monocytes, and macrophages via activation of integrin signaling; and (3) NAMPT (nicotinamide phosphoribosyltransferase; also known as visfatin), which induces the expression of monocyte chemoattractant protein (MCP)-1 in human endothelial cells via NF-κB and has been associated with coronary atherosclerosis. On the other hand, clinical studies have identified an association between low serum adiponectin and coronary disease, hypertension, left ventricular hypertrophy, and a greater risk of myocardial infarction. The biological mechanisms underlying these clinical effects are summarized in Table 1.

COPD and Systemic Inflammation

Research in COPD (27) has shown that (1) smoking per se, in the absence of pulmonary disease, can induce a specific systemic “inflammome” best described by increased leukocyte counts and serum levels of IL-8 and TNF-α; (2) about 30% patients with COPD have no evidence of systemic inflammation, whereas 20% of them present persistent systemic inflammation, defined by the maintenance of abnormal values of several inflammatory markers through time; (3) the systemic “inflammomes” of smoking and COPD are distinct, the latter being characterized by increased levels of C-reactive protein, IL-6, and fibrinogen, as well as a further increase in circulating leukocytes; and (4) patients with COPD with persistent systemic inflammation have much worse outcomes than “noninflamed” patients with COPD, despite similar functional and structural pulmonary abnormalities. In particular, compared with the noninflamed, those with persistent systemic inflammation have a six times higher mortality in 3 years and double the annual exacerbation rate (27). In the context of the model proposed herein, it is of note that patients with persistent systemic inflammation have a higher BMI than those without it despite their similar pulmonary derangements (including the severity of airflow limitation and/or the presence of emphysema) (27).

COPD and CVD: Closing the Loop

CVD is often present in patients with COPD (5). Conversely, a high percentage of patients with CVD have undiagnosed airflow limitation (70, 71). Although this may be due to shared risk factors such as aging, smoking, and/or sedentarism, the higher prevalence of CVD in smokers with COPD, as compared with those smokers who manage to maintain normal lung function values despite their habit, suggests the presence of specific pathogenic mechanisms, including low-grade persistent systemic inflammation, deregulated adipokine metabolism, and/or abnormal repair capacity. The relationships between all elements of the network proposed here (lungs, circulation, bone marrow, adipose tissue, and the inflammatory response) have not been previously considered in combination (Figure 1). Our hypothesis predicts that the development of COPD and CVD would be the end result of the interplay between the injured lungs (a major source of danger signals) and the response of the bone marrow and adipose tissue, major (but not the only) sources of both inflammatory and repair signals.

The network hypothesis proposed here highlights potentially important and previously overlooked relationships in COPD between the lungs, endothelium, bone marrow, and adipose tissue. We recognize, however, that our proposal has caveats and limitations that deserve discussion. First, we fully acknowledge that COPD is a complex condition, with many different domains/compartments, and that it is heterogeneous in that not all domains are present in all patients. In this regard the model per se does not account for the complexity of COPD, but we believe it provides a basis for understanding how the interrelationship(s) of these components vary with distinct COPD phenotypes. As we propose below, the extent and nature of the variation will be better revealed by testing the model in a clinical setting (72). Second, we discussed herein the implications of our model for the pathobiology of CVDs in COPD, the most prevalent concomitant disease in these patients (73). However, our model might be equally relevant for other comorbid diseases in these patients. For instance, it is well established that skeletal muscle dysfunction is a prominent extrapulmonary manifestation in some patients with COPD. The causes of such muscle dysfunction are likely multifactorial and include sedentarism, malnutrition, hypoxia, oxidative stress, and others (74). Whether or not skeletal muscle dysfunction can also modulate the pulmonary and endothelial abnormalities discussed in our model is unclear. Finally, we wholeheartedly support the idea that a similar network model can apply to other prevalent chronic noncommunicable diseases (75). Thus, the network model we propose is not specific for COPD (i.e., there is no “index” disease). Rather multimorbidity may develop simultaneously through the same model in response to common risk factors such as aging, smoking, and physical inactivity, among others (76). What makes COPD unique in this context is that the tobacco smoke–induced initial injury and innate immune response (77) occur at the pulmonary epithelial–interstitial interface within the lungs and that this site may later became the prime battle field due to “back attack” via systemic inflammation, the last involving a mainly acquired immune response (72, 77). In this context, other responder cells and tissues, such as macrophages, regional lymph nodes, and the spleen and thymus need to be considered in relation to our newly proposed basic model.

Of course, the proposed working network model can and should be challenged by current and further experimental and clinical research. For instance, in chimeric mice emphysema appears to be inducible without a significant bone marrow response (78), suggesting that different COPD compartments may be affected differently by different biological mechanisms. However, because experimental models do not always mimic completely the complexity of human disease (79), direct extrapolation of animal findings to humans needs to be made with caution and clinical research, where possible and ethical, is to be preferred. In this context, we propose that future descriptive and/or interventional investigations of our model in patients with COPD should monitor markers from all elements of the triangle (Figure 1) and apply the principles of network medicine (80), which has the potential to incorporate a wealth of “independent” knowledge into a computable gene–environment–disease systems biologic network model (3, 81). For instance, an integrated analysis of different markers of the different compartments identified in the model (Figure 1), including lung tissue (bronchoalveolar lavage, biopsy), endothelium (imaging, function), bone marrow (biopsy), adipose tissue (biopsy), and circulatory markers (inflammome, adipokines, microparticles) in well-characterized COPD phenotypes (obese/lean, with/without cardiovascular morbidity) has the potential to provide new insights into the pathogenesis of this complex disease.

We have presented herein a working network model that links the pulmonary epithelium, bone marrow, adipose tissue, and systemic endothelium (Figure 1) and provides an integrated framework that can be tested in clinical studies of distinct phenotypes of COPD, the results of which are likely to provide a novel understanding of COPD, its complexity, and its associated comorbidities. We have discussed the rationale and provided initial evidence to support the model and considered its potential applicability in the case of CVD, the most frequently encountered comorbid disease in these patients. We have also acknowledged potential caveats and limitations of the model in its present form and hope that consideration of it may encourage the design of new clinical studies in patients with COPD, the results of which are likely to provide better insight into the pathobiology of COPD and associated comorbidities and further avenues for the development of novel therapies.

The authors thank Richard Follows, David Leather, and Raj Sharma (GSK) for stimulating this discussion; and GSK for providing the economic support needed to organize three face-to-face meetings among the authors in Barcelona that allowed the discussion of ideas and the agreement on the current text.

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Correspondence and requests for reprints should be addressed to Alvar Agustí, M.D., Ph.D., Institut del Tòrax, Hospital Clinic, Villarroel 170, Escala 3, Planta 5, 08036 Barcelona, Spain. E-mail:

Supported by an unrestricted grant from GSK.

Author Contributions: All authors have contributed to the design, content, and discussion of this pulmonary perspective.

Originally Published in Press as DOI: 10.1164/rccm.201308-1404PP on October 31, 2013

Author disclosures are available with the text of this article at


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American Journal of Respiratory and Critical Care Medicine

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