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Abstract

Chronic obstructive pulmonary disease (COPD) has traditionally been considered a disease of the lungs secondary to cigarette smoking and characterized by airflow obstruction due to abnormalities of both airway (bronchitis) and lung parenchyma (emphysema). It is now well known that COPD is associated with significant systemic abnormalities, such as renal and hormonal abnormalities, malnutrition, muscle wasting, osteoporosis, and anemia. However, it is still unclear whether they represent consequences of the pulmonary disorder, or whether COPD should be considered as a systemic disease. These systemic abnormalities have been attributed to an increased level of systemic inflammation. Chronic inflammation, however, may not be the only cause of the systemic effects of COPD. Recent data from humans and animal models support the view that emphysema may be a vascular disease. Other studies have highlighted the role of repair failure, bone marrow abnormality, genetic and epigenetic factors, immunological disorders and infections as potential causes of COPD systemic manifestations. Based on this new evidence, it is reasonable to consider COPD, and emphysema in particular, as ‘a disease with a significant systemic component’ if not a ‘systemic disease’ per se. The aim of this review is to give an overview of the most relevant and innovative hypothesis about the extrapulmonary manifestations of COPD.

Keywords

chronic obstructive pulmonary disease inflammation oxidative stress systemic manifestations

Introduction

The American Thoracic Society and the European Respiratory Society define chronic obstructive pulmonary disease (COPD) as ‘a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences’ [Celli and MacNee, ATS/ERS Task Force, 2004]. It is interesting to point out how the definition of COPD has evolved including the ‘systemic consequences’ of the disease.

The natural history of the disease reveals numerous extrapulmonary manifestations and comorbidity factors that complicate the evolution of COPD, thereby altering the prognosis and quality of life of patients [Barnes and Celli, 2009; Agusti and Soriano, 2008]. Many extrapulmonary effects of COPD have been described over the last two decades, including renal and hormonal abnormalities [Palange, 1998], muscle wasting [Remels et al. 2007], osteoporosis [Bolton et al. 2004], anemia [John et al. 2005] and reduction in circulating bone marrow progenitors [Palange et al. 2006]. Although these systemic manifestations have been described for years in COPD patients, it is still unclear whether they represent consequences of the pulmonary disorder, or whether COPD should be considered as a systemic disease. The importance of establishing the distinction between a respiratory disease with extrapulmonary manifestations and a systemic inflammatory state with multiple compromised organs is justified by different therapeutic options: in the first definition, therapy is primarily centered on the lungs, whereas in the second, therapy could aim at the systemic inflammatory state.

Furthermore, since COPD represents a group of pulmonary abnormalities of either airways (bronchitis) or lung parenchyma (emphysema), it is reasonable to raise the question: does the systemic involvement of the disease vary depending on the etiology and pathophysiology of each of the two different COPD phenotypes?

The aim of this review is to give an overview of the most relevant and innovative hypotheses regarding the extrapulmonary manifestations of COPD.

Systemic inflammation

Among the numerous extrapulmonary effects of COPD, systemic inflammation has been widely studied and considered as an important key between the pulmonary disease and the related systemic manifestations. Many studies have reported changes in various inflammatory cells and mediators, including neutrophils, lymphocytes, acute-phase reactants, and cytokines. Gan and colleagues recently performed a meta-analysis that showed systemic inflammation is present during COPD exacerbations and stable phases of the disease: increased numbers of leukocytes, levels of acute-phase response proteins (C-reactive protein and fibrinogen), cytokines such as interleukin (IL)-6, and tumor necrosis factor (TNF)-α are present in the peripheral blood of COPD patients [Gan et al. 2004]. Systemic inflammation has been implicated in the pathogenesis of the majority of COPD systemic effects, including weight loss [Wouters, 2002], skeletal muscle dysfunction [Langen et al. 2001], cardiovascular diseases [Sin and Man, 2003], and osteoporosis [Biskobing, 2002], although it is still controversial whether this so-called low-grade systemic inflammation represents the consequence of pulmonary inflammation into the systemic vascular bed [Agustì et al. 2003], or whether it is a systemic inflammation. Vernooy and colleagues, as well as Hurst and colleagues, failed to show a relationship between TNF-α and IL-8 values in induced sputum and plasma, suggesting that the systemic inflammation in COPD is not linked to the pulmonary inflammation in these patients [Hurst et al. 2005; Vernooy et al. 2002]. Although inflammation is certainly one of the major features of COPD, we still need to understand whether the local inflammation is sufficient to induce systemic effects, or whether a second pathogenetic event is required. Therefore, further studies are needed to elucidate the origin of the systemic inflammation in COPD.

Malnutrition

Several studies have demonstrated an association between poor nutrition and COPD, where weight loss and low body mass index (BMI) are associated with increased mortality [Schols et al. 1998; Gray-Donald et al. 1996]. Interestingly, a randomized, controlled trial showed that nutritional supplementation resulted in improved exercise capacity in well nourished, but not in undernourished patients [Steiner et al. 2003]. It is also known that patients with low BMI have higher levels of inflammation than normal BMI patients [Huertas et al. 2010]. On the other hand, it has been shown that patients who have relative anorexia and high levels of inflammation are least likely to respond to nutritional supplementation [Creutzberg et al. 2000]. Therefore, it is reasonable to wonder whether the inflammation causes the reduction in BMI, whether the low BMI induces a higher level of inflammation, or whether a factor causing both inflammation and low BMI could exist in these patients. Understanding this aspect is important in order to choose whether to treat the inflammation or the outcome.

Vascular abnormalities

The loss of alveolar capillary endothelial cells has been observed in emphysema for almost 50 years [Liebow, 1959], but new data derived from investigations on the vascular nature of emphysema suggest a systemic involvement of the disease [Voelkel and Taraseviciene-Stewart, 2005; Santos et al. 2002; Shapiro, 2000; Yamato et al. 1996]. The vascular endothelial growth factor (VEGF) plays an important role in the vascular pathogenesis of COPD, particularly in emphysema. The VEGF has a fundamental role in physiological and pathophysiological angiogenesis and regulation of endothelial cell differentiation. This has been demonstrated by the lethality of VEGF knockout mice and by the abnormal vasculogenesis of the heart and large vessels following the loss of a single copy of the VEGF gene [Carmeliet et al. 1996]. The VEGF, also known as the vascular permeability factor, displays several key functions in the lung, such as migration and proliferation of endothelial cells, monocyte adhesion, angiogenesis, vasodilatation, and enhanced permeability, as well as early hemangioblast development. Above all, a crucial role in the genesis of emphysema has been developed based on the observation that blockade of VEGF receptor (VEGFR) -1 and -2 arrests lung growth and leads to an emphysematous phenotype in a murine model [McGrath-Morrow et al. 2005]. Therefore, an interesting model of VEGFR blockade with SU5416 results in endothelial cell apoptosis causing apoptosis-dependent emphysema in rodents [Tang et al. 2004; Kasahara et al. 2000].

Alveolar maintenance is defined as the preservation of the alveolar gas-exchange area by limiting the destruction of alveoli and airspace enlargement, the hallmark of emphysema. The finding that decreased VEGF or VEGF signaling causes experimental emphysema leads to the concept that alveolar maintenance is required for structural preservation of the lung. This structure, when disrupted by cigarette smoke, for example, causes emphysema [Taraseviciene-Stewart and Voelkel, 2008; Tuder and Voelkel, 2001]. Therefore, it appears quite legitimate to raise the question whether maintaining cell homeostasis by growth factors, such as VEGF, could rescue emphysema. Unfortunately, no data are so far available on the potential benefits of VEGF gene therapy in emphysematous lung. VEGF is a tightly regulated gene in the lung, playing specific roles in different structural and cellular compartments. While the VEGF protein and mRNA contents in the lung are reduced in severe emphysema, VEGF gene expression is increased in the pulmonary arteries of smokers and patients with moderate COPD, and correlates with medial thickening of the pulmonary vascular walls [Santos et al. 2003]. These data confirm the systemic pathogenesis of emphysema, but also underlie the multifactorial aspect of the disease [Yoshida and Tuder, 2007].

Repair failure

The destruction of the alveolar walls leading to enlargement of the alveolar spaces, which is a well known characteristic of emphysema, could also be considered as the result of an impaired repair capacity. In addition to this, there is an indication that lung repair, as evidenced by de novo synthesis and tissue accumulation of elastin and collagen, is inhibited by cigarette smoke [Rennard et al. 2006]. Exposure to cigarette smoke extract also inhibits fibroblast proliferation [Nakamura et al. 1995], and fibroblasts isolated from patients with emphysema exhibit decreased proliferative capacity [Holz et al. 2004; Nobukuni et al. 2002]. Exposure to cigarette smoke extract induces cell-cycle arrest in fibroblasts, mediated through the activation of p53 and p16, which inhibit the cell cycle, leading to cellular senescence [Nyunoya et al. 2006]. This may represent a response of fibroblasts to DNA damage by cigarette smoke extract [Bartek et al. 2004]. This may result in abnormal wound healing and prevention of repair of lung injury. In addition, cigarette smoke can kill endothelial cells and endothelial cell precursors [Hoshino et al. 2005], and inhibit airway epithelial cell chemotaxis and proliferation [Wang et al. 2001]. Abnormal mesenchymal repair functions have been observed in fibroblasts obtained from emphysematous human lung. Holz and colleagues have demonstrated that fibroblasts cultured from lungs of emphysematous patients proliferate more slowly than fibroblasts obtained from age-matched control lungs [Holz et al. 2004]. Rennard and colleagues have extended these results to demonstrate that fibroblasts from emphysematous patients are also less capable of responding to a chemotactic stimulus and are less potent in contracting three-dimensional collagen gels [Rennard et al. 2006].

It is unclear whether the differences between fibroblasts obtained from normal or emphysematous individuals represent underlying genetic differences and hence susceptibility to develop emphysema, or if they are an acquired defect.

Bone marrow-derived cells

Circulating bone marrow-derived progenitors have been shown to be decreased in COPD patients and to correlate with disease severity [Huertas and Palange, 2011; Huertas et al. 2010; Palange et al. 2006; Fadini et al. 2006]. Several clinical factors have been implicated in the mobilization of endothelial progenitor cells (EPCs), and mechanisms have begun to be elucidated. Defective lung development or defective lung repair in the setting of protracted inflammation and injury may result in part from an inadequate contribution of local or circulating EPCs. Age has previously been reported to be inversely correlated with EPC number [Chang et al. 2007]. Newer data suggest that there are also differences in the ability of EPCs to home to ischemic tissues based on age, and that this may be mediated through the inability of aged tissues to activate normally the hypoxia-inducible factor-1α-mediated hypoxia response [Llevadot et al. 2001].

It has also been shown that in COPD patients, bone marrow dysfunction is related to lung function impairment, poor nutritional state, and levels of systemic inflammation [Huertas et al. 2010]. In this study, patients with low BMI had reduced circulating hemopoietic and endothelial progenitor counts, suggesting lower progenitor release from the bone marrow, pronounced systemic inflammation with high levels of proangiogenetic growth factors, and proinflammatory markers, compared with normal BMI patients. Interestingly, these growth factors and cytokines, as well as BMI, were inversely correlated with markers of disease severity. Furthermore, among patients with similar pulmonary impairment, those who displayed low BMI had a greater bone marrow dysfunction.

All together, these data suggest that, in addition to disease progression in terms of airflow obstruction, systemic involvement in COPD leads to a more pronounced bone marrow impairment. Whether this pool of precursor cells is reduced as a consequence of the pulmonary disease or whether the bone marrow involvement represents a systemic disease needs to be defined.

Genetics and epigenetics

The genetic etiology of COPD is certainly in favor of considering the disease as a systemic syndrome: although smoking is considered to be the major risk factor for COPD, only 15% to 20% of smokers develop the clinically relevant disease [Celli and MacNee, ATS/ERS Task Force, 2004; Ouellette, 2004]. Genetic susceptibility to COPD has been investigated in recent years and numerous candidate genes have been found to encode proteins that regulate: proteases and antiproteases (i.e. α₁-antitrypsin, Serpine2, α₁-antichymotrypsin, α₂-macroglobulin, secretory leukocyte proteinase inhibitor, matrix metalloproteinases (MMP), ADAM33, protease-activated receptor-2); mucociliary clearance (i.e. cystic fibrosis transmembrane regulator, mucins); antioxidants (i.e. microsomal epoxide hydrolase, glutathione-S-transferases, cytochrome P450, extracellular superoxide dismutase); inflammatory mediators (i.e. TNF-α, IL-11, IL-1 family). Interestingly, the MMP-1 promoter has been shown to be a direct target of cigarette smoke in lung epithelial cells and regions of the human MMP-1 promoter have been recently defined [Mercer et al. 2009]. This extensive list of candidate genes attests to the relevance of the genetic pathophysiology of COPD and, in particular, emphysema. Many animal models have helped in defining the genes involved in the pathogenesis of this latter disorder, strongly suggesting the systemic origin of the disease. Recently, cellular senescence has also been shown in a mouse model of emphysema, where knocking out the senescence marker protein-30, which protects against aging, leads to airspace enlargement [Sato et al. 2006]. Interestingly, in experimental models of emphysema, genes that encode proteins important for the systemic immune response have been shown to be involved. Mice lacking toll-like receptor 4, which is activated during the innate immune response, spontaneously developed emphysema associated with an oxidative stress imbalance (i.e. increased Nox3 gene expression, a novel NAPDH oxidase, and elastin degradation) [Zhang et al. 2006], but without any inflammatory infiltration of the lung parenchyma.

Lung gene expression studies from endstage COPD patients have shown impaired mitochondrial energy metabolism and protein synthesis [Golpon et al. 2004], suggesting DNA damage and posttranscriptional modifications, but little is known about epigenetic marks in respiratory diseases. Interestingly, it has been shown in COPD that the expression and activity of histone deacetylase (HDAC)-2 are markedly reduced in lung parenchyma, bronchial biopsies, and alveolar macrophages. This decrease is correlated with disease severity and intensity of the inflammatory response [Ito et al. 2005]. Overexpression or knockdown of HDAC2 in alveolar macrophages from COPD patients affects not only the inflammatory response but also corticosteroid responsiveness, suggesting an additional role for HDAC2 in the anti-inflammatory actions of the corticosteroid [Ito et al. 2006].

The clinical impact of cigarette smoking, which ranges from negligible to endstage lung disease, is, in part, determined by individual susceptibility factors. Understanding the factors that lead to emphysema is useful for predicting high-risk individuals. Except for α₁-antitrypsin, a deficiency of which results in a predisposition to smoking-induced emphysema, few other susceptibility factors are defined. Genetic susceptibility and epigenetic modifications strongly suggest a systemic etiology of COPD, but further data are needed to define better the precise etiopathology of the disease.

Immunology

An interesting characteristic of emphysema is the lack of attenuation in inflammatory and disease parameters years after the cessation of smoking: tobacco smoke seems to contain antigens that induce immunological responses in susceptible individuals. It might also be a more complex pathogenesis in which smoking induces an autoimmune response to an endogenous lung antigen. This alternative concept of emphysema pathogenesis has been raised by Voelkel and colleagues, who showed that humoral and CD4⁺ cell-dependent mechanisms are sufficient to trigger emphysema development, suggesting that alveolar septal cell destruction might result from immune mechanisms [Taraseviciene-Stewart et al. 2005]. Using a murine model, they showed that intraperitoneal injection of endothelial cells causes emphysema, leading to alveolar septal cell apoptosis, and the activation of MMP-9 and MMP-2. Furthermore, naïve immunocompetent animals developed emphysema following the administration of CD4⁺ T cells. This hypothesis has also been investigated in humans: by isolating peripheral blood CD4⁺ T cells from emphysematous patients, Lee and colleagues were able to show that exposure to cigarette smoke induces secretion of proteolytic enzymes from cells of the innate immune system. These cells liberate lung elastin fragments which, in susceptible individuals, could initiate T cell and B cell-mediated immunity against elastin [Lee et al. 2007]. These data strongly suggest an autoimmune pathogenesis of emphysema, characterized by the presence of antielastin antibody and T helper type 1 (Th₁) responses that correlate with emphysema severity.

It is interesting to point out that elastin is abundant in various tissues, in particular in arteries, arterioles, and skin. In addition to emphysema, tobacco smokers are at high risk for coronary artery disease, aortic aneurysms, and elastolytic changes of the skin [Patel et al. 2006; Pepine et al. 2006]. These findings link emphysema to adaptive immunity against a specific lung antigen and suggest the risk for smokers of developing autoimmune diseases in other elastin-rich tissues, such as arteries and skin. Findings of antielastin autoimmunity in emphysema therefore suggest a broader, systemic autoimmune process involving the major elastin-bearing organs that may explain these diverse clinical observations.

On the other hand, several clinical reports have described cases of emphysema in patients with hypocomplementemia, and in particular, those with a history of hypocomplementemic urticarial vasculitis. Although we need to better define this possible pathogenesis, these reports suggest that an impaired immunological condition could lead to the development of emphysema [Jamison et al. 2008; Ghamra and Stoller, 2003], underlying the systemic pattern of the disease.

Infections

Other observations keep the question of COPD as a systemic disease open: emphysematous lung destruction has been reported in other nonsmoking-related disorders or hypersensitivity pneumonitis [Tuder and Voelkel, 2001], and recent data indicate that starvation causes lung cell apoptosis in mouse lung [Massaro et al. 2004]. Furthermore, in a recent observational study, HIV was identified as an independent risk factor for COPD after adjusting for age, race, pack-years of smoking, intravenous drug abuse, and alcohol abuse. HIV subjects were 50–60% more likely to receive a diagnosis of COPD when these risk factors were taken into accounted [Crothers et al. 2011, 2006]. A series of 114 HIV⁺ patients, when compared with 44 HIV^– controls, revealed a significantly higher rate of emphysema among the HIV⁺ individuals [Diaz et al. 2000]. When controlled for tobacco exposure, the HIV⁺ subjects again had significantly more emphysematous damage for a given level of tobacco use. HIV is now frequently cited as a susceptibility factor for the development of emphysema, independently of cigarette smoking status. The presence of common coexistent factors that may predispose patients to chronic lung injury such as drugs, opportunistic infections, and malnutrition, limits the scope of studies of direct mechanisms involved in HIV-associated emphysematous lung disease. Adding to the complexity of HIV-associated COPD, several risk factors associated with HIV infection may themselves play a pathogenic role in the development of emphysema, such as infection or colonization with Pneumocystis, intravenous drug use, malnutrition, etc. In the non-HIV infected population, Pneumocystis colonization has been associated with increased severity of airway obstruction in COPD [Morris et al. 2004; Palange et al. 1994]. In the studied cohort of patients, 36.7% of patients with GOLD stage IV were colonized with Pneumocystis compared with only 5.3% of patients with less severe COPD or normal lung function. These data led to the hypothesis that Pneumocystis colonization may accelerate the development of airway obstruction. Further studies of the pathogenic role of fungal colonization in the development of airspace enlargement in emphysema are needed to understand better the role of colonization by Pneumocystis and infection in the pathogenesis of HIV-related emphysema. HIV-seropositive individuals have a propensity to develop emphysematous changes in their upper lobes at an accelerated rate independently of their smoking status. Confounding factors in HIV-infected individuals, including Pneumocystis colonization, drug use, and malnutrition, may play a role in predisposition for emphysema. However, HIV itself is emerging as an independent factor in the pathogenesis of emphysema. A recent review [Petrache et al. 2008] emphasized how HIV infection may affect cytotoxic lymphocyte activation, lung capillary endothelial cell injury and apoptosis, sphingolipid imbalance, and oxidative stress in the lung. A better understanding of the pathogenesis of HIV-associated pulmonary emphysema may provide clues and therapeutic targets that have broader application in this disease, including cigarette smoke-induced emphysema.

Conclusion

Many extrapulmonary effects of COPD have been described in the last two decades: some of these manifestations have been extensively studied, but it is still unclear whether they represent consequences of the pulmonary disorder, or whether COPD should be considered as a systemic disease. In this review, we have tried to give an overview of the most relevant and innovative hypothesis about the extrapulmonary effects of COPD. Even if precise cellular and molecular mechanisms are still unclear, evidence has been provided suggesting that COPD, and emphysema in particular, might be considered as a systemic disease.

Further studies are needed to understand better this complex and multifaceted disease in order to treat patients with more specific tools.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

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COPD: a multifactorial systemic disease

Abstract

Keywords

Introduction

Systemic inflammation

Malnutrition

Vascular abnormalities

Repair failure

Bone marrow-derived cells

Genetics and epigenetics

Immunology

Infections

Conclusion

Footnotes

Funding

Conflict of interest statement

References