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Systemic Effects of Chronic Obstructive

Pulmonary Disease
What We Know and What We Don’t Know (but Should)
Alvar Agustı´1
1
Servei de Pneumologia, Hospital Universitari Son Dureta, Fundacio Caubet-Cimera Illes Balears, Mallorca, Spain

Chronic obstructive pulmonary disease (COPD) is associated with in this field, and to stimulate research in this area with the hope
pulmonary and systemic inflammation. The latter is likely to contrib- that a better understanding of these mechanisms may lead to better
ute significantly to the pathobiology of numerous extrapulmonary treatment options for patients with COPD (Table 1).
effects of the disease—the so-called systemic effects of COPD. The
clinical relevance of these systemic effects has been recently recog-
COPD IS ASSOCIATED WITH
nized; however, many important questions about its pathophysiol-
ogy remain unanswered. This article reviews what is known about
SYSTEMIC INFLAMMATION
it and, more importantly, highlights what is not (but should be) Many different studies performed over the past decade have
known in order to stimulate research in this area, in the hope that clearly established that COPD is associated with low-grade sys-
a better understanding of this field may lead to better treatment temic inflammation (reviewed in References 5, 8). Gan and co-
options for patients with COPD. workers have recently reviewed them all in the form of a meta-
analysis (4). That analysis confirmed that patients with stable
Keywords: chronic bronchitis; chronic obstructive pulmonary disease;
emphysema; inflammation COPD present increased numbers of leukocytes (some of them
with an activated phenotype) (9, 10) and increased levels of
Chronic obstructive pulmonary disease (COPD) has been tradi- acute phase response proteins (C-reactive protein [CRP] and
tionally understood as a disease of the lungs characterized by fibrinogen) and cytokines (IL-6) and tumor necrosis factor
chronic airflow obstruction, which, in turn, is due to the presence (TNF)-␣ (4). The intensity of this systemic inflammation in-
of specific structural abnormalities of both the airways (bronchi- creases during exacerbations of COPD (11–14). Interestingly,
tis and bronchiolitis) and the pulmonary parenchyma (emphy- other chronic conditions, such as chronic heart failure, obesity,
sema) (1). Much more recently, a number of studies have indi- or diabetes, and even the normal process of aging, also appear
cated that these structural abnormalities were associated with to be associated with a similar low-grade systemic inflammatory
an inflammatory reaction of the airways, alveoli, and pulmonary process (15–17).
vessels (2). This inflammatory reaction seems to occur in all
smokers but, for reasons that are still not clear, it appears to be THE ORIGIN OF SYSTEMIC INFLAMMATION IN
greatly enhanced in those smokers who develop COPD (3). COPD IS UNCLEAR
Furthermore, this abnormal inflammatory reaction can also be
detected in the systemic circulation (4). It is likely that this Given that COPD is associated with an abnormal inflammatory
systemic inflammation contributes significantly to the pathobiol- response of the lung parenchyma to inhaled pollutant and gases
ogy of numerous extrapulmonary effects of the disease—the so- (mostly through cigarette smoking) (7), the most obvious expla-
called systemic effects of COPD (5, 6). The clinical relevance nation for the presence of systemic inflammation in these pa-
of these systemic effects has been recognized in the more recent tients was that, somehow, this pulmonary inflammation was
international guidelines for COPD diagnosis and treatment (7). “spilling over” into the systemic circulation (5). However, several
In fact, it is likely that important clinical outcomes, including observations do not support this explanation. For instance,
mortality or health status, eventually result from the interplay Vernooy and colleagues measured the levels of soluble TNF-␣
between the intrapulmonary and extrapulmonary effects that (and its receptors) and IL-8 in induced sputum and in plasma
occur in COPD (Figure 1). of 18 patients with COPD (mean FEV1, 56% predicted) and
Despite the significant advancement in our understanding of could not find any relationship between values in sputum and
COPD that has occurred over the past decade or so, many impor- values in blood (18). More recently, Hurst and colleagues were
tant questions about the pathophysiology of the disease remain also unable to find such relationships (19). Overall, therefore,
unanswered. One particular area of interest is systemic inflamma- the hypothesis that systemic inflammation in COPD was origi-
tion in relation to the extrapulmonary effects that can occur in nating in a form of “spillover” of the pulmonary compartment
these patients. The goal of this article is to review the current is not proven.
understanding of this topic, to identify relevant gaps of knowledge Other potential origins of systemic inflammation in COPD
include smoking, lung hyperinflation, tissue hypoxia, skeletal
muscle dysfunction, and the bone marrow. It is well known that,
in the absence of COPD, smoking is one important risk factor
of cardiovascular disease (albeit, as discussed subsequently here,
(Received in original form January 3, 2007; accepted in final form February 27, 2007 ) the presence of COPD increases significantly the risk of cardio-
Supported in part by Govern Balear and Associacio´ Balear par l’estudi de malalties vascular disease in smokers) (20). Furthermore, smoking does
respiratories (ABEMAR). so through the induction of low-grade systemic inflammation
Correspondence and requests for reprints should be addressed to Dr. Alvar Agustı´, and endothelial dysfunction, even in passive smokers (21). Thus,
Servei Pneumologı´a. Hospital Universitari Son Dureta, Andrea Doria 55, 07014
it is clear that smoking, per se, can cause systemic inflammation.
Palma Mallorca, Spain. E-mail: aagusti@hsd.es
However, Vernooy and colleagues found that former smokers also
Proc Am Thorac Soc Vol 4. pp 522–525, 2007
DOI: 10.1513/pats.200701-004FM had evidence of systemic inflammation (18), indicating that smok-
Internet address: www.atsjournals.org ing cannot be the only factor inducing systemic inflammation in

. 48% predicted) bronchodilator therapy. The identification of the different factors potentially contributing to it and their relative importance inflammation may be linked to early perturbations of pulmonary needs to be established. This relationship The origin of systemic inflammation in COPD is likely to be occurs even in never-smoker subjects.Agustı´: Systemic Effects of COPD 523 Figure 1. If so. Second. It is likely (but currently unproven) that systemic inflammation SYSTEMIC INFLAMMATION: LIKELY TO HAVE MAJOR contributes to the pathophysiology of many systemic effects of COPD. COPD. In this context. cardiovascular CLINICAL IMPACT disease. and has COPD are the skeletal muscle and the bone marrow. The bone marrow is the production The chronic airflow obstruction that characterizes COPD of. The persistence of inflammation after smoking cessation Other potential sites of origin of systemic inflammation in also occurs in the lungs of patients with COPD (3. aging. including weight loss. Systemic inflammation has been implicated in the pathogenesis The impact on relevant clinical outcomes. However. and osteoporosis. site of inflammatory cells. and Description evidence for cell senescence has been recently identified in the lung parenchyma of patients with emphysema (37. smoking is a key question that is so far unanswered. tween CRP concentrations and FEV1 (39). and COPD is an CHRONIC OBSTRUCTIVE PULMONARY DISEASE: age-related disease (17). systemic inflammation persists after quitting smoking may be very valuable in this setting. cardiovascular disease. however. depression. Whether systemic inflammation precedes or fol- Unknowns Why systemic (and pulmonary) inflammation persists after quitting lows changes in lung function requires longitudinal studies. smoking has been shown FACTS AND UNKNOWNS to enhance telomeric loss (a marker of cell aging) (36). Definition of abbreviation: COPD ⫽ chronic obstructive pulmonary disease. however. systemic inflammation in COPD should be responsive to duced in 18 patients with COPD (mean FEV1. even in subjects and increases during exacerbations of the disease. Importantly. described to date. (24). It has been shown that the latter can. 35). that contribute to the physiologic (airflow obstruction) and clinical characteristics of patients. 38). Furthermore. when considering the origin of systemic inflammation in COPD. 34. including skeletal muscle dysfunction. Modified from Reference 6. indicating that systemic multifactorial. In COPD. including the physiologic process of aging). contrary to healthy subjects. stimulate whether the bone marrow has specific abnormalities in COPD the production of cytokines from the lungs (25–27). 22). and osteoporosis (5. 40–42). both inside and outside the lungs. A very recent investigation therefore. therefore. a better understanding of the mechanisms of lung stable COPD (and in many other chronic diseases. Finally. it is worth noting the as compared with 12 control subjects. First. ECOPD ⫽ exacerbation of COPD. HRQL ⫽ health-related quality of life. the normal aging process is also associated with TABLE 1. two other considerations need to be taken into ac- count. and their relationship with the pathogenesis of COPD. and CD34⫹ cell counts observation by Casanova and colleagues that lung hyperinflation correlated with exercise capacity and severity of airflow obstruc- influences prognosis in COPD very significantly (28). All in Facts Low-grade systemic inflammation occurs in patients with clinically all. Rabinovitch actually raised the possibility that the pathogenesis of COPD may and colleagues have shown that. Chronic obstructive pulmonary disease (COPD) can be considered to have several domains. function (39). has not been systematically studied. in turn. this finding may also systemic inflammation increases after muscular exercise in pa- contribute to explaining systemic inflammation in these patients. showed that circulating inflammation in COPD. This action is. of a pharmacologically induced reduction of systemic inflammation in COPD is unproven. include an autoimmune component (23). another potential mechanism contributing to systemic by Palange and colleagues. SYSTEMIC INFLAMMATION IN low-grade systemic inflammation (16. with lung function values within the normal range (FEV1 values Steroid therapy (both inhaled and oral) decreases systemic above 80% predicted). if this were the hemopoietic progenitors (CD34⫹ cells) were significantly re- case. skeletal muscle dysfunc- tion. the release of which is known to ten leads to increased work of breathing and lung hyperinflation be stimulated by smoking and air pollution (30–32). such as mortality or of the majority (if not all) of the systemic effects of COPD health status. tients with COPD (29). an inverse linear relationship exists be- inflammatory markers in patients with stable COPD. tion (33). 20.

Chronic obstructive pulmonary dis- Other less well recognized systemic effects of COPD include a ease: molecular and cellular mechanisms. Fletcher CM. particularly TNF-␣.38:172–176. The BODE their potential effects on systemic (and pulmonary) inflammation (body mass index. on survival of the combination of salmeterol and fluticasone 11.1: of these cardiovascular abnormalities (20). Fahy B. in absolute terms. The origin of the latter is unclear (48). Second. CONCLUSIONS more. Utokaparch S. health status) remain to be demonstrated. and facilitate the apy (both oral and inhaled). Wouters EF. persistent. Therefore. ment with inhaled fluticasone (or oral prednisolone) reduced Calverley P. Enhanced neutrophil response in chronic obstructive tion in COPD Health) has explored the potential beneficial effect pulmonary disease. Noguera A. propionate (vs. Buzatu L. as recently shown to occur in patients with avenue to improve the therapy and care of patients with this COPD and low body weight (50). The potential effects of this observa- degradation of myosin heavy chains through the ubiquitin– tion on clinically relevant outcomes in these patients (e. Am J Respir Crit Care Med 2000. mor- proteasome complex (49). reach the predetermined level of statistical significance (p ⬍ 12. For instance. phodiesterase 4 inhibitors (58. Agusti AG. Heard BE. Systemic oxidative receiving the combination of salmeterol and fluticasone propio. The nature inflammation described above may also contribute to these disor. It has been recently recog. nary disease. Am J Respir reduced by 32% in those receiving low doses of inhaled steroids Crit Care Med 1998. Elliott WM. Iglesias J. 59). such as tion) whose effects on this particular domain of the disease have FEV1 or PaO2 (45). Anzueto A. (56). 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