Background
Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Long-term smoking causes airway inflammation characterized by neutrophil, macrophage, and activated T lymphocyte infiltration and by increased cytokine concentrations such as tumor necrosis factor-alpha (TNF-α), interleukins (IL)-6 and IL-8 [
1‐
4]. Although nearly all smokers show some evidence of lung and systemic cellular and/or humoral inflammation, only a few will suffer an amplified response and develop COPD [
5,
6].
Several studies have shown systemic inflammation in COPD patients with increased neutrophil, macrophage, and T-lymphocyte numbers and high concentrations of inflammatory mediators in peripheral blood (C-reactive protein (CRP), IL-6, IL-8 and TNF-α) [
7‐
12]. TNF-α, a powerful pro-inflammatory cytokine primarily produced by activated macrophages, is thought to play a critical role in the pathogenesis of COPD by promoting and maintaining the expression and release of various proinflammatory mediators which lead to tissue damage and remodeling [
13,
14].
Very little is known about the mechanism of increased TNF-α concentration in the plasma of COPD patients and its relationship with disease severity and active smoking has not been established [
9,
15]. Evaluation of soluble receptors, an indirect marker of proinflammatory state related to systemic TNF-α, showed no influence of smoking on systemic inflammation in small sample of COPD patients [
16]. However, in a study with the aim to examine levels of inflammatory markers in COPD and asthma patients, the influence of smoking on TNF-α serum concentration was identified only in the subgroup of COPD patients [
12]. We hypothesed that active smoking may be associated with more severe systemic inflammation in COPD patients. In order to test our hypothesis, we analyzed concentrations of TNF-α, IL-6, IL-8 and CRP in the peripheral blood of current smoker and ex-smoker COPD patients, with a wide range of airway, current smoker and never-smoker controls.
Discussion
This study aimed to evaluate the relationship between systemic inflammation and smoking status in COPD patients. The main finding was that current smokers presented significantly higher plasma levels of TNF-α compared to no-smokers. These results suggest that smoking may be associated with higher TNF-α mediated systemic inflammation in COPD patients who are current smokers. We also reinforce previous findings that patients with COPD, regardless of smoking status, present evidence of systemic inflammation when compared to control subjects.
We could not identified studies designed to assess the influence of active smoking on plasma TNF-α concentration in COPD patients. Higashimoto et al. showed increased levels of serum TNF-α, IL-6 and tissue inhibitors of metalloproteinase-1 in asthma and COPD patients when compared to control subjects. In the subgroups analysis, in partial agreement with our findings, they showed increased levels of TNF-α in current smoker with COPD when compared to ex-smoker COPD patients; however, they failed to show higher levels of TNF-α in current smoker control subjects when compared to non-current smoker control subjects [
12]. Vernooy et al. compared local and systemic inflammation in a small sample of COPD patients (ex-smokers = 6; current smokers = 12) and did not show influence of smoking on plasma concentration of soluble TNF receptors (sTNF-R55 and sTNF-R75) [
16]. Although the TNF receptors are considered to be markers of a proinflammatory state inducible by cytokines such as TNF-α, they present different biological functions [
24,
25]. In summary, our results bring new evidence related to the influence of active smoking on TNF-α plasma concentration in control subjects and COPD patients.
There is consensus about the presence of small airway and lung parenchyma inflammation in smokers and COPD patients [
3,
4,
16,
26‐
28]. Local inflammation is characterized by increased numbers of inflammatory cells, such as neutrophils, lymphocytes, and macrophages and higher TNF-α and IL-8 concentrations than healthy controls [
1,
3,
4,
26,
27,
29‐
32]. However, it is unclear whether established inflammation in smokers returns to normal after smoking cessation [
2,
33]. In a recent study, Gamble et al. 2007 compared bronchial biopsies of COPD current smokers and COPD ex-smokers and did not find any differences in cell counts or inflammatory markers (CD8+, CD4+, CD 68+, or TNF-α) between groups [
2]. In another study, neutrophil and lymphocyte numbers, and IL-8 concentration in the sputum of COPD patients increased one year after smoking cessation [
33].
Smoking cessation is the only management measure associated with reduced FEV
1 decline in COPD patients [
5,
17]; however, to date, no reduction in airway inflammation has been demonstrated when ex-smokers are compared to current smokers [
2,
33]. We speculate that the association of smoking with systemic TNF-α concentrations observed in this study may partially explain some of the benefit associated with smoking cessation [
17,
34,
35].
Our results showed higher serum CRP and IL-6 levels in COPD patients than in never-smoker and current smoker controls. Several previous studies have also shown higher serum CRP levels in COPD patients than in no-smoking controls and current smokers [
8,
11,
36]. Higher CRP concentration has been associated with airway obstruction severity, increased resting energy expenditure, and impaired exercise capacity and quality of life in COPD patients [
15,
37]. Although there is little data regarding IL-6 concentration in COPD patients [
8,
9], in agreement with our findings elevated serum IL-6 levels have been shown in COPD patients compared to no-smoker controls [
15,
36,
38].
No influence of airway obstruction severity and use of LTOT on systemic inflammation in COPD patients was observed in our study. This result is in contrast with findings of a recent report showing higher serum TNF-α levels in COPD patients with FEV
1 < 30% in comparison with mild-moderate COPD patients; however, the comparison between groups was not adjusted for smoking status of the patients [
40]. In agreement with previous findings no difference in inflammatory markers was also shown when COPD patients with and without FFM depletion were compared [
39,
40]. In addition, we did not show influence of inhaled corticosteroids on systemic inflammation in COPD patients. However, when we classified the COPD patients according GOLD classes, use of LTOT or inhaled corticosteroids we had few patients to compare between groups and poor power to detect potential differences.
There were other limitations to this study. Firstly, the analyses were performed using cross sectional data and therefore valid inferences regarding causal pathways cannot be drawn. Secondly, we did not analyze local inflammation and some data suggest that local and systemic inflammation can be regulated differently [
16].
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
The authors' responsibilities were as follow. SET: performed selection and the medical assessment of the individuals, statistical analysis and interpret the data and draft the final manuscript; NRGP: performed the medical assessment; AYOA: conducted the laboratory analysis; CRC: laboratory analysis; IG: had overall responsibility for the study, designed the research, analyzed and interpret the data, and wrote the final manuscript. All the authors contributed to the revision of the manuscript.