CHEST

Systemic Effects of Smoking*

Special Feature

Dilyara G. Yanbaeva, PhD; Mieke A. Dentener, PhD; Eva C. Creutzberg, PhD; Geertjan Wesseling, MD, PhD; and Emiel F. M. Wouters, MD, PhD, FCCP

Smoking is one of the major lifestyle factors influencing the health of human beings. Life-long cigarette smokers have a higher prevalence of common diseases such as atherosclerosis and COPD with significant systemic impact. The present review evaluates current knowledge concerning possible pathways through which cigarette smoking can affect human health, with special focus on extrapulmonary effects. Long-term smoke exposure can result in systemic oxidants-antioxidants imbalance as reflected by increased products of lipid peroxidation and depleted levels of antioxidants like vitamins A and C in plasma of smokers. A low-grade systemic inflammatory response is evident in smokers as confirmed by numerous population-based studies: elevated levels of C-reactive protein (CRP), fibrinogen, and interleukin-6, as well as increased counts of WBC have been reported. Furthermore, rheologic, coagulation and endothelial function markers like hematocrit, blood and/or plasma viscosity, fibrin d-dimer, circulating adhesion molecules (intracellular adhesion molecule-1, selectins), tissue plasminogen activator antigen, and plasminogen activator inhibitor type I are altered in chronic cigarette smokers. Although most of smoking-induced changes are reversible after quitting, some inflammatory mediators like CRP are still significantly raised in ex-smokers up to 10 to 20 years after quitting, suggesting ongoing low-grade inflammatory response persisting in former smokers. New longitudinal epidemiologic and genetic studies are required to evaluate the role of smoking itself and possible gene/environment interplay in initiation and development of smoking-induced common diseases affecting humans. (CHEST 2007; 131:15571566)
Key words: endothelial dysfunction; hemostasis; smoking; systemic inflammation; systemic oxidative stress Abbreviations: APP acute-phase protein; CRP C-reactive protein; Cys cysteine; CySS oxidized cysteine; GSH glutathione; ICAM intracellular adhesion molecule; IL interleukin; LDL low-density lipoprotein; NHANES National Health and Nutrition Examination Survey; NO nitric oxide; PAI plasminogen activator inhibitor; PGF2 prostaglandin F2; PMN polymorphonuclear neutrophil; ROS reactive oxygen species; TBARS thiobarbituric acid-reactive substances; TEAC Trolox-equivalent antioxidant capacity; TNF tumor necrosis factor; t-PA tissue plasminogen activator

of human beings for 4 centuries. Smoking is now increasing rapidly throughout the developing world and is one of the biggest threats to current and future world health.1 Furthermore, while the prevalence of tobacco use has declined among men in some highincome countries, it is still increasing among young people and women.2 Cigarette smoking is the most common type of tobacco use. In average, to date
*From the Department of Respiratory Medicine (Drs. Yanbaeva, Dentener, Wesseling, and Wouters), University Hospital Maastricht/Maastricht University, Maastricht, the Netherlands; and CIRO Horn (Dr. Creutzberg), Haelen, the Netherlands. Funding was provided by the European Respiratory Society (fellowship No. 161). The authors have no conflicts of interest to disclose.
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smoking is one of the most potent and T obacco prevalent addictive habits, influencing behavior

47.5% of men and 10.3% of women are current smokers. Tobacco continues to be the second major cause of death in the world. By 2030, if current trends continue, smoking will kill 9 million people annually.3 Tobacco smoking affects multiple organ systems resulting in numerous so-called tobacco-related diseases. The well-known health risks in tobacco smokManuscript received September 1, 2006; revision accepted October 16, 2006. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Emiel F. M. Wouters, MD, PhD, FCCP, Department of Respiratory Medicine, University Hospital Maastricht/Maastricht University, PO Box 580, 6202 AZ Maastricht, the Netherlands; e-mail: e.wouters@lung.azm.nl DOI: 10.1378/chest.06-2179
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ing pertain to diseases of the respiratory tract such as COPD and cancer, particularly lung cancer and cancers of the larynx and tongue.4,5 While the adverse effects of cigarette smoke on lung health are well established, it is becoming more evident that smoke has an important extrapulmonary toxicity. Injury in the lung, primary target of inhaled smoke, can be explained by the direct chemical exposure to cigarette smoke, but effects causing chronic diseases in other organ systems are likely to be the result of indirect consequences of the exposure. However, despite the overwhelming amount of studies demonstrating the relationship of smoking with numerous widespread systemic diseases such as atherosclerosis and COPD, the precise mechanisms how smoke potentiates its systemic effects need to be clarified. In a article by van der Vaart et al,6 the local and systemic effects of acute smoke exposure on oxidative stress and inflammatory mediators were reviewed. In the present article, we aim to review systemic effects of long-term smoking exposure in humans. In particular, traditional markers of generalized response to smoking such as systemic oxidative stress and systemic inflammation are reviewed. In addition, in view of findings suggesting the relationship between some of these markers and atherosclerosis, aspects of hemostatic and coagulation systems are discussed in relation to tobacco smoking. Systemic Oxidative Stress in Smokers Cigarette smoke contains approximately 1017 oxidant molecules per puff.7 This oxidative stress can be

registered in several different ways, either by direct measurements of the oxidative burden (reactive oxygen species [ROS] production by peripheral blood cells) or by the effects of oxidative stress on target molecules (lipid peroxidation products and oxidized proteins), or as the responses to the oxidative stress (antioxidant capacity of plasma)8 [Table 1]. Only a few studies9 11 have used ROS production by blood cells extracted from the circulation of smokers. Perhaps more important than the presence of oxidative stress are the effects of this oxidative stress on a variety of vital target molecules. Numerous markers for oxidative damage have been proposed, including oxidation and nitration of proteins. For example, nitration of tyrosine residues of proteins leads to the production of 3-nitrotyrosine, which may be considered as a marker of nitric oxide (NO)-dependent oxidative damage. Indeed, NOmediated and peroxynitrite-mediated formation of 3-nitrotyrosine is elevated in plasma and platelets of chronic smokers.12,13 Furthermore, Pignatelli and coworkers14 reported significantly higher levels of nitrated and oxidized fibrinogen, transferrin, plasminogen, and ceruloplasmin in smokers than in nonsmokers. Free radicals from cigarette smoke also cause peroxidation of the polyunsaturated fatty acids of cell membranes that amplify oxidative stress during smoking. The F2-isoprostanes, prostaglandin-like compounds, are products of free radical-catalyzed lipid peroxidation of arachidonic acid. Several studies1517 have reported an increased level of isoprostane 8-iso-prostaglandin F2 (PGF2) formation in smokers. It has been found that urinary 8-epi-

Table 1Markers of Increased Oxidative Stress in Smokers

Markers Direct measurements of oxidative burden Release of ROS from circulating phagocytes Release of superoxide from peripheral blood neutrophils ROS production by endothelial progenitor cells Intraplatelet peroxynitrite Effects of oxidative stress on target molecules Oxidized and nitrated proteins Oxidized LDL Lipid peroxidation products F2 isoprostanes Malondialdehyde TBARS Antioxidants Reduced TEAC Reduced vitamin C Reduced -carotene Decreased GSH and oxidized GSH/GSSG couple Decreased cysteine and oxidized Cys/CySS couple *GSSG oxidized GSH. 1558
Special Feature

Source van Antwerpen et al9 Ludwig and Hoidal10 Michaud et al11 Takajo et al13 Petruzzelli et al12; Pignatelli et al14 Yamaguchi et al75 Morrow et al15; Reilly et al16; Helmersson et al17 Rumley et al20; Smith et al21 Orhan et al22; Ochs-Balcom et al23 Petruzelli et al12; Rahman et al24 Wei et al25; Lykkesfeldt et al26; Schectman et al27; Marangon et al28 Wei et al25; Marangon et al28 Moriarty et al31 Moriarty et al31

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PGF2 excretion was significantly increased in longterm current and former smokers compared with the age- and sex-matched nonsmoking control subjects.17 In addition, a dose-response relationship was observed between the number of cigarettes smoked and both urinary cotinine and urinary 8-epiPGF2.16 The biological role of isoprostanes is not clear yet. It has been shown that F2 isoprostane levels are significantly increased in atherosclerotic plaques compared with normal vascular tissue, suggesting that these compounds may play a role in the pathogenesis of the disease.18 The observation of elevated levels urinary 8-iso-PGF2 in patients with coronary heart disease strengthens this hypothesis.19 Increased levels of malondialdehyde, which are degradation product of lipid peroxides, have been found associated with current smoking status in population-based studies.20,21 Similarly, higher levels of thiobarbituric acid reactive substances (TBARS) have been found in smokers compared to nonsmokers.22 New evidence for the association of systemic oxidative stress with pulmonary function comes from population-based study23 conducted in the New York State (n 2,346). Ochs-Balcom and coworkers23 showed an inverse association of TBARS with percentage of predicted FEV1 and percentage of predicted FVC in men but not in women, suggesting gender differences in the relation of oxidative stress to pulmonary function. Exposure to oxidant chemicals in smoke is associated with depletion of endogenous levels of antioxidants in the systemic compartment. Numerous studies have reported that smoking results in low antioxidant concentrations in plasma. The total plasma Trolox-equivalent antioxidant capacity (TEAC) was significantly lower in smokers than in nonsmokers.12,24 However, no relationship was found between spirometric end points (FEV1 or FEV1/FVC) and plasma levels of TEAC in healthy smokers.24 The third National Health and Nutrition Examination Survey (NHANES) and other studies17,25 reported that smokers have significantly lower serum levels of vitamin C, -carotene, -carotene, -cryptoxanthin, melatonin, -tocopherol, and lutein/zeaxanthin. However, diet could also influence levels of antioxidants, and independent effects of smoking have only been shown on plasma levels of vitamin C and -carotene.2527 In addition, an inverse relationship between cigarette consumption and plasma levels of vitamin C and -carotene corrected for habitual dietary intake has been found.27,28 Such decreases in plasma antioxidants can disturb the normal oxidative-antioxidative balance in smokers. Remarkably, numerous studies29,30 have shown that antioxidant supplements provide at best only a limited protection.
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Glutathione (GSH) is a major antioxidant used to eliminate peroxides to nontoxic hydroxyl fatty acids and/or water and to maintain vitamins C and E in their reduced and functional forms. Cigarette smoke contains ROS that oxidize GSH to disulfide form (oxidized glutathione), resulting in decreased plasma GSH levels.31 Similar processes are responsible for an even more extensive oxidation of the cysteine (Cys)/oxidized cysteine (CySS) redox couple and reduced Cys levels showing that smoking has additional effects on sulfur amino acid metabolism. Taking into account that cysteine is the critical molecule for normal GSH synthesis, this observation suggests that evaluation of the Cys/CySS redox couple may be a new sensitive marker of oxidative stress in smokers. In summary, the oxidative burden in the systemic compartment of smokers is mainly characterized by elevated levels of peroxides (isoprostanes and TBARS) and decreased levels of traditional plasma antioxidants (vitamins A and C), whereas GSHrelated antioxidants are affected to a lesser extent. Systemic Inflammation in Smokers Activation and release of inflammatory cells into the circulation, and an increase in circulating inflammatory mediators such as acute phase proteins and proinflammatory cytokines, characterize the systemic inflammation. Circulating Inflammatory Cells The systemic inflammatory response is characterized by the stimulation of the hematopoietic system, specifically the bone marrow resulting in the release of leukocytes and platelets into the circulation. Numerous studies3234 have shown that long-term cigarette smoking increases total WBC counts, mainly due to an increase in polymorphonuclear neutrophil (PMN) counts in the circulation of smokers. A large population-based study35 of 6,902 men and 8,405 women performed in Great Britain revealed that current smoking had a stronger effect on mean total WBC than cumulative exposure as measured by pack-years. However, other authors36 reported a dose-response relationship with pack-years smoked and WBC. This inflammatory response in smokers is characterized not only by an increase in the number of circulating cells but also by phenotypic changes. Indeed, neutrophilia related to chronic smoking was associated with an increase in numbers of circulating band cells, a hallmark of early bone marrow release of PMNs, and an increase in L-selectin expression, a cell adhesion molecule, constitutively highly expressed on maturating PMNs.32 L-selectin could initiate the adherence of PMNs to endothelium and
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has been shown to be important for the recruitment of PMNs to inflamed tissue.37 In addition, PMNs from smokers have higher levels of myeloperoxidase, an enzyme produced at the early stages of PMN proliferation.32,38 Overall, these findings suggest that smoking causes bone marrow stimulation and the release of younger cells from bone marrow. van Eeden and colleagues39 speculated that circulating cytokines like interleukin (IL)-1 and IL-6 may be responsible for bone marrow stimulation induced by lung inflammation. Indeed, the same authors39 have shown that IL-6 cytokine also potently stimulates the bone marrow to release leukocytes and platelets. Reports40 have underlined the role of T-lymphocytes as a potentially important factor in the systemic inflammatory process associated with smoking-induced diseases like COPD. Some studies41 43 have reported increased total numbers of circulating Tlymphocytes in humans exposed to cigarette smoke. Studies investigating the influence of smoking on different lymphocyte subsets have produced conflicting data. In heavy smokers, a decrease in CD4 cells (helper T-cells) and increase in CD8 cells (suppressor T-cells) with subsequent decrease in CD4/CD8 ratio have been reported.41 In contrast, Tollerud and colleagues44 found that cigarette smoke was associated with an increase in leukocyte count with a selective increase in CD4 cells, resulting in significant increase in the CD4/CD8 ratio in healthy white subjects. Other studies45,46 support these findings. Further analysis has shown that smokers have higher absolute numbers of peripheral blood memory T-cells and naive T-cells as compared with nonsmokers.43,46 Analysis of T-cell subpopulations in heavy and light-to-moderate smokers revealed that numbers of memory T-cells were significantly correlated with daily cigarette consumption.42 Overall, the results of these studies suggest that smoking may exert a selective influence on subsets of T-cells. Therefore, taking into account the role of lymphocytes in a number of inflammatory conditions associated with smoking, additional studies would be relevant to better understand the response of circulating lymphocytes to cigarette smoke. Inflammatory Mediators in Peripheral Blood of Smokers Activated inflammatory cells produce a great variety of inflammatory mediators in response to cigarette smoke, first of all, acute-phase proteins (APPs) and cytokines. Conditions that commonly lead to substantial changes in the plasma concentrations of APPs and cytokines include infection, trauma, surgery, burns, tissue infarction, various immunologi1560

cally mediated inflammatory conditions, and cancer. In recent years, these inflammatory mediators have been studied as potential markers of subtle and persistent systemic alterations. Many studies have reported changes in levels of inflammatory mediators not only in the lungs but also in the circulation of healthy smokers. Several studies47 49 have reported strong associations between cigarette smoking and different APPs such as C-reactive protein (CRP) and fibrinogen (Table 2). For example, the large-scale, population-based NHANES III study revealed a strong independent dose-response relationship between cigarette smoking and elevated levels of CRP and fibrinogen.50 This analysis was based on 4,187 current smokers, 4,791 former smokers, and 8,375 never-smokers with smoking status based on cotinine levels and was adjusted for different confounders. These findings are in accordance with results of two other studies47,51 of APPs in smokers. Data from several prospective studies support the hypothesis that CRP, and fibrinogen levels in particular, are primarily related to lifetime exposure of smoking (pack-years) and not to years since quitting smoking. In the MONICA Augsberg Study49 and the Speedwell Study,52 CRP was still significantly raised 10 years after smoking cessation. Data from the British Regional Heart Study33 indicate that smoking cessation results in a rapid reduction in hemostatic and inflammatory markers, but CRP levels remained significantly raised after 10 to 19 years and did not revert to that of never-smokers until after 20 years; for CRP, the reduction was dependent on the number of cigarettes smoked. A dose-effect relationship between the number of cigarette smoked per day and plasma fibrinogen concentrations have also been reported.53,54 Interestingly, the NHANES III study (of 7,685 participants) confirmed that cigarette smoking contributes significantly to low-grade systemic inflammation and, furthermore, shows that reduced lung function by itself is also associated with increased odds of elevated CRP, fibrinogen, and blood leukocytes; but having both risk factors suggests an additive effect contributing to higher levels of systemic inflammation in susceptible individuals.55 Furthermore, a large-scale population-based study56 confirmed that low FVC was associated with higher plasma levels of fibrinogen, 1-antitrypsin, haptoglobin, ceruloplasmin, and 1-acid glycoprotein, and with increased incidences of myocardial infarction and cardiovascular death. However, the nature of the observed associations between decreased lung function and APPs induction is still unclear. The role of other APPs is less extensively investigated. It has been reported that concentrations of 1-acid glycoprotein, ceruloplasmin, and 2-macroSpecial Feature

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Table 2Baseline Information on Complex Studies of Smoking Effect on Levels of Inflammatory, Endothelial Dysfunction and Hemostatic Markers*
Study Groups Self-reported and validated using hsCRP1; WBC1; albumin2 carboxyhemoglobin measurements Smoking Status Determination Inflammatory Markers Markers of Hemostasis and Endothelial Dysfunction Fibrinogen1; blood viscosity1; plasma viscosity1; hematocrit1; fibrin-d-dimer1; tPA antigen1

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Source

Study Design

Wannamethee et al33 British Regional Heart Study; population based; crosssectional

Helmersson et al17 Self-reported

Uppsala longitudinal study of adult men; population based; cross-sectional Self-reported and validated by blood carboxyhemoglobin

IL-61; PGF21; CRP %; SAA %

N/D

Downloaded From: http://journal.publications.chestnet.org/ on 04/08/2014 Fibrinogen 1 1-acid glycoprotein1; 1-antitrypsin1; haptoglobin1; ceruloplasmin1 2,920 men aged 60 to 79 yr with no history of myocardial infarction, angina, stroke, or diabetes; 837 never-smokers; 1,503 ex-smokers; 391 current smokers 642 men at 77 yr; no history of diabetes; 55 current smokers; 391 ex-smokers; 196 neversmokers 6,075 men aged 28 to 61 yr with no history of myocardial infarction, cancer, stroke; 1,489 never-smokers; 1,685 former smokers; 2,901 current smokers 2,305 men and 2,211 women aged 2574 yr Self-reported WBC1; hsCRP1 (men only); albumin % CRP1; homocysteine1 Self-reported and confirmed by serum cotinine levels Fibrinogen1 Fibrinogen1 (men only); plasma viscosity1 (men only) Self-reported hsCRP1; IL-61 Soluble ICAM-11; E-selectin1 Self-reported hsCRP1 Fibrin d-dimer1 Self-reported WBC1 Self-reported and confirmed by cotinine level WBC1; IL-61 Self-reported and confirmed by nicotine and cotinine levels N/D Fibrinogen1; plasma viscosity1; tPA antigen1; PAI-I activity1; fibrin d-dimer1 Fibrinogen1; hematocrit1; blood viscosity1 (only in women); red cell aggregations1 (only in women) Fibrinogen1; tPA activity %; PAI-I activity %

Lind et al58

Malm Preventive Project; population based, crosssectional

Frohlich et al49

Bazzano et al50

MONICA Augsburg Survey; population based; crosssectional NHANES III; population based; cross-sectional

Bermudez et al51

Lowe et al52

Yarnell et al34

Woodward et al67

CHEST / 131 / 5 / MAY, 2007

Eliasson et al83

4,187 current smokers, 4,791 former smokers, and 8,375 never-smokers 18 yr old of both genders Womens Health Study; 340 apparently healthy women; population based; cross28% current smokers; 28% exsectional smokers; 43% never-smokers Speedwell Study; community 1,690 men aged 49 to 67 yr; 527 based; cross-sectional current smokers; 734 ex-smokers; 265 never-smokers Caerphilly Study; community2,188 men aged 4955 yr; 726 based; cross-sectional current smokers; 819 ex-smokers; 388 never-smokers Third MONICA Survey in North 753 men and 821 women (IL-6 Glasgow; community based; measured as in 196 men and cross-sectional 221 women) aged 2574 yr; 47% current smokers; 26% exsmokers; 27% never-smokers Northern Sweden MONICA 604 men and 662 women 25 to Study; community based; cross64 yr old; 317 current smokers; sectional 238 ex-smokers; 581 neversmokers

*1 increased levels; % no differences found; 2 decreased levels; N/D not determined; SAA serum amyloid A; hsCRP high-sensitivity CRP.

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globulin are increased in the plasma of smokers as compared to nonsmokers by 39%, 28%, and 12%, respectively.57 Furthermore, the large prospective Malmo Preventive Project study58 with 18-year follow-up revealed that all measured APP levels (1acid glycoprotein, 1-antitrypsin, haptoglobin, fibrinogen, and ceruloplasmin) increased significantly with increasing cigarette consumption in healthy adult men, independent of other known cardiovascular risk factors. While these blood changes in smokers may simply be markers of smoking-induced tissue damage, it is also possible that high APP levels may have a direct effect on the promotion of cardiovascular diseases. Increased levels of CRP and fibrinogen have been associated with risk for subsequent cardiovascular events in several large prospective studies.59,60 Another study61 showed that CRP might be not only a biomarker of different cardiovascular diseases but may have direct effects on the pathogenesis of atherosclerosis and endothelial dysfunction. For example, CRP stimulates IL-6 and endothelin-1 production and upregulates adhesion molecules, promoting a cascade of events that can lead to clot formation and even promotes atherosclerosis in apolipoprotein E-deficient mice.62 However, the exact role of CRP in development of cardiovascular diseases is still under discussion.63 Some causative speculations are also discussed concerning the role of fibrinogen in atherogenesis. Probably, fibrinogen may promote cardiovascular diseases through effects on blood viscosity, platelet aggregation, and fibrin formation.64 In conclusion, these data clearly indicate that CRP and fibrinogen levels are markedly increased in smokers, possibly contributing to the proinflammatory and proatherogenic effects of chronic smoking exposure. Raised levels of plasma APPs may partly reflect elevations of inflammatory cytokines such as IL-6 and tumor necrosis factor (TNF)-, which are major inductors of APP and, therefore, regulators of systemic inflammatory response. Similarly to APPs, increased levels of proinflammatory cytokines like TNF- and IL-6 have been shown to be a risk factor and predictor for myocardial infarction, coronary heart disease, and stroke.65,66 Several studies17,51 have shown increased levels of TNF- and IL-6 in smokers. The population-based MONICA III North Glasgow study67 revealed that mean IL-6 levels were substantially raised in current smokers (by approximately 46% compared to neversmokers), while ex-smokers had similar levels of IL-6 to never-smokers. Furthermore, a significant correlation was found between IL-6 and fibrinogen, and IL-6 and WBC counts, reflecting the major role of IL-6 as inducer of fibrinogen. The Womens Health
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Study51 from the United States showed a trend toward increasing IL-6 levels across never, former, and current smoking women. Further, Wirtz and colleagues68 reported a trend for higher baseline TNF- levels among healthy smokers. However, a study conducted by Gander and coworkers69 failed to show significant effects of smoking on TNF- plasma levels. Taken as a whole, these data suggest that there are limited data yet on circulating concentrations of IL-6 and TNF- in healthy smokers. Taking into account the possible predictive effects of major cytokines for cardiovascular diseases, it would be worth to address large-scale population-based studies to investigate potential relationship of cytokine plasma levels with traditional cardiovascular risk factors including smoking. Smoking and Markers of Endothelial Dysfunction, Coagulation, and Hemostasis The biological mechanism linking smoking and atherogenesis, the process leading to cardiovascular diseases, is complex and not fully understood. Besides inflammation, proposed potential mechanisms by which smoking increases the risk of cardiovascular pathology include several other pathways: vascular endothelial dysfunction, systemic hemostatic and coagulation disturbances, and lipid abnormalities. Many of these indexes including fibrinogen (marker of coagulation), fibrin d-dimer (a marker of crosslinked fibrin turnover), and tissue plasminogen activator antigen (t-PA, marker of endothelial dysfunction) have been identified as independent predictors of subsequent cardiovascular events in prospective studies70,71 conducted in healthy subjects. In addition, platelet hyperaggregation and activation, plasma viscosity, and plasminogen activator inhibitor (PAI) type I (marker of impaired fibrinolysis) levels have also been associated with cardiovascular morbidity and mortality in prospective studies.72,73 The effect of smoking on these variables has also been investigated in several cross-sectional studies, as will be discussed below (Table 2). Vascular Endothelial Dysfunction Endothelial dysfunction is mainly caused by diminished production or availability of NO.61 It has been demonstrated that the serum concentration of nitrate and nitrite, metabolic end-products of NO, is significantly decreased in smokers relative to that in nonsmokers.74 In cigarette smokers, low-density lipoprotein (LDL) is more prone to oxidation due to higher level of ROS and reactive nitrogen species.75 Oxidatively modified LDL limits the bioactivity of
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endothelium-derived NO; and, in turn, the loss of NO bioactivity is associated with increased inflammatory cell entry into the arterial wall.76 Oxidatively modified LDL is taken up by macrophage scavenger receptors, promoting cholesterol ester accumulation and foam cell formation. Most recently, upregulation of the CD40/CD40L dyad and increased platelet/monocyte aggregation have been proposed as potential contributors to the atherothrombotic consequences of smoking.77 CD40-CD40 ligand couples, members of TNF family, are coexpressed by all of the major cellular players in atherosclerosis. In particular, smokers appeared to have elevated plasma levels of soluble CD40 and increased surface expression of CD40 on monocytes together with increased CD40 ligand on platelets. Furthermore, plasma cotinine concentrations correlated with CD40 and CD40 ligand expression, and with rate of platelet-monocyte aggregations. A recent study suggests that oxidatively modified LDL may play the role of initial trigger for CD40/CD40L expression in human endothelial and smooth-muscle cells.78 Dysfunctional endothelial cells lose their critical physiologic property of nonadherence to circulating immune effector cells (monocytes, macrophages, T-lymphocytes, platelets). Some adhesion molecules are known to be elevated in plasma of smokers. Several groups reported significantly higher levels of soluble intracellular adhesion molecule (ICAM)-1 and P-selectin and E-selectin in current smokers than in nonsmokers among healthy women.51,79 A dose-dependent relationship was observed between plasma ICAM-1 concentration and daily cigarette consumption, plasma cotinine level, and exhaled carbon monoxide level.80 Generally, impaired endothelial function caused by cigarette smoking may lead to increased susceptibility of vasculature to atheroma formation and can be considered as an early feature of atherogenesis in humans.81 Hemostatic and Coagulation Markers There is increasing evidence that blood levels of rheologic variables are associated with subsequent cardiovascular events.70 These indexes include whole-blood viscosity and its main determinants: hematocrit and plasma viscosity, principally composed by plasma fibrinogen and lipoproteins.67 Several studies33,67 revealed that current smokers have increased blood viscosity, associated with increased hematocrit or/and plasma viscosity resulting in a procoagulant condition. Increased plasma viscosity may be caused by higher levels of fibrinogen reported in plasma of smokers, as have been discussed before in this review.
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Furthermore, elevated levels of markers of fibrinolysis have been reported in healthy smokers. t-PA, the main fibrinolytic activator, converting plasminogen to plasmin is synthesized by endothelial cells. In vivo studies82 have demonstrated major impairment of t-PA release from the vascular endothelium of smokers. The primary inhibitor of fibrinolysis is PAI-I, which inhibits plasminogen activation by binding with t-PA to form the PAI/t-PA complexes. Current smoking is associated with a significant increase in t-PA antigen, which represents mainly the circulating PAI/t-PA complexes and indicates impaired fibrinolytic activity in smokers.33,34 Supporting previous findings,34,83 plasma PAI-1 antigen and/or activity is significantly higher in smokers than in nonsmokers and is correlated with pack-years smoked. Plasmin promotes the degradation of fibrin within the thrombus, disintegrating clots, and hence maintains vascular patency. Fibrin d-dimer is a degradation product of cross-linked fibrin that is related to cardiovascular diseases risk.52 As been reported, smoking is positively associated with fibrin d-dimer.33,84 The increased d-dimer in smokers probably reflects increased coagulation activation because this antigen is present in several degradation products from the cleavage of cross-linked fibrin by plasmin.85 Taking into account possible adverse effects of abnormal fibrinolysis and excess coagulation on vascular health, further studies are essential to evaluate the impairment of the fibrinolytic system in smokers. Overall, data presented in this review suggest that smoking is one of the major lifestyle factors influencing levels of a number of novel inflammatory, coagulation, and hemostatic markers associated with common widespread diseases in population-based prospective studies. Systemic oxidative stress followed by low-grade inflammation and endothelial dysfunction caused by chronic smoking exposure could be one of real-working mechanisms that explain increased prevalence of common diseases of modern civilization like coronary heart disease, peripheral vascular disease, and COPD in smokers. However, this hypothesis has to be taken cautiously because not all smokers acquire one or more of these diseases. It clearly suggests the existence of other mechanisms influencing common disease development, and, beyond doubt, genetic susceptibility is one of them.86 Different approaches like case-control and whole-genome association studies, linkage analysis of extended pedigrees, and affected sibling pairs are used to dissect genetic component of complex traits. For genetically complex disease like cardiovascular diseases, common disease-common variant hypothesis has been put forward, which
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assumes that common disease susceptibility or resistance variants are expected to be few at each genetic locus, relatively common in the human population and enriched in the coding and regulatory sequence of genes.87 Despite the small effects of such genes individually, the magnitude of their attributable risk may be large because they are quite frequent in the population, making them of public health significance. However, there is a possibility that many rare variants, each with small contribution, underlie the susceptibility to common human disease.88 Nevertheless, it seems that complete model of complex disease initiation and progression is based on cooperation where these multiple genes are likely to operate through interactions with many environmental factors where smoking is only one but a very important variable. Conclusion The possible biological mechanisms responsible for the observed association of smoking with various diseases and global mortality are numerous and, in spite of a many attempts to find causative relationships, are still unclear. It is a great scientific task to unravel exact pathways through which smoking affects human health. Although the effects of smoking on inflammatory markers may persist for many years, a majority of the adverse health effects of smoking are reversible. Therefore, quitting smoking avoids much of the excess health-care risk associated with smoking and allows increasing life expectancy. References
1 Edwards R. The problem of tobacco smoking. BMJ 2004; 328:217219 2 Tobacco control: country profiles. Atlanta, GA: American Cancer Society, 2000 3 World health report 2002: Reducing risks, promoting healthy life. Geneva, Switzerland: World Health Organization, 2002 4 Crofton J, Bjartveit K. Smoking as a risk factor for chronic airways disease. Chest 1989; 96(3 suppl):307S312S 5 Boyle P. Cancer, cigarette smoking and premature death in Europe: a review including the Recommendations of European Cancer Experts Consensus Meeting, Helsinki, October 1996. Lung Cancer 1997; 17:1 60 6 van der Vaart H, Postma DS, Timens W, et al. Acute effects of cigarette smoke on inflammation and oxidative stress: a review. Thorax 2004; 59:713721 7 Pryor W, Stone K. Oxidants in cigarette smoke radicals, hydrogen peroxides, peroxynitrate, and peroxynitrite. Ann N Y Acad Sci 1993; 28:1227 8 MacNee W. Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005; 2:50 60 9 van Antwerpen VL, Theron AJ, Richards GA, et al. Vitamin E, pulmonary functions, and phagocyte-mediated oxidative stress in smokers and nonsmokers. Free Radic Biol Med 1995; 18:935941
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10 Ludwig PW, Hoidal JR. Alterations in leukocyte oxidative metabolism in cigarette smokers. Am Rev Respir Dis 1982; 126:977980 11 Michaud SE, Dussault S, Haddad P, et al, Circulating endothelial progenitor cells from healthy smokers exhibit impaired functional activities. Atherosclerosis 2006; 187:423 432 12 Petruzzelli S, Puntoni R, Mimotti P, et al. Plasma 3-nitrotyrosine in cigarette smokers. Am J Respir Crit Care Med 1997; 156:19021907 13 Takajo Y, Ikeda H, Takajo Y, et al. Augmented oxidative stress of platelets in chronic smokers: mechanisms of impaired platelet-derived nitric oxide bioactivity and augmented platelet aggregability. J Am Coll Cardiol 2001; 38:1320 1327 14 Pignatelli B, Li CQ, Boffetta P, et al. Nitrated and oxidized plasma proteins in smokers and lung cancer patients. Cancer Res 2001; 61:778 784 15 Morrow JD, Frei B, Longmire AW, et al. Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers: smoking as a cause of oxidative damage. N Engl J Med 1995; 332:1198 1203 16 Reilly M, Delanty S, Lawson JA, et al. Modulation of oxidant stress in vivo in chronic cigarette smokers. Circulation 1996; 94:19 25 17 Helmersson J, Larsson A, Vessby B, et al. Active smoking and a history of smoking are associated with enhanced prostaglandin F(2), interleukin-6 and F2-isoprostane formation in elderly men. Atherosclerosis 2005; 181:201207 18 Gniwotta C, Morrow JD, Roberts LJ II, et al. Prostaglandin F2-like compounds, F2-isoprostanes, are present in increased amounts in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 1997; 17:3236 3241 19 Schwedhelm E, Bartling A, Lenzen H, et al. Urinary 8-isoprostaglandin F2 as a risk marker in patients with coronary heart disease: a matched case-control study. Circulation 2004; 109:843 848 20 Rumley AG, Woodward M, Rumley A, et al. Plasma lipid peroxides: relationships to cardiovascular risk factors and prevalent cardiovascular disease. QJM 2004; 97:809 616 21 Smith FB, Lowe GD, Fowkes FG, et al. Smoking, haemostatic factors and lipid peroxides in a population case control study of peripheral arterial disease. Atherosclerosis 1993; 102:155162 22 Orhan H, Evelo CT, Sahin G. Erythrocyte antioxidant defense response against cigarette smoking in humans: the glutathione S-transferase vulnerability. J Biochem Mol Toxicol 2005; 19:226 233 23 Ochs-Balcom HM, Grant BJ, Muit P, et al. Oxidative stress and pulmonary function in the general population. Am J Epidemiol 2005; 162:11371145 24 Rahman I, Swarska E, Henry M, et al. Is there any relationship between plasma antioxidant capacity and lung function in smokers and in patients with chronic obstructive pulmonary disease? Thorax 2000; 55:189 193 25 Wei W, Kim Y, Boudreau N. Association of smoking with serum and dietary levels of antioxidants in adults: NHANES III, 1988 1994. Am J Public Health, 2001; 91:258 264 26 Lykkesfeldt J, Christen S, Wallock LM, et al. Ascorbate is depleted by smoking and repleted by moderate supplementation: a study in male smokers and nonsmokers with matched dietary antioxidant intakes. Am J Clin Nutr 2000; 71:530 536 27 Schectman G, Byrd JC, Gruchow HW. The influence of smoking on vitamin C status in adults. Am J Public Health 1989; 79:158 162 28 Marangon K, Herbeth B, Lecomte E, et al. Diet, antioxidant status, and smoking habits in French men. Am J Clin Nutr 1998; 67:231239
Special Feature

Downloaded From: http://journal.publications.chestnet.org/ on 04/08/2014

29 Fuller CJ, May MA, Martin KJ. The effect of vitamin E and vitamin C supplementation on LDL oxidizability and neutrophil respiratory burst in young smokers. J Am Coll Nutr 2000; 19:361369 30 Pellegrini MP, Newby DE, Johnston NR, et al. Vitamin C has no effect on endothelium-dependent vasomotion and acute endogenous fibrinolysis in healthy smokers. J Cardiovasc Pharmacol 2004; 44:117124 31 Moriarty SE, Shah JH, Lynn M, et al. Oxidation of glutathione and cysteine in human plasma associated with smoking. Free Radic Biol Med 2003; 35:15821588 32 van Eeden SF, Hogg JC. The response of human bone marrow to chronic cigarette smoking. Eur Respir J 2000; 15:915921 33 Wannamethee SG, Lowe GD, Shaper AG, et al. Associations between cigarette smoking, pipe/cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease. Eur Heart J 2005; 26:17651773 34 Yarnell JW, Sweetnam PM, Runley A, et al. Lifestyle and hemostatic risk factors for ischemic heart disease: the Caerphilly Study. Arterioscler Thromb Vasc Biol 2000; 20:271279 35 Smith MR, Kinmonth KL, Luben RN, et al. Smoking status and differential white cell count in men and women in the EPIC-Norfolk population. Atherosclerosis 2003; 169:331337 36 Yarnell JW, Sweetnam PM, Rogers S, et al. Some long term effects of smoking on the haemostatic system: a report from the Caerphilly and Speedwell Collaborative Surveys. J Clin Pathol 1987; 40:909 913 37 Tedder TF, Steeber DA, Chen A, et al. The selectins: vascular adhesion molecules. FASEB J 1995; 9:866 873 38 Dash S, Sen S, Behera D. High neutrophil myeloperoxidase activity in smokers [letter]. Blood 1991; 77:1619 39 van Eeden SF, Yeung A, Quinlam K, et al. Systemic response to ambient particulate matter: relevance to chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005; 2:61 67 40 Kim WD, Kim WS, Koh Y, et al. Abnormal peripheral blood T-lymphocyte subsets in a subgroup of patients with COPD. Chest 2002; 122:437 444 41 Miller LG, Goldstein G, Murphy M, et al. Reversible alterations in immunoregulatory T cells in smoking: analysis by monoclonal antibodies and flow cytometry. Chest 1982; 82: 526 529 42 Tanigawa T, Araki S, Nakata A, et al. Increase in memory (CD4CD29 and CD4CD45RO) T and naive (CD4CD45RA) T-cell subpopulations in smokers. Arch Environ Health 1998; 53:378 383 43 Hughes DA, Haslam PL, Townsend PJ, et al. Numerical and functional alterations in circulatory lymphocytes in cigarette smokers. Clin Exp Immunol 1985; 61:459 466 44 Tollerud DJ, Clark JW, Brown LM, et al. The effects of cigarette smoking on T cell subsets: a population-based survey of healthy Caucasians. Am Rev Respir Dis 1989; 139:1446 1451 45 Mili F, Flanders WJ, Boring JR, et al. The associations of race, cigarette smoking, and smoking cessation to measures of the immune system in middle-aged men. Clin Immunol Immunopathol 1991; 59:187200 46 Schaberg T, Theilacker C, Nitschke OT, et al. Lymphocyte subsets in peripheral blood and smoking habits. Lung 1997; 175:387394 47 Rohde LE, Hennekens CH, Ridker PM. Survey of C-reactive protein and cardiovascular risk factors in apparently healthy men. Am J Cardiol 1999; 84:1018 1022 48 Mendall MA, Strachan DP, Butland BK, et al. C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men. Eur Heart J 2000; 21:1584 1590
www.chestjournal.org

49 Frohlich M, Sund M, Frolich M, et al. Independent association of various smoking characteristics with markers of systemic inflammation in men: results from a representative sample of the general population (MONICA Augsburg Survey 1994/95). Eur Heart J 2003; 24:13651372 50 Bazzano LA, He J, Muntner P, et al. Relationship between cigarette smoking and novel risk factors for cardiovascular disease in the United States. Ann Intern Med 2003; 138:891 897 51 Bermudez EA, Rafai N, Buring JE, et al. Relation between markers of systemic vascular inflammation and smoking in women. Am J Cardiol 2002; 89:11171119 52 Lowe GD, Yarnell JW, Rumley A, et al. C-reactive protein, fibrin d-dimer, and incident ischemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis? Arterioscler Thromb Vasc Biol 2001; 21: 603 610 53 Kannel WB, DAgostino RB, Belanger AJ. Fibrinogen, cigarette smoking, and risk of cardiovascular disease: insights from the Framingham Study. Am Heart J 1987; 113:1006 1010 54 Heinrich J, Balleisen L, Schulte H, et al. Fibrinogen and factor VII in the prediction of coronary risk: results from the PROCAM study in healthy men. Arterioscler Thromb 1994; 14:54 59 55 Gan WQ, Man SF, Sin DD. The interactions between cigarette smoking and reduced lung function on systemic inflammation. Chest 2005; 127:558 564 56 Engstrom G, Lind P, Hedblad B, et al. Lung function and cardiovascular risk: relationship with inflammation-sensitive plasma proteins. Circulation 2002; 106:25552560 57 Tappia PS, Troughton KL, Langley-Evans SC, et al. Cigarette smoking influences cytokine production and antioxidant defences. Clin Sci (Lond) 1995; 88:485 489 58 Lind P, Engstrom G, Stavenow L, et al. Risk of myocardial infarction and stroke in smokers is related to plasma levels of inflammation-sensitive proteins. Arterioscler Thromb Vasc Biol 2004; 24:577582 59 Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2000; 321:199 204 60 Ridker PM, Haughie P. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998; 98:731733 61 Szmitko PE, Wang CH, Weisel RD, et al. New markers of inflammation and endothelial cell activation: part I. Circulation 2003; 108:19171923 62 Paul A, Ko KW, Li L, et al. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Circulation 2004; 109:647 655 63 Jialal I, Devaraj S, Venugopal SK. C-reactive protein: risk marker or mediator in atherothrombosis? Hypertension 2004; 44:6 11 64 Kamath S, Lip GY. Fibrinogen: biochemistry, epidemiology and determinants. QJM 2003; 96:711729 65 Ridker PM, Rifai N, Stampfer MJ, et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101:1767 1772 66 Cesari M, Penninx BW, Newman AB, et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation 2003; 108:23172322 67 Woodward M, Rumley A, Tunstall-Pedoe H, et al. Associations of blood rheology and interleukin-6 with cardiovascular risk factors and prevalent cardiovascular disease. Br J Haematol 1999; 104:246 257 68 Wirtz PH, von Kanel R, Kunz-Ebrecht S, et al. Enhanced
CHEST / 131 / 5 / MAY, 2007

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Downloaded From: http://journal.publications.chestnet.org/ on 04/08/2014

69

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glucocorticoid sensitivity of cytokine release from circulating leukocytes stimulated with lipopolysaccharide in healthy male smokers. Brain Behav Immun 2004; 18:536 543 Gander ML, Fischer JE, Maly FE, et al. Effect of the G-308A polymorphism of the tumor necrosis factor (TNF)- gene promoter site on plasma levels of TNF- and C-reactive protein in smokers: a cross-sectional study. BMC Cardiovasc Disord 2004; 4:17 Lowe GD, Lee AJ, Rumley A, et al. Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study. Br J Haematol 1997; 96:168 173 Koenig W, Sund M, Lowel H, et al. Association between plasma viscosity and all-cause mortality: results from the MONICA-Augsburg Cohort Study 1984 92. Br J Haematol 2000; 109:453 458 Lowe GD, Danesh J, Lewington S, et al. Tissue plasminogen activator antigen and coronary heart disease: prospective study and meta-analysis. Eur Heart J 2004; 25:252259 Thogersen AM, Jansson JH, Boman K, et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98: 22412247 Node K, Kitakazi M, Yoshikawa H, et al. Reversible reduction in plasma concentration of nitric oxide induced by cigarette smoking in young adults. Am J Cardiol 1997; 79:1538 1541 Yamaguchi Y, Haginaka J, Morimoto S, et al. Facilitated nitration and oxidation of LDL in cigarette smokers. Eur J Clin Invest 2005; 35:186 193 Stocker R, Keaney JF Jr. Role of oxidative modifications in atherosclerosis. Physiol Rev 2004; 84:13811478 Harding SA, Sarma J, Josephs DH, et al. Upregulation of the CD40/CD40 ligand dyad and platelet-monocyte aggregation in cigarette smokers. Circulation 2004; 109:1926 1929 Schonbeck U, Gerdes M, Varo N, et al. Oxidized low-density lipoprotein augments and 3-hydroxy-3-methylglutaryl coen-

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zyme A reductase inhibitors limit CD40 and CD40L expression in human vascular cells. Circulation 2002; 106:2888 2893 Bergmann S, Seikmeier R, Mix C, et al. Even moderate cigarette smoking influences the pattern of circulating monocytes and the concentration of sICAM-1. Respir Physiol 1998; 114:269 275 Scott DA, Stapleton JA, Wilson JF, et al. Dramatic decline in circulating intercellular adhesion molecule-1 concentration on quitting tobacco smoking. Blood Cells Mol Dis 2000; 26:255258 Behrendt D, Ganz P. Endothelial function: from vascular biology to clinical applications. Am J Cardiol 2002; 90:40L 48L Newby DE, Wright RA, Labinjoh C, et al. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation 1999; 99:14111415 Eliasson M, Asplund K, Evrin PE, et al. Relationship of cigarette smoking and snuff dipping to plasma fibrinogen, fibrinolytic variables and serum insulin: the Northern Sweden MONICA Study. Atherosclerosis 1995; 113:4153 Yarnell JW, Sweetnam PM, Rumley A, et al. Lifestyle factors and coagulation activation markers: the Caerphilly Study. Blood Coagul Fibrinol 2001; 12:721728 Lowe GD, Rumley A. Use of fibrinogen and fibrin d-dimer in prediction of arterial thrombotic events. Thromb Haemost 1999; 82:667 672 Cambien F, Tiret L. Atherosclerosis: from genetic polymorphisms to system genetics. Cardiovasc Toxicol 2005; 5:143 152 Collins FS, Guyer MS, Charkravarti A. Variations on a theme: cataloging human DNA sequence variation. Science 1997; 278:1580 1581 Pritchard JK, Cox NJ. The allelic architecture of human disease genes: common disease-common variant, or not? Hum Mol Genet 2002; 11:24172423

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