The Causal Relationship Between Passive Smoking ... - IngentaConnect

328

Inflammation & Allergy - Drug Targets, 2009, 8, 328-333

The Causal Relationship Between Passive Smoking and Inflammation on the Development of Cardiovascular Disease: A Review of the Evidence Constantine I. Vardavas*,1 and Demosthenes B. Panagiotakos2 1

Department of Social Medicine, Faculty of Medicine, University of Crete, Greece

2

Department of Nutrition - Dietetics, Harokopio University, Athens, Greece Abstract: During the past years several factors have been established as risk markers for the development of heart disease, including both active and passive smoking. Current evidence has indicated that exposure to passive smoking can lead to a 70-80% increase in the risk of coronary heart disease, nearly as much as light smoking. This disproportionate effect could possibly be explained by a number of different interactions between human physiology of the cardiovascular system and passive smoke exposure. In this review we present the different mechanisms through which passive smoking may induce an inflammatory response that may lead to the development of cardiovascular disease, on a whole and through certain of its toxic constituents. Passive smoke itself, is a volatile mixture of numerous toxins, chemicals and carcinogens, that interact with in vivo mechanisms and induce vascular damage, including endothelium inflammation, atherosclerosis development, lipid peroxidisation, alterations in cytokines and acute phase proteins (such as CRP), as well as platelet aggravation. Acting alone or in synergy, the above mentioned effects suggest a causal relationship between exposure to passive smoking and the development of cardiovascular disease.

Keywords: passive smoking, inflammation, vascular dysfunction, cardiovascular disease, CRP. Cardiovascular disease (CVD) is a major cause of death and disability throughout the developed world. During the past years several factors have been established as risk markers for the development of the disease, including advanced age, male sex, heredity, history of hypertension, diabetes and dyslipidaimia, psychological disorders, as well as various lifestyle habits, like smoking, physical inactivity and unhealthy dietary choices [1-5]. Beyond active smoking, exposure to secondhand smoke (SHS), or passive smoking, is also considered as a risk factor for CVD [2, 6-9]. Meta analyses and reviews have indicated that the pooled relative risk of developing coronary heart disease when exposed chronically to SHS is 1.3, interpreted as a 30% increase in risk [9-10]. While the risk has been estimated using self report, evidence using biomarkers that assessed exposure to SHS found an even greater risk of CVD, close to 70-80%, which was almost the same as light smoking [11]. Although surprising, this disproportionate effect has been attributed to a number of different interactions between human physiology of the cardiovascular system and SHS exposure, including inflammation, platelet aggravation, endothelium dysfunction, lipid peroxidisation and alterations in c-reactive protein (CRP), homocystein and fibrinogen levels [9, 12-15]; however, the evidence is still under evaluation. Thus, taking the latter into account, the purpose of this review is to investigate into the current scientific literature the extent of evidence that suggests a causal relationship between exposure to SHS and the development of CVD, through the perspective of a systemic inflammation.

*Address correspondence to this author at the Department of Social Medicine, Faculty of Medicine, University of Crete, P.O. Box 2208, Heraklion 71003, Crete, Greece; Tel: +30 2810 394599; Fax: +30 2810 394606; E-mail: [email protected]

1871-5281/09 $55.00+.00

SHS AND OXIDATIVE STRESS SHS is a potent concoction of a few thousand chemicals, 200 toxic substances, and a substantial number of carcinogens, found in the gas phase that the passive smoker inhales [16, 17]. SHS is comprised of both mainstream smoke (inhaled by the smoker and exhaled after lung filtration) and sidestream smoke (from the smoldering cigarette), which have a different chemical consistency due to the different temperatures involved [18, 19]. Specifically, sidestream smoke is more toxic, more carcinogenic and more responsible for the majority of the respiratory tract epithelium damage in comparison to mainstream smoke [18]. Cigarette smoke additionally contains free radicals and other oxidants in abundance. It has been estimated that each puff of a cigarette exposes the smoker to 1015 oxidative free radicals, a severe source of oxidative stress [20]. While this large amount of oxidative stress primarily affects the active smoker, reactive oxygen species production can be mediated through inflammatory processes induced by the toxins inhaled through passive smoking also [21]. One factor through which exposure to SHS can increase the risk of CVD is through its effect on circulating lipids and lipoproteins. Cigarette smoking increases the oxidative modification of LDL with circulating products of lipid peroxidation and levels of oxidized LDL found to be significantly increased in both active and passive smokers [14, 22]. Epidemiological and laboratory evidence has indicated that smoking decreases plasma high lipoprotein levels (HDL) and alters the ratios between HDL and low density lipoproteins (LDL), HDL and triglycerides (TG) and HDL and total cholesterol levels, both in animal models and humans [23, 24]. Such an alteration in the lipidaimic profile of the exposed to SHS can evidently lead to the development of cardiovascular disease, a major part of which is mediated

© 2009 Bentham Science Publishers Ltd.

Passive Smoking and Inflammation

by the circulating serum lipids and specifically the ratio between HDL cholesterol and other harmful circulating lipid transferring factors, such as serum LDL, or triglycerides [25]. Even a short term exposure to SHS increases the risk of the development of CVD, through the decrease in the circulating levels of HDL and the altered ratio of TC/HDL as demonstrated though experimental studies on humans [25]. These unfavourable changes in HDL reduce its cardioprotective influence, which normally promotes cholesterol clearance and decreases the tendency for LDL oxidization through the absorption of cholesterol esters. Specifically, apolipoprotein I interacts with circulating serum phospoholipids and forms the nascent discoidial HDL (ndHDL), which catalyses the influx of cholesterol in the macrophages and fibroblasts. Subsequently, the ndHDL molecules increases in size and form the HDL particles which are beneficial for human health and thus can remove circulating lipids from the blood stream, through catabolism in the liver [26]. SHS AND VASCULAR INFLAMMATION One of the main determinants of CVD is the development of atherosclerosis. Atherosclerosis itself is regarded as an inflammatory disease, with progressive stages of atherosclerosis associated with the enhanced activation of Tcells, inflammatory cytokines and platelet aggravation [9]. Cigarette smoke can promote atherosclerosis, in part, by its effects on the lipid profile of the passive smoker, which as noted above is more oxidised than that of a non exposed subject. This oxidised LDL, may lodge into the arterial endothelial wall, thus attracting macrophages, lymphocytes and subsequently paracrinine factors that will lead to platelet accumulation and thus initiate the creation of foam cells, the first step in developing an atherosclerotic plaque [26]. In line with the above, exposure to SHS has been demonstrated to stimulate human fibroblasts to express several chemokines, including MCP-1 (monocyte chemoattractant protein-1), which plays a key role in the formation of atherosclerotic lesions. MCP-1 is responsible for attracting monocytes that are subsequently differentiated into active macrophages that become activated and digest oxidatised lipids and thus has a central role in the cellular response towards the development of atherosclerosis. Indeed, laboratory experiments have shown that mice that did not possess MCP-1 molecules or their receptors (knockout mice) had notably reduced atherosclerotic lesions in comparison to their wild counterparts indicating this chemokines role in the process of atherogenesis [27]. Indeed, mice exposed to sidestream SHS have been also found to have increased levels of proinflammatory cytokines, Interleukin (IL)-6, IL-1b and tumor necrosis factor (TNF)-a, which play an important role not only in the pathology of atherogenesis but also in heart failure and in a number of other diseases [28, 29]. Such relationships have also been indicated in humans exposed for one hour to moderate SHS leading to marked changes in interleukin 1 beta, interleukin 4, and tumor necrosis factor alpha. Additionally, two-hours of moderate exposure to SHS is accompanied by unfavorable changes in systolic blood pressure [30-32] In vitro experiments on human placental cells have also indicated that such chemokines, such as IL-6 and IL-8 are

Inflammation & Allergy - Drug Targets, 2009, Vol. 8, No. 5

329

up-regulated at low CSE concentrations, while the upregulation of endothelial IL-8 secretion has been shown to play a role in monocyte recruitment to the vessel wall [3334]. Accumulation of monocytes and monocyte-derived phagocytes in the wall of large arteries leads to chronic inflammation and the development and progression of atherosclerosis [35]. One such potent immune mediators involved in atherogenesis is CD40, which is an activation receptor located on B lymphocytes, monocytes, macrophages and endothelium cells and over expressed in atherosclerotic lesions [36]. Exposure to SHS, not only impairs endothelium function as noted above, but also can impair endothelial regeneration and maintenance. This regeneration process is mediated in part by endothelial progenitor cells (EPCs) that circulate in peripheral blood, and depends on their number and functional activity. Research has indicated that even short time exposure to SHS can lead to an increase in circulating EPC’s in response to the acute vascular injury sustained during exposure to SHS, these cells are dysfunctional and do not indicate to follow a chemokine gradient, a key role in vascular repair [37]. Furthermore, in vitro experiments have indicated that SHS exposure may inhibit chemotaxis and EPC proliferation by inhibiting nitrous oxide production [38]. Nitrous oxide (NO) plays an important regulatory role in endothelial biology and directional cell movement and is primarily responsible for the vasodilatory function of the endothelium [39]. NO bioactivity is influenced by the production of superoxide ions, which are produced through exposure to tobacco smoke and stimulate NADPH oxidase. Once activated, NADPH oxidase catalyzes the transfer of electrons from NADPH system to molecular oxygen with subsequent increase in production of endothelial superoxide anions, resulting in endothelial dysfunction [40]. Furthermore, cytokines increase the expression and activity of this enzyme in endothelial cells, resulting in the production of superoxide anions for prolonged periods [41]. SHS has been found to posses atherogenic properties, through the role of certain compounds found in cigarette smoke extract, such as acrolein and its particulate matter (an unsaturated aldehyde) [42]. Research has shown that acrolein elevates oxidative stress via the inactivation of the enzyme thioredoxin reductase and the stimulation of the expression of cyclooxygenase. Cyclooxygenase, is an enzyme that catalyses the oxygenation of arachidonic acid to prostaglandin endoperoxides, which are subsequently converted into prostaglandins, such as PGE2 that play a significant role in the physiology and pathophysiology of vascular function [43]. Acrolein, through the stimulation of the above molecular system can lead to a significant in vitro increase in prostaglandin levels, a mediator of inflammation. One must take into account that SHS is a potent mixture of about 4000 chemical substances, each on with a different effect on human health, without taking into account their possible synergistic effects, which might be amplified in the presence of the other [19]. An additional constituent of SHS is particulate matter, which in its self is usually measured as a proxy for SHS exposure during air monitoring studies [44]. Particle pollution itself, is associated with increases in

330


Table 1.

Vardavas and Panagiotakos

An Overview of the Studies Used in this Review that Investigated into the Cardiovascular Inflammatory Response to SHS Exposure

Author (Year)

Study Design

Participants

Main Finding

Flouris et al. (2009)

Experimental (Human study)

16 adults exposed for 1-h to SHS. Blood samples taken at 0, 1, and 3 hours after exposure

SHS exposure lead to increased IL-4 and TNF-alpha in men, whereas IL-5, IL-6, and IFN-gamma were different between sexes after exposure.

Leone et al. (2008)


28 adults (18 health adults and 10 prior myocardial infarction patients)

A strong correlation between SHS exposure and endothelial dysfunction was observed in both groups.

Park et al. (2008)

Experimental (Human cell line study)

Human umbilical vein endothelial cells exposed to acrolein for a number of hours

Acrolein, a known toxin in tobacco smoke, elevates oxidative stress via inactivation of thioredoxin reductase indicating a role in the progression of atherosclerosis.

Delfino et al. (2008)

Cohort study

29 elderly participants followed up for 12 weeks, blood samples weekly

Fine particles lead to increased systemic inflammation and platelet activation and decreased antioxidant enzyme activity in elderly people with coronary heart disease.

Flouris et al. (2008)


Twenty-eight exposed for 1-h to SHS and a 1-h control trial. Blood samples before and after

After exposure, IL-1beta and systolic blood pressure were increased in men but not women.

Clark et al. (2008)

Cross sectional study

Subpopulation of employed participants (20 years and older) who were non-smokers and denied home SHS exposure from the National Health and Nutrition Examination Survey (NHANES)

Exposure to SHS in the workplace may result in increased homocysteine levels among adult workers. Results for CRP and other inflammatory markers were not conclusive.

Yuan et al. (2007)

Experimental (Animal study)

A mouse model system, transgenic for human apoB100 was used, exposed to SHS.

Long-term exposure to SHS creates a state of permanent inflammation and an imbalance in the lipid profile that leads to lipid accumulation in the blood vessels of the heart and aorta.

Wilkinson et al. (2007)


Non smoking 6-18 year olds from the NHANES III study. Serum cotinine and CRP levels were investigated into.

They found a significant association between secondhand smoke exposure, assessed by serum cotinine, and elevated serum CRP among nonsmoking youth.

Venn et al. (2007)


7599 never smoking adults of the NHANES III study. Cotinine levels were taken into account

SHS exposed adults had higher fibrinogen and homocystein levels but not CRP or white blood cell counts.

Bernhard et al. (2005)


Human umbilical vein endothelial cells exposed to cigarette smoke extract

A smoke extract-induced, degradation of the intracellular form of platelet-endothelial cell adhesion molecule 1/CD31, as well as a release of P-selectin/CD62P, IL-6, and IL-8 from endothelial cells into the supernatant was noticed.

Whincup et al. (2004)

Prospective cohort study

4729 men in 18 towns in the UK followed up for 20 years. Non smokers divided into quartiles depending on their cotinine levels

Elevated risk for coronary heart disease in relationship to the increase in quartile of exposure, after adjustment for established risk factors for coronary heart disease.

Rubenstein et al. (2004)


Human platelets were exposed to mainstream and sidestream smoke

Cigarette smoke extracts directly cause platelet activation but also markedly increase the susceptibility of platelets to activation.

Panagiotakos et al. (2004)

Cross sectional

1128 men and 1154 women randomly selected from the province of Attica Greece. Self reported exposure to SHS

Those exposed more than 3 days per week had higher white blood cell counts, CRP, homocystein, fibrinogen and oxidized LDL levels.

Jaimes et al. (2004)

Experimental (Cell line study)

Short exposure of bovine pulmonary artery endothelial cells, human pulmonary artery endothelial cells, and rat pulmonary arteries to extracts from cigarette smoke

Thiol-reactive stable compounds in CS can activate NADPH oxidase and increase endothelial O2 production, thereby reducing NO bioactivity and resulting in endothelial dysfunction.

Heiss et al. (2004)


10 adults exposed to 30minutes of SHS, blood samples taken before, during and after exposure

SHS exposure increased endothelial progenitor cell count as also endothelial microparticles which remained elevated even 24hours later.

Passive Smoking and Inflammation


331

(Table 1) contd…..

Author (Year)

Study Design

Participants

Main Finding

Moffatt et al. (2004)


12 male adults exposed for 6 hours to SHS, blood samples before, during and after exposure

HDL lipoprotein subfractions were significantly reduced after SHS exposure, even 24hours later. Total cholesterol levels were not altered.

Zhang et al. (2002)

Experimental (Animal study)

Mice exposed to sidestream secondhand smoke for different time periods over 16 weeks

Exposed mice had a noted systemic inflammatory response (elevated TNF-a, and IL-6) as also increased peroxide levels. Decreased stroke volume and increased peripheral resistance was also noted.

Case control

847 cases with a first event of acute coronary syndromes and 1078 cardiovascular disease-free controls. Self reported SHS exposure was noted.

Cases were 47% more likely to report regular exposure to SHS compared to controls. Exposure to SHS at work was associated with a greater risk of acute coronary symptoms compared to home exposure.

Meta analysis

Seventeen studies (nine cohort, eight case-control) comprising more than 485,000 lifelong nonsmokers and 7,345 coronary heart disease events were included in a meta-analysis

The relative risk (RR) for fatal or nonfatal coronary events among never smokers married to smokers, compared to those whose spouses did not smoke, was RR = 1.25 across the combined studies. This association was regardless of gender or study design.

Heitzer et al. (1996)


55 participants of different smoking status and with different blood lipid levels

The acetylcholine-induced increase in forearm blood flow was significantly attenuated in patients with hypercholesterolemia who smoked compared with hypercholesterolemic nonsmokers and normocholesterolemic smokers.

Davis et al. (1989)


10 health male non smokers exposed to real life SHS exposure. Blood derived before and after exposure

Passive exposure to tobacco smoke was found to affected the endothelial cell count and platelet aggregate ratio.

Pitsavos et al. (2002)

Thun et al. (1999)

hospital admissions and mortality as its effect on human health is the similar regardless of the primary source of exposure (i.e., traffic of SHS) [45]. Recent evidence has indicated that exposure to airborne particles with a diameter