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Experimental Biology and Medicine 227:823-829 (2002)
© 2002 Society for Experimental Biology and Medicine

ORIGINAL ARTICLE

Side-Stream Cigarette Smoke Induces Dose–Response in Systemic Inflammatory Cytokine Production and Oxidative Stress

Jin Zhang*, Yingying Liu*, Jiaqi Shi{dagger}, Douglas F. Larson{dagger} and Ronald Ross Watson*,1,{dagger}

* Health Promotion Science Division, College of Public Health, and
{dagger} Sarver Heart Center, The University of Arizona Health Science Center, Tucson, Arizona 85724


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Side-stream cigarette smoke (SSCS), a major component of secondhand smoke, induces reactive oxygen species, which promote oxidative damage in tissues and organs. Inflammatory cytokines play an important role in the pathogenesis of atherosclerosis and heart failure. The present 4-month study examined the effect of various chronic SSCS exposure levels on splenic inflammatory cytokine secretion, heart contractile function, and pathology at 60- and 120-min per day, 5 days per week, for a total of 16 weeks. Tissue vitamin E level and lipid peroxide production also were tested to estimate the oxidative stress. The study found that the pro-inflammatory cytokines, interleukin (IL)-6, tumor necrosis factor (TNF)-{alpha}, and IL-1ß, significantly increased in 120-min SSCS-exposed mice. Decreased stroke volume and increased peripheral arterial resistance were observed in mice exposed to 120-min SSCS per day. Heart pathology was only found in 120-min SSCS-exposed mice. Cardiac and hepatic antioxidant vitamin E levels were decreased as a result of oxidative stress. Hepatic lipid peroxides were increased upon 60-min SSCS exposure. The data also demonstrated that the cardiac {alpha}-tocopherol level has a strong correlation with stroke volume; splenic IL-1ß has a strong negative correlation with stroke volume; splenic TNF-{alpha} has a very strong negative correlation with stroke volume. In conclusion, SSCS exposure induced systemic inflammatory responses. SSCS exposure also accentuated systemic lipid peroxidation with depletion of cardiac and hepatic antioxidant vitamin E level. Finally, SSCS exposure at 120 min per day decreased stroke volume and increased vascular resistance. Systemic IL-1ß and TNF-{alpha} production are responsible for heart contractile dysfunction. Free radicals may be responsible for the progression to heart contractile dysfunction induced, in part, by SSCS. Oxidized lipoprotein could contribute to the vascular functional changes. Exploring the mechanism of vascular dysfunction in mice is warranted. A more precise quantification of the smoking exposure dose in mice needs to be determined as well.

Key Words: pro-inflammatory cytokines • cardiac vitamin E • arterial resistance


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Side-stream cigarette smoke (SSCS) is a major component of second-hand smoke, which contains thousands of different chemical constituents (1). The toxicity of tobacco smoke is due to nicotine, cadmium, benzopyrene, oxidants, and inducers of reactive oxygen species (ROS) like NO, NO2, peroxynitrite, and nitrosamines that initiate, promote, or amplify oxidative damage (2). Free radicals disturb biological systems by reacting with a variety of their constituent molecules. Lipids are one of the potential targets for the oxidative attack of radicals. Polyunsaturated fatty acid residues in lipoproteins have a chemical structure that makes them particularly vulnerable targets for free radical oxidation (or lipid peroxidation; 3). Pregnant women smokers had significantly lower plasma {alpha}-tocopherol levels than nonsmokers (4). Prolonged in vitro exposure of plasma to cigarette smoke depletes vitamin E (5). Therefore, tissue vitamin E level and lipid peroxidation are indicators of oxidative stress induced by tobacco smoke.

Inflammatory cytokines, including tumor necrosis factor-{alpha} (TNF-{alpha}) and other cytokines, including interleukin-6 (IL-6) and interleukin-1beta (IL-1ß), play an important role in the pathogenesis of atherosclerosis and heart failure (6–9). Elevated levels of TNF-{alpha}, IL-6, IL-1ß, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1 were detected in the plasma and in the myocardium of patients with heart failure. These elevated levels apparently are correlated with the severity of heart failure (10–12).

SSCS is a significant risk factor for cardiovascular disease. Epidemiologic studies demonstrated an increase in coronary artery disease risk and mortality with exposure to secondhand smoke (13). There is growing concern about the potential impact of second-hand smoke on cardiovascular disease. However, research on the pathologic mechanisms that SSCS promotes the development of cardiovascular disease is limited. SSCS increased myocardial infarct size in a rat model of ischemia and reperfusion (14). It also increased experimental atherosclerosis in cholesterol-fed rabbits (15). The present study examined the effect of various chronic SSCS exposure levels at 60- and 120-min per day, 5 days per week, for a total of 16 weeks in mice, on splenic inflammatory cytokine secretion and heart contractile function. Tissue vitamin E level and lipid peroxide production in mice were tested as well to estimate the oxidative stress.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and Study Design.
All animal studies were performed with approval by the University of Arizona animal review committee. C57BL/6 female mice, 4–5 months old, were purchased from Charles River Laboratories (Wilmington, DE). They were housed in transparent plastic cages with stainless wire lids (4 mice per cage) in the animal facility of the Arizona Health Science Center. The housing facility was maintained at 20–22°C and 60%–80% relative humidity with a 12-hr light-dark cycle. The mice had free access to water and semipurified feed (4% mouse diet, #7001, Teklad, Madison, WI). After 2 weeks of housing, the mice were randomly divided into three groups containing 12 mice each: sham control, 60-min SSCS exposure per day; and 120-min SSCS exposure per day. All treatments were performed 5 days per week. By the end of 16-week-exposure, the heart contractile function of sham control and those exposed to 60- and 120-min were investigated. The splenocyte cytokine production and cardiac vitamin E level were examined in all three groups.

Side-Stream Cigarette Exposures.
SSCS is produced from the lit end of a burning cigarette, unfiltered and generated from tobacco combustion at lower temperature. It has the potential to produce similar damages as mainstream cigarette smoke (16). Standard research cigarettes (IR4F, University of Kentucky Smoking & Health Effects Laboratory, Lexington, KY) were used in this study. The methodology for SSCS exposure was adapted from a previous study in mouse model with minor modifications (17). The mice were exposed to SSCS through a 24-port nose-only exposure chamber (IN-TOX, Albuquerque, NM) using a constant vacuum (15 l/min; See Fig. 1Go illustration). The time-integrated mass of SSCS total particulate matter delivered to the mice was 2 mg/exposure averaged, at a concentration of 0.4 mg/m3, as measured by a seven-stage multi-jet impactor (IN-TOX, Albuquerque, NM). The chosen concentration of SSCS was referred from realistic measurements of indoor air concentrations of total suspended particles (TSPs) (range from 10 to 1000 g/m3) in smoker-occupied residences; up to approximately 2 mg respirable suspended particulates/m3 in restaurants (18). The first four cigarettes were placed upright in a clamp 2.5 cm below the bottom edge of an inverted 220 cm3 funnel and allowed to burn for 10-min. The second four cigarettes were ignited after 10-min to replace the first four cigarettes. This sequence was repeated until the various times were reached, at which time the exposed mice were removed. The sham control was treated in a similar manner except that the cigarettes were not lit. All the exposures were conducted 5 days a week.



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  		Figure 1. An illustration of SSCS exposure.

 
Determination of {alpha}-Tocopherol Levels.
{alpha}-Tocopherol levels in heart and liver were measured by HPLC, as described previously, with few modifications (19). Briefly, 0./~0.2 g of wet tissue was homogenized in 1.0 ml of distilled water. Butylated hydroxytoluene was added to prevent oxidation of {alpha}-tocopherol from the homogenate. Pentane, ethanol, and sodium dodecyl sulfate were used to extract {alpha}-tocopherol from the homogenate. Extracts were evaporated under a steady flow of nitrogen gas at 20°C and then redissolved in 1.0 ml of methanol injection onto a C18 column (3.9 x 150 mm NovaPak, Millipore, Bedford, MA). A mobile phase which is composed of methanol, distilled water in the ratio of 93: 7 (by volume) with a flow rate of 0.8 ml/min. {alpha}-Tocopherol, eluting at 26 min, was monitored by an HP 1046A programmable fluorescence detector (HP Company, Wilmington, DE) at 290 nm excitation and 340 nm emission wavelengths. A set of {alpha}-tocopherol standard concentrations was analyzed to make a standard curve and to verify calibration.

Lipid Peroxidation Assays.
Liver tissues were removed gently and stored at -70°C. Quantitative determination of lipid peroxides in liver was done using the LPO-CC K-ASSAY (Kamiya Biomedical Company, Seattle, WA). Phospholipids were extracted from approximately 0.2 g liver in chloroform/methanol (2:1, v/v). After centrifuging, the chloroform layer was mixed with 0.6 ml of saline to separate protein. The chloroform layer was evaporated in a steady flow of nitrogen gas, and lipid residues were dissolved with 100 µl of isopropanol. Test samples, standards, and controls were added in triplicate in the same 96-well microplate. In principle, in the presence of hemoglobin, lipid hydroperoxides are reduced to hydroxyl derivatives (lipid alcohol) and the MCDP (10-N-methylcarbamoyl-3,7-dimethylamino-10H-phenothiazine) chromogen is oxidatively cleaved to form methylene blue in an equal molar reaction. Lipid peroxidase are quantitated by colorimetrically measuring the methylene blue at 675 nm. Lipid peroxide (LPO) values were calculated by the following equation: LPO value in nmol/ml = (sample absorbance - blank absorbance) x 50.0 (absorbance of 50 nmol/ml standard -blank absorbance). LPO value was converted to nmol/g-wet tissue for illustration.

Preparation of Splenocytes.
Mitogen-stimulated splenocytes were cultured in triplicate in 96-well microtiter plates as described previously (20). Briefly, spleens were removed and gently teased with cell strainers (Falcon #2340, Lincoln Park, NJ) in culture medium (RPMI 1640 containing 10% fetal bovine serum, 2 mmol/L glutamine, 1 x 105 units/l of penicillin and streptomycin), producing suspension of spleen cells. Red blood cells were lysed by the addition of a lysis buffer (0.16 mol/l ammonia chloride Tris buffer, pH 7.2) at 37°C for 3 min. Then, the cells were washed twice with culture medium. Cell viability exceeded 95% by trypan blue exclusion. Splenocyte concentrations were adjusted to 1 x 106 cells/100 µl. Splenocyte suspension was added 100 µl per well in triplicate on 96-well flat-bottom culture plates (Falcon #3072, Lincoln Park, NJ) with culture medium. Splenocytes in 96-well microtiter plates were incubated for 24 h after addition of lipopolysaccharide (1 x 10-2 g/L. Gibco, Grand Island, NY) for the induction of cytokines. After incubation, the plates were centrifuged for 10 min at 800g Supernatants were collected and stored at -70°C until analysis.

Enzyme-Linked Immunosorbent assay (ELISA).
To measure the quantity of murine IL-6, TNF-{alpha}, and IL-1ß in supernatants of splenocyte cultures, a specific solid-phase ELISA assay using the multiple antibody sandwich principle was used (20). Rat anti-murine IL-6, TNF-{alpha}, and IL-1ß purified antibodies; rat anti-murine IL-6, TNF-{alpha}, and IL-1ß biotinylated antibodies; and recombinant murine IL-6, TNF-{alpha}, and IL-1ß were obtained from Pharmingen (Endogen, Woburn, MA). All tests were performed according to the manufacturer’s instructions. All tests were performed in triplicate in 96-well microtiter plates.

Heart Contractile Function.
Mice were tested for heart contractile function as described by Yang et al. (21). All mice were anesthetized with urethane in saline (1000 mg/kg, ip) and {alpha}–chloralose in propylene glycol (50 mg/kg ip). The mice were ventilated through a tracheostomy connected to a pressure-controlled respirator (RSP 1002, Kent, CT) at a rate of 120 times/min, FIO2 of 1.0. The mice were placed on a surgical table maintained at 37.5°C. The external jugular vein was cannulated with a #23-gauge butterfly, and volume administration was limited to 300 µl of hetastarch (6% hetastarch in 0.9% saline) Abbott Laboratories, N. Chicago, IL). Precise volume management was adhered to as described in detail by Yang et al. (21). The apical portion of the heart and the interior vena cava were exposed through a substemal-transverse incision. A conductance catheter 1.4 Fr (Millar Corporation, Houston, TX) was inserted into the apex of the left ventricle, with the distal electrode in the aortic root and the proximal electrode in the LV apex. The parameters of contractility were expressed.

Statistical Analysis.
Statistical analyses were performed by using the SAS 8.1 Windows (SAS Institute, Cary, NC) statistical package. All data were reported as mean ± SE. Variables were compared using a one-way analysis of variance (ANOVA), followed by a two-tailed Student’s t test for comparison between two groups. Differences between two groups were considered significant at P < 0.05. Pearson correlation was conducted between tissue vitamin E, lipid peroxide, splenic cytokines and heart function parameters.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Cardiac Vitamin E Level.
Vitamin E level in the heart was significantly reduced 55% by 120-min SSCS exposure compared with sham control (Fig. 2AGo, dotted line). SSCS exposure of 120 min further decreased cardiac vitamin E by 47% compared with SSCS exposure of 60-min. However, there is no significant difference between 60-min SSCS exposure and sham control.




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  		Figure 2. Effects of different doses of side-stream cigarette exposure on tissue vitamin E levels and hepatic lipid peroxide production. (A) Tissue vitamin E level was used as an indicator for oxidative stress. The assay was performed by HPLC. The solid line represents hepatic vitamin E; the dotted line represents cardiac vitamin E. (B) Lipid peroxide was determined with 0.2 g of mouse liver tissue. Phospholipids in the liver tissue were extracted by the CHCl3/methanol 2:1, v/v) method. LPO was measured with a spectrophotometer at 675 nm. Values were mean ± SE of 10 to 12 mice in each group. Sham control = no smoke exposure; 60-min = 60-min smoke exposure; 120-min = 120-min smoke exposure. a, compared with sham control mice significantly different at P < 0.05; b, compared with 60-min smoking mice significantly different at P < 0.05.

 
Hepatic Vitamin E Level.
In contrast, the liver tissue vitamin E level decreased during SSCS exposure (Fig. 2AGo, solid line). Vitamin E level in liver was significantly reduced 23% and 35%, respectively, by 60- and 120-min SSCS exposure (P < 0.05). Also, SSCS exposure of 120-min significantly reduced hepatic vitamin E level compared with that of 60-min (P < 0.05). SSCS exposure of 60-min significantly reduced hepatic vitamin E level than sham control (P < 0.05).

Hepatic Lipid Peroxides Production.
The liver is a major organ for tissue lipid peroxidation. Hepatic lipid peroxides were significantly increased by 60- and 120-min SSCS exposure compared with sham controls (P < 0.05; Fig. 2BGo). SSCS exposure of 120-min produced higher hepatic lipid peroxides than that of 60 min (P < 0.05).

Splenocyte Pro-Inflammatory Cytokines Production.
In vitro production of the pro-inflammatory cytokines was stimulated in splenocytes from SSCS-exposed mice. IL-1ß production was 26.9 ± 5.8 pg/ml and 43.5 ± 4.6 pg/ml, respectively, in cells from mice given 60- and 120-min SSCS exposure compared with 20.9 ± 3.6 pg/ml in cells from sham control mice (Fig. 3AGo). IL-6 was 2126.9 ± 125.5 pg/ml and 2619.1 ± 122.8 pg/ml, respectively, in 60- and 120-min SSCS-exposed mice, whereas it was 1821.9 ± 291.1 pg/ml in sham control mice. TNF-{alpha} was 1034.8 ± 57.2 pg/ml and 1453.2 ± 208.6 pg/ml, respectively, in cells from mice given 60- and 120-min SSCS exposure, whereas it was 855.8 ± 68.5 pg/ml in sham control mice (Fig. 3BGo). In 120-min SSCS-exposed mice, IL-1ß, IL-6, and TNF-{alpha} were more significantly increased than in both sham control and 60-min SSCS-exposed mice (P < 0.05). TNF-{alpha} in 60-min SSCS-exposed mice was more significantly increased than in sham control mice (P < 0.05) whereas IL-1ß and IL-6 in 60-min SSCS-exposed mice did not show significant difference compared to sham control mice (Fig. 3Go, A and B).




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  		Figure 3. In vitro splenocyte IL-1ß, TNF-{alpha}, and IL-6 production upon different dose of side-stream cigarette smoke exposure. The assay was conducted by ELISA. Values were mean ± SE of 12 mice in each group. Sham control = no smoke exposure; 60-min = 60-min smoke exposure; 120-min = 120-min smoke exposure; a, compared with sham control mice significantly different at P < 0.05; b, compared with 60-min smoke exposure mice significantly different at P < 0.05. (A) IL-1ß; (B) Solid line represents IL-6; dotted line represents TNF-{alpha}.

 
Heart Contractile Function.
The left ventricle functional parameters, cardiac output index, stroke volume index, preload recruitable stroke work, and derivative of change in systolic pressure over time, showed no significant difference in 60- and 120-min SSCS-exposed mice compared with sham controls (data not shown). However, stroke volume (SV) was significantly reduced in 120-min SSCS-exposed mice compared with sham controls (P < 0.05; Table IGo). Vascular impedance (arterial elastance, Ea) of smoke-exposed mice was significantly increased in those exposed to 120-min/d for 16 weeks (P < 0.05; Table IGo).


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  		Table I. Left Ventricular Contractile Parametersa
 
Correlation Between Tissue {alpha}-Tocopherol, Lipid Peroxide, Splenic Cytokines, and Heart Function Parameters.
Results from Table IIGo show that the cardiac {alpha}-tocopherol level has a strong correlation with stroke volume (P < 0.05); splenic IL-1ß has a strong negative correlation with stroke volume (P < 0.05); and splenic TNF-{alpha} has a very strong negative correlation with stroke volume (P = 0.01).


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  		Table II. Correlation Analysis
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Cigarette smoke affects various systems, including immune and cardiovascular systems. Cigarette smoke contains vast amounts of both carbon- and oxygen-centered free radicals, directly or indirectly initiating lipid peroxidation. Lipid-soluble vitamin E ({alpha}-tocopherol), as an integral part of cell membranes, acts as cytosolic antioxidant, scavenges the free radicals that promote peroxidative chain reactions (22). Thus, reduced hepatic and cardiac vitamin E levels indicate that vitamin E is involved in antioxidant defense against oxidative stress. A decrease in antioxidant defense in myocytes can promote oxidative stress. Dhalla and Singal found that the production of superoxide in cardiac tissue is increased as a result of the reduced antioxidant reserve in heart failure (23). However, the liver is a major organ subjected to the free radical attack. Hepatic lipid peroxide production is higher in the SSCS exposure. It has been shown that antioxidant depletion would initiate and accelerate cytotoxic or mutagenic events during excessive production of ROS (24).

Increased pro-inflammatory cytokine production was associated with increased SSCS exposure. ROS can activate redox-sensitive transcription factors, nuclear factor-kappa B, and activator protein-1, activating the genes of pro-inflammatory mediators TNF-{alpha}, IL-1ß, and IL-6 (25, 26). We previously observed that 13-month-old C57BL/6 female mice exposed to SSCS for 30-min per day, 5 days a week for 16 weeks exhibited increased IL-6 production in splenocytes (19). In the present study, the dosage of 120-min per day is sufficient to significantly increase all three pro-inflammatory cytokines IL-1ß, IL-6, and TNF-{alpha}. These pro-inflammatory cytokines are closely linked with pathology in a wide range of diseases and conditions that have an inflammatory basis.

The heart contractile function data showed SV decreased significantly upon 120-min SSCS exposure. SV is determined by three parameters: preload, afterload, and inotropic effects. The correlation analysis indicated that systemic elevated TNF-{alpha} and IL-1ß was associated with decreased SV. TNF-{alpha} and IL-1ß can both depress myocardial function (27). Oral and co-workers demonstrated that TNF-{alpha} induced an early depression mediated by sphingosine (28). Sphingosine is rapidly produced via sphingomyelin degradation after the intermediate formation of ceramide upon cardiomyocyte exposure to TNF-{alpha} (29, 30). Sphingosine decreases calcium transients by blocking the ryanodine receptor, thereby impeding calcium-induced calcium release from the sarcoplasmic reticulum. A common pathway that TNF-{alpha} and IL-1ß can induce myocardial functional depression is to activate inducible nitric oxide synthase and induce nitric oxide-dependent myofilament desensitization to calcium (27). IL-1ß, however, can also directly inhibit aerobic energy metabolism and myocardial contractility via a direct inhibition of the mitochondria enzyme activities (31). Cardiac vitamin E content was significantly correlated with SV, as indicated in Table IIGo. The beneficial effects if vitamin E in protecting from depression of left ventricular function may be occurring though the reduction of oxidative stress (32).

The heart function data suggest that 120-min per day of SSCS affects arterial elastance (Ea). Ea is defined as end-systolic pressure over stroke volume; it is the diameter of afterload. The augmentation of arterial elastance, reflecting the resistance of peripheral arteries, suggests that SSCS exposure could induce cellular alterations in the peripheral arteries. If Ea is high, the resistance is high, and the heart needs to do more work to pump the same amount of blood. Vascular impedance of smoke-exposed mice was significantly increased during 120-min SSCS exposure. Cigarette smoking is a highly significant risk factor for development of peripheral arterial occlusive disease (33). SSCS impaired endothelium-dependent relaxation of isolated rabbit arteries (34). Endothelial dysfunction of the peripheral vasculature contributes to the elevated peripheral vascular resistance in patients with heart failure (35). Free radical-mediated oxidative damage can also take place in lipoproteins. Oxidized lipoprotein is an important factor in predisposing SSCS-exposed mice to uptake foam cells in the vascular wall. These events have been correlated with the initiation and progression of coronary heart disease. The most often proposed mechanism for endothelial dysfunction related to ROS activity in heart failure is the enhanced biodegradation of nitric oxide by ROS. Elevated levels of ROS deplete bioavailable nitric oxide and exacerbate local oxidant stress by reacting directly with nitric oxide to form peroxynitrite, which, in turn, imparts further oxidative injury to the endothelium (36). Free radicals and oxidized lipoproteins that are oxidized by free radicals derived from cigarette smoke can inhibit endothelium-dependent vasodilation; the antioxidant diet reversed the impairment of the endothelial function (37, 38). The precise component of cigarette smoke that contributes to the pathogenesis of vascular disorder is unclear. Nicotine is a major component besides reactive oxygen species. We cannot exclude the effect of nicotine on vascular dilation at this point. Mayhan and Patel found that nicotine contributed to endothelium-dependent arteriolar dilatation in vivo (39).

Taken together, SSCS exposure at 120-min per day induced systemic inflammatory responses. SSCS exposure at both 60-min and 120-min per day accentuated systemic lipid peroxidation with depletion of cardiac and hepatic antioxidant vitamin E levels. Finally, SSCS exposure at 120-min per day decreased stroke volume and increased vascular resistance. Systemic IL-1ß and TNF-{alpha} production are responsible for heart contractile dysfunction. Free radicals may be responsible for the progression to heart contractile dysfunction induced, in part, by SSCS.

There are some limitations in the present study. Oxidative stress should be not only observed in major organs (such as heart and liver), but also in the vessel wall. Oxidized lipoprotein may contribute to the vascular functional changes. SSCS is very complex in chemical composition. Exploring the defined mechanism of vascular dysfunction in mice is warranted. A more precise quantification of the smoking exposure dose in mice needs to be determined so that it can be comparable to human exposure.


   Acknowledgments
 
We sincerely thank Dr. Mark Witten for use of the exposure equipment that was vital to this project.


   Footnotes
 
This work was supported in part by a grant from the Phi Beta Psi Sorority.

1 To whom requests for reprints should be addressed at Ronald W. Watson, Health Promotion Science Division, College of Public Health, University of Arizona Health Science Center, 1501 North Campbell Avenue, PO Box 245155, Tucson, AZ 85724-5155. E-mail: rwatson{at}u.arizona.edu Back


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received for publication April 1, 2002. Accepted for publication June 24, 2002.




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