CIGARETTE SMOKE—Its Effect on Pulmonary Function Measurements

Inhaling cigarette smoke with each breath, with the subject at rest, by use of a smoking device that brought more smoke into the lungs than would be the case in ordinary smoking, produced consistent significant decreases in arterial blood oxygen saturation and in arterial pO₂ in most subjects who had severe or very severe pulmonary emphysema. In normal subjects and in those with a moderate degree of emphysema no significant changes in blood gas exchange resulted.No consistent significant changes in blood gas exchange were noted after the smoking of two cigarettes, either with the subject at rest or after a one-minute step-up exercise.A decrease in oxygen uptake occurred when treadmill exercise was done after smoking two cigarettes, and the ventilation volume was also decreased, probably accounting for part of the oxygen decrease.Pulmonary compliance measurements after smoking one cigarette were consistently and significantly decreased in most subjects—normal as well as those with pulmonary emphysema. The elastic work of breathing was increased in the majority of cases.In two cases in which studies were done after the subjects stopped smoking, one for three months and one for two years, significant reductions in residual air were noted.The results indicated that persons with severe or very severe emphysema would be better off to stop smoking.     

Immediate effects of cigarette smoking on cardiorespiratory responses to exercise

To determine the acute action of cigarette smoking on cardiorespiratory function under stress, the immediate effects of cigarette smoking on the ventilatory, gas exchange, and cardiovascular responses to exercise were studied in nine healthy male subjects. Each subject performed an incremental exercise test to exhaustion on two separate days, one without smoking (control) and one after smoking 3 cigarettes/h for 5 h. The order of the two tests was randomized. Arterial blood gases and pH were measured during rest and all levels of exercise; CO blood levels confirmed the absorption of cigarette smoke. In addition, minute ventilation (VE), end-tidal PCO2 and PO2, O2 uptake (VO2), CO2 production, directly measured blood pressure, electrocardiogram, and heart rate (HR) were recorded every 30 s. The dead space-to-tidal volume ratio (VD/VT), maximal aerobic capacity (VO2max), and anaerobic threshold (AT) were determined from the gas exchange data. Cigarette smoking resulted in a significantly lower VO2max, AT, and VO2/HR (O2 pulse) and a significantly higher HR, pulse-pressure product, and pulse pressure (P less than 0.05) compared with the control. Additionally, a trend toward a higher VD/VT and arterial-end-tidal PCO2 difference was found during exercise after smoking. We conclude that cigarette smoking causes immediate detrimental effects on cardiovascular function during exercise, including tachycardia, increased pulse-pressure product, and impaired O2 delivery. The acute effects on respiratory function were less striking and primarily limited to abnormalities reflecting ventilation-perfusion mismatching.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute effects of cigarette smoking and inhalation of carbon monoxide during maximal exercise

The acute effect of inhaling the smoke of three cigarettes was compared to the effect of inhalation of an amount of carbon monoxide (CO), giving the same CO-saturation of the arterial blood as smoking during rest and during maximal exercise on a Krogh cycle ergometer. Sixteen male subjects were tested in the morning (1) after about 8 h without smoking (control), (2) after inhalation of the smoke of three cigarettes (smoke), and (3) after CO-inhalation (CO). It was found that the average maximal rate of O2-uptake (VO2 max) decreased during both smoke and CO by about 7%. Endurance time at VO2 max decreased 20% during smoke but only 10% during CO. A significant decrease in maximal heart rate (HR), and an increase in HR at rest, was demonstrated only during smoke. The peak lactate concentration (HLa) following maximal exercise was significantly decreased after smoke. The results suggest that the decrease in VO2 max during smoke is due to the CO-saturation of the blood, and hence to a decrease in the oxygen capacity of the blood, while the decrease in endurance time during smoke is combined effect of the CO-saturation and an increased cost of breathing caused by the smoke particles. It is further suggested that nicotine, or possibly some other components of the smoke, have an enhancing effect on the heart at rest rest, while an inhibition is seen during maximal exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

CARDIORESPIRATORY FUNCTION

Accurate evaluation of the degree of impairment of pulmonary function in persons with fibrosis and emphysema requires: (1) ventilatory measurements from rapid spirogram tracings (vital capacity, maximal breathing capacity and the time required to blow the air from the lungs); (2) determination of the degree of bronchospasm present; (3) determination of the degree of pulmonary emphysema (residual air expressed quantitatively as percent of total lung volume); (4) determination of the arterial blood oxygen saturation at rest and immediately after step-up exercise; (5) measurement of the oxygen extraction from inspired air (per cent of oxygen removed) during rest and exercise; (6) determination of the oxygen up-take during exercise; and (7) observation of the duration of dyspnea after step-up exercise.No single physiologic test is adequate in evaluating impairment of pulmonary function, and roentgenograms of the chest are unreliable as a sole basis for appraisal of disability.In industrial medicine, pulmonary function studies make possible (a) more accurate diagnosis and evaluation of pulmonary disability; and (b) earlier detection and thus prevention of prolonged exposure by susceptible individuals to environmental hazards.     

Differential thiol status in blood of different mouse strains exposed to cigarette smoke

C57Bl/6J, DBA/2 and ICR mouse strains are known to possess different susceptibilities to developing emphysema after exposure to cigarette smoke with DBA/2 and C57Bl/6J strains being significantly more susceptible to pulmonary damage than the ICR strain. This study was aimed at analysing the occurrence of systemic oxidative stress in the blood of these different mouse strains after exposure to cigarette smoke. This study did not observe a significant decrease in glutathione in erythrocytes or in plasma cysteine, cysteinylglycine, homocysteine and glutathione in C57Bl/6J or DBA/2 mice, whereas a significant increase in the corresponding oxidized forms was observed in plasma. However, the ICR strain showed a significant increase in glutathione in erythrocytes and a significant decrease in most of the oxidized forms of cysteine, cysteinylglycine, homocysteine and glutathione in plasma after the same exposition. These experiments demonstrate that exposure to cigarette smoking induces systemic oxidative stress only in some mouse strains which are susceptible to developing emphysema.     

Clove cigarettes. The basis for concern regarding health effects.

The smoking of clove cigarettes has been associated with 13 cases of serious illness in the United States, including hemorrhagic pulmonary edema, pneumonia, bronchitis, and hemoptysis. We describe a patient in whom, after she smoked a clove cigarette, pneumonia complicated by lung abscess developed. Her lung disease may have been caused by aspiration pneumonia as a consequence of pharyngolaryngeal anesthesia from clove cigarette smoke. Clove cigarettes appeal to adolescents experimenting with smoking practices and may influence the development of later smoking habits.     

Bronchial Reactivity to Cigarette and Cigar Smoke

The change in specific airway conductance produced by smoking a cigarette under standard conditions was measured in 91 heavy smokers. Subsequently 19 of the most reactive subjects smoked two cigarettes with different filters and another containing cigar tobacco. The results indicated that reactivity to cigarette smoke was reduced significantly by increasing the retention efficiency of the filter and that reactivity to inhaled cigar-tobacco smoke was no less than that to cigarette smoke.     

Extracellular regulated kinase/mitogen activated protein kinase is up-regulated in pulmonary emphysema and mediates matrix metalloproteinase-1 induction by cigarette smoke

The interstitial collagenase matrix metalloprotein-ase-1 (MMP-1) is up-regulated in the lung during pulmonary emphysema. The mechanisms underlying this aberrant expression are poorly understood. Although cigarette smoking is the predominant cause of emphysema, only 15-20% of smokers develop the disease. To define the signaling pathways activated by smoke and to identify molecules responsible for emphysema-associated MMP-1 expression, we performed several in vitro and in vivo experiments. In this study, we showed that cigarette smoke directly induced MMP-1 mRNA and protein expression and increased the collagenolytic activity of human airway cells. Treatment with various chemical kinase inhibitors revealed that this response was dependent on the extracellular regulated kinase-1/2 (ERK) mitogen activated protein kinase pathway. Cigarette smoke increased phosphorylation of residues Thr-202 and Tyr-204 of ERK in airway lining cells and alveolar macrophages in mice at 10 days and 6 months of exposure. Moreover, analysis of lung tissues from emphysema patients revealed significantly increased ERK activity compared with lungs of control subjects. This ERK activity was evident in airway lining and alveolar cells. The identification of active ERK in the lungs of emphysema patients and the finding that induction of MMP-1 by cigarette smoke in pulmonary epithelial cells is ERK-dependent reveal a molecular mechanism and potential therapeutic target for excessive matrix remodeling in smokers who develop emphysema.     

Cardiorespiratory function

ACCURATE EVALUATION OF THE DEGREE OF IMPAIRMENT OF PULMONARY FUNCTION IN PERSONS WITH FIBROSIS AND EMPHYSEMA REQUIRES: (1) ventilatory measurements from rapid spirogram tracings (vital capacity, maximal breathing capacity and the time required to blow the air from the lungs); (2) determination of the degree of bronchospasm present; (3) determination of the degree of pulmonary emphysema (residual air expressed quantitatively as percent of total lung volume); (4) determination of the arterial blood oxygen saturation at rest and immediately after step-up exercise; (5) measurement of the oxygen extraction from inspired air (per cent of oxygen removed) during rest and exercise; (6) determination of the oxygen up-take during exercise; and (7) observation of the duration of dyspnea after step-up exercise. No single physiologic test is adequate in evaluating impairment of pulmonary function, and roentgenograms of the chest are unreliable as a sole basis for appraisal of disability. In industrial medicine, pulmonary function studies make possible (a) more accurate diagnosis and evaluation of pulmonary disability; and (b) earlier detection and thus prevention of prolonged exposure by susceptible individuals to environmental hazards.     

Effect of a patent foramen ovale on pulmonary gas exchange efficiency at rest and during exercise

The prevalence of a patent foramen ovale (PFO) is ~30%, and this source of right-to-left shunt could result in greater pulmonary gas exchange impairment at rest and during exercise. The aim of this work was to determine if individuals with an asymptomatic PFO (PFO+) have greater pulmonary gas exchange inefficiency at rest and during exercise than subjects without a PFO (PFO-). Separated by 1 h of rest, 8 PFO+ and 8 PFO- subjects performed two incremental cycle ergometer exercise tests to voluntary exhaustion while breathing either room air or hypoxic gas [fraction of inspired O(2) (FI(O(2))) = 0.12]. Using echocardiography, we detected small, intermittent boluses of saline contrast bubbles entering directly into the left atrium within 3 heart beats at rest and during both exercise conditions in PFO+. These findings suggest a qualitatively small intracardiac shunt at rest and during exercise in PFO+. The alveolar-to-arterial oxygen difference (AaDo(2)) was significantly (P < 0.05) different between PFO+ and PFO- in normoxia (5.9 ± 5.1 vs. 0.5 ± 3.5 mmHg) and hypoxia (10.1 ± 5.9 vs. 4.1 ± 3.1 mmHg) at rest, but not during exercise. However, arterial oxygen saturation was significantly different between PFO+ and PFO- at peak exercise in normoxia (94.3 ± 0.9 vs. 95.8 ± 1.0%) as a result of a significant difference in esophageal temperature (38.4 ± 0.3 vs. 38.0 ± 0.3°C). An asymptomatic PFO contributes to pulmonary gas exchange inefficiency at rest but not during exercise in healthy humans and therefore does not explain intersubject variability in the AaDO(2) at maximal exercise.     

The role of glutathione in the toxicity of smoke condensates from cigarettes that burn or heat tobacco

Inhalation of cigarette smoke aerosol via active smoking is associated with the development of pulmonary inflammation. The cytotoxic potential of cigarette smoke has been hypothetically related to development of pulmonary inflammation since the release of intracellular contents from dead and dying cells has been reported to induce inflammatory foci. In this study, cigarette smoke condensates (CSCs) were prepared from Kentucky 1R4F reference cigarettes and cigarettes that primarily heat tobacco (Eclipse). The two CSCs were then compared for their ability to induce killing in human-hamster A_L hybrid cells. CSCs prepared from Eclipse were much less cytotoxic than those prepared from reference cigarettes. At 60 μg CSC/ml culture medium, survival for CSC from Eclipse cigarettes was approximately 70% compared with 1% for CSC from burned K1R4F cigarettes. The observed reduction in CSC-Eclipse cytotoxicity toward these mammalian cells is consistent with the previously published observation of a 30% decline in pulmonary white cell count and 40% reduction in visual bronchitis index in human smokers who switched to Eclipse for 2 months. Results with N-acetylcysteine and buthionine-S-R-sulfoximine indicate that glutathione markedly reduces the cytoxicity of both CSCs.     

Effect of beta-adrenergic blockade on hyperventilation and exercise tolerance in emphysema

Ventilation, heart rate, and arterial blood gas tensions were measured at rest and during incremental exercise in 10 patients with emphysema after intravenous placebo or 7 mg metoprolol. Metoprolol reduced heart rate by 14% (P less than 0.001) and ventilation by 11% (P less than 0.01), but there was no significant difference in arterial O2 or CO2 tension (Pao2 and PaCO2, respectively). Metoprolol increased the time to exhaustion on a cycle ergometer (P less than 0.05) but did not improve the 12-min walking distance. A double-blind randomized crossover comparison of 4 wk treatment with atenolol (100 mg/day), metoprolol (100 mg/day), or matched placebo was performed in 12 patients with emphysema. Both beta-adrenoceptor antagonists reduced resting heart rate by 33% (P less than 0.001) and resting minute ventilation by 11% (P less than 0.025). There was no change in resting or exercise Pao2 or Paco2. During steady-state exercise on a cycle ergometer, atenolol and metoprolol reduced ventilation by 14 and 4%, respectively. This was accompanied by 11 and 5% reductions in O2 consumption (P less than 0.05) and 13 and 6% falls in CO2 production (P less than 0.05). There were no significant changes in tests of exercise tolerance, but forced expiratory volume in 1 s and forced vital capacity were reduced during beta 1-adrenergic blockade. beta 1-Blocking drugs reduce hyperventilation in emphysema by reducing pulmonary gas exchange without a change in arterial blood gas tensions. Increased airflow obstruction prevents this reduction being of therapeutic value.     

Interaction between cigarettes and propranolol in treatment of angina pectoris.

To determine whether cigarette smoking interferes with the medical management of angina pectoris, 10 patients with angina pectoris who smoked at least 10 cigarettes a day were studied before, during, and after a standardised maximal exercise test. This was done at the end of four randomly allocated one-week treatment periods during which the patients took glyceryl trinitrate while not smoking, took glyceryl trinitrate while smoking, took glycerly trinitrate and propranolol (380 mg/day) while not smoking, and took glyceryl trinitrate and propranolol while smoking. Carboxyhaemoglobin was measured to ensure compliance. Smoking was associated with a significantly higher heart rate, blood pressure, number of positions with ST-segment depression, and total ST-segment depression after exercise than non-smoking (p < 0.01) whether or not the patients were taking propranolol. These results suggest that smoking aggravates the simple haemodynamic variables used to assess myocardial oxygen requirements and the exercise-induced precordial electrocardiographic signs of myocardial ischaemia. These effects were still evident after treatment with propranolol and represent a hindrance to the effective medical treatment of angina pectoris.     

Intrapulmonary shunting and pulmonary gas exchange during normoxic and hypoxic exercise in healthy humans.

Exercise-induced intrapulmonary arteriovenous shunting, as detected by saline contrast echocardiography, has been demonstrated in healthy humans. We have previously suggested that increases in both pulmonary pressures and blood flow associated with exercise are responsible for opening these intrapulmonary arteriovenous pathways. In the present study, we hypothesized that, although cardiac output and pulmonary pressures would be higher in hypoxia, the potent pulmonary vasoconstrictor effect of hypoxia would actually attenuate exercise-induced intrapulmonary shunting. Using saline contrast echocardiography, we examined nine healthy men during incremental (65 W + 30 W/2 min) cycle exercise to exhaustion in normoxia and hypoxia (fraction of inspired O(2) = 0.12). Contrast injections were made into a peripheral vein at rest and during exercise and recovery (3-5 min postexercise) with pulmonary gas exchange measured simultaneously. At rest, no subject demonstrated intrapulmonary shunting in normoxia [arterial Po(2) (Pa(O(2))) = 98 +/- 10 Torr], whereas in hypoxia (Pa(O(2)) = 47 +/- 5 Torr), intrapulmonary shunting developed in 3/9 subjects. During exercise, approximately 90% (8/9) of the subjects shunted during normoxia, whereas all subjects shunted during hypoxia. Four of the nine subjects shunted at a lower workload in hypoxia. Furthermore, all subjects continued to shunt at 3 min, and five subjects shunted at 5 min postexercise in hypoxia. Hypoxia has acute effects by inducing intrapulmonary arteriovenous shunt pathways at rest and during exercise and has long-term effects by maintaining patency of these vessels during recovery. Whether oxygen tension specifically regulates these novel pathways or opens them indirectly via effects on the conventional pulmonary vasculature remains unclear.     

Carbon monoxide and exercise tolerance in chronic bronchitis and emphysema.

The effects of carbon monoxide on exercise tolerance as assessed by the distance walked in 12 minutes were studied in 15 patients with severe chronic bronchitis and emphysema (mean forced expiratory volume in one second 0.56 1, mean forced vital capacity 1.54 1). Each subject walked breathing air and oxygen before and after exposure to sufficient carbon monoxide to raise their venous carboxyhaemoglobin concentration by 9%. There was a significant reduction in the walking distance when the patients breathed air after exposure to carbon monoxide (p less than 0.01), and the significant increase in walking distance seen after exercise when breathing oxygen at 2 1/minute via nasal cannulae was abolished if carbon monoxide has previously been administered. Thus concentrations of carboxyhaemoglobin frequently found in bronchitic patients who smoke may reduce their tolerance of everyday exercise, possibly by interfering with the transport of oxygen to exercising muscles.     

Relationship between cigarette yields,puffing patterns,and smoke intake: evidence for tar compensation?

The relationship between cigarette yields (of nicotine, tar, and carbon monoxide), puffing patterns, and smoke intake was studied by determining puffing patterns and measuring blood concentrations of nicotine and carboxy-haemoglobin (COHb) in a sample of 55 smokers smoking their usual brand of cigarette. Regression analyses showed that the total volume of smoke puffed from a cigarette was a more important determinant of peak blood nicotine concentration than the nicotine or tar yield of the cigarette, its length, or the reported number of cigarettes smoked on the test day. There was evidence of compensation for a lower tar yield over and above any compensation for nicotine. When nicotine yield was controlled for, smokers of lower-tar cigarettes not only puffed more smoke from their cigarettes than smokers of higher-tar cigarettes but they also had higher plasma nicotine concentrations, suggesting that they were compensating for the reduced delivery of tar by puffing and inhaling a greater volume of smoke. The results based on the COHb concentrations were consistent with this interpretation. If an adequate intake of tar proves to be one of the main motives for smoking, then developing a cigarette that is acceptable to smokers and also less harmful to their health will be much more difficult.     

Effect of chronic cigarette smoke exposure on pulmonary vasomotion in beagle dogs

To study the effect of chronic cigarette smoke exposure on the resistive properties of the pulmonary vasculature, left lower lobes from 12 control beagles and 6 beagles who had smoked cigarettes (50 cigarettes/wk for 40 wk) were perfused in situ to measure the vascular pressure-flow relationship and the resistance of the three vascular segments with the arterial and venous occlusion technique. In control subjects the vascular resistance in the arterial, middle, and venous segments was 23, 36, and 41% of the total, respectively. The segmental distribution of vascular resistance was not significantly different in the cigarette smoke-exposed dogs, despite the fact that the absolute values were 30-40% less than that of the control group. The longitudinal distribution of resistance among the three vascular segments and their response to drugs were different in beagles than was previously found in mongrels. In all beagles the veins were considerably more reactive than arteries. Vasoconstriction with serotonin (5-HT) prostaglandin F2 alpha (PGF2 alpha), norepinephrine, histamine, and methacholine (M) infusion occurred predominantly in the veins. The effect of PGF2 alpha and 5-HT was totally different than that previously observed in mongrels in which the constriction was predominantly in the arteries. Chronic cigarette smoking reduced the basal pulmonary vascular resistance and attenuated the venoconstrictor response to 5-HT and M but potentiated the hypoxic pressor response of the microvessels.     

On the Influence of Moisture Content in Cigarettes on Combustion Temperature and Transferred Amount of Nicotine into Cigarettes Smoke

The effects of moisture content of cigarettes on both combustion temperature and the amount of nicotine transferred into the smoke were studied under different smoking conditions. The combustion temperatures of domestic commercial blended cigarettes were not affected by smoking procedures or amount of moisture in the cigarette. No significant differences in the amount of nicotine transferred into smoke were observed between the cigarettes with medium (10.9%) and high (15.4%) moisture contents, while the values obtained from the low moisture content (6.6%) cigarettes were always slightly higher than those obtained from medium or high moisture content cigarette.     

Menthol Attenuates Respiratory Irritation and Elevates Blood Cotinine in Cigarette Smoke Exposed Mice

Addition of menthol to cigarettes may be associated with increased initiation of smoking. The potential mechanisms underlying this association are not known. Menthol, likely due to its effects on cold-sensing peripheral sensory neurons, is known to inhibit the sensation of irritation elicited by respiratory irritants. However, it remains unclear whether menthol modulates cigarette smoke irritancy and nicotine absorption during initial exposures to cigarettes, thereby facilitating smoking initiation. Using plethysmography in a C57Bl/6J mouse model, we examined the effects of L-menthol, the menthol isomer added to cigarettes, on the respiratory sensory irritation response to primary smoke irritants (acrolein and cyclohexanone) and smoke of Kentucky reference 2R4 cigarettes. We also studied L-menthol’s effect on blood levels of the nicotine metabolite, cotinine, immediately after exposure to cigarette smoke. L-menthol suppressed the irritation response to acrolein with an apparent IC₅₀ of 4 ppm. Suppression was observed even at acrolein levels well above those necessary to produce a maximal response. Cigarette smoke, at exposure levels of 10 mg/m³ or higher, caused an immediate and marked sensory irritation response in mice. This response was significantly suppressed by L-menthol even at smoke concentrations as high as 300 mg/m³. Counterirritation by L-menthol was abolished by treatment with a selective inhibitor of Transient Receptor Potential Melastatin 8 (TRPM8), the neuronal cold/menthol receptor. Inclusion of menthol in the cigarette smoke resulted in roughly a 1.5-fold increase in plasma cotinine levels over those observed in mice exposed to smoke without added menthol. These findings document that, L-menthol, through TRPM8, is a strong suppressor of respiratory irritation responses, even during highly noxious exposures to cigarette smoke or smoke irritants, and increases blood cotinine. Therefore, L-menthol, as a cigarette additive, may promote smoking initiation and nicotine addiction.     

Cigarette Smoking Induces Formation of 8-Hydroxydeoxyguanosine,One of the Oxidative Dna Damages in Human Peripheral Leukocytes

Active oxygen species (AOS) such as O and H₂O₂ have been shown to be generated from both gas and tar phases of cigarette smoke and it has been suggested that they are involved in carcinogenesis due to cigarette smoking. Therefore, we investigated the effect of cigarette smoking on oxidative DNA damages in human peripheral blood cells using 8-hydroxydeoxy-guanosine (8-OH-dG) as a marker.

From ten healthy male volunteers aged 20-22 years, 5 ml of blood was taken before and 10 minutes after smoking 2 cigarettes in 10 minutes. After lysis of blood cell membranes leukocyte DNA was isolated using a DNA extractor and 8-OH-dG levels were determined using high performance liquid chromatography (HPLC) with electrochemical detection.

The mean levels of 8-OH-dG increased significantly (P <0.05) from 3.3 ± 0.8/10⁶dG (mean ± SD) to 5.1 ± 2.5 after smoking.

These results indicate that cigarette smoking induces oxidative DNA damage in peripheral blood cells in a relatively short time.