Chronic Tobacco Smoke Exposure Research Articles

Chronic tobacco smoke exposure increases cough to capsaicin in awake guinea pigs

Chronic exposure to irritants such as tobacco smoke (TS) can induce spontaneous and enhanced irritant-induced coughing, especially in asthma. To determine if the mechanism of enhanced coughing involves activation of capsaicin-sensitive sensory receptors (C-fibers), we exposed both non-sensitized (NS) and ovalbumin-sensitized guinea pigs to TS (5 mg/L air, 30 min exposure, and 7 days/week). Similar groups were exposed to compressed air. After 90 days of exposure, we challenged the airways with capsaicin, bradykinin, histamine and methacholine. Capsaicin induced coughing as well as bronchoconstriction in guinea pigs exposed to TS. In ovalbumin (OA) guinea pigs coughing and bronchoconstriction were enhanced. Tachykinin receptor antagonists attenuated coughing to both capsaicin and acute TS challenge. Bradykinin also induced coughing and bronchoconstriction in guinea pigs exposed to TS. There was no statistical separation between the two TS groups however. Histamine and methacholine induced similar bronchoconstriction but fewer coughs in all four experimental groups. In conclusion, chronic TS exposure induced coughing to capsaicin and bradykinin challenge. The effect of capsaicin was further enhanced in OA guinea pigs. Enhanced coughing induced by TS exposure likely involves activation of capsaicin-sensitive sensory C-fibers and neuropeptide release with possible subsequent activation of rapidly-adapting receptors.

Chronic tobacco smoke exposure increases airway sensitivity to capsaicin in awake guinea pigs.

Tobacco smoke (TS) exposure induces airway hyperreactivity, particularly in sensitive individuals with asthma. However, the mechanism of this airway hyperreactivity is not well understood. To investigate the relative susceptibility of atopic and nonatopic individuals to TS-induced airway hyperreactivity, we exposed ovalbumin (OA)-sensitized and nonsensitized guinea pigs to TS exposure (5 mg/l air, 30-min exposure, 7 days/wk for 120-156 days). Two similar groups exposed to compressed air served as controls. Airway reactivity was assessed as an increase in enhanced pause (Penh) units using a plethysmograph that allowed free movement of the animals. After 90 days of exposure, airway reactivity increased in OA-TS guinea pigs challenged with capsaicin, bradykinin, and neurokinin A fragment 4--10 aerosols. In addition, substance P content increased in lung perfusate of OA-TS guinea pigs in response to acute TS challenge compared with that of the other groups. Airway hyperirritability was not enhanced by phosphoramidon but was attenuated by a cocktail of neurokinin antagonists, nor was airway hyperreactivity observed after either methacholine or histamine challenge in OA-TS guinea pigs. Chronic TS exposure enhanced neither airway reactivity to histamine or methacholine nor contractility of isolated tracheal rings. In conclusion, chronic TS exposure increased airway reactivity to capsaicin and bradykinin aerosol challenge, and OA-TS guinea pigs were most susceptible to airway dysfunction as the result of exposure to TS compared with the other groups. Increased airway reactivity to capsaicin suggests a mechanism involving neurogenic inflammation, such as increased activation of lung C fibers.

Smoking a single cigarette does not produce a measurable reduction in brain MAO B in non-smokers.

Positron emission tomography (PET) studies with [11C]L-deprenyl-D2 have shown that brain monoamine oxidase (MAO) B is 40% lower in smokers than in non-smokers. Here we investigated whether MAO B inhibition can be detected after smoking a single cigarette. Eight normal healthy non-smokers (35 +/- 11 years) received two PET studies 2 h apart with [11C]L-deprenyl-D2, one at baseline and the second 5-10 min after the subject had smoked a single cigarette. Plasma nicotine and expired carbon monoxide (CO) were measured prior to smoking and 10 min after smoking completion as an index of tobacco smoke exposure. A three-compartment model was used to calculate lambda k3, a model term which is proportional to MAO B activity and which is derived from the time course of carbon-11 in the brain and the time course of the radiotracer in the plasma and K1, the plasma-to-brain transfer constant (for [11C]L-deprenyl-D2) which is related to brain blood flow. Subjects experienced difficulty inhaling and became dizzy and/or nauseous after smoking. Plasma nicotine averaged 11.6 +/- 5.5 ng/ml and expired CO averaged 8 +/- 10 ppm after smoking. The average lambda k3 and K1 for 11 different brain regions did not differ significantly between baseline and smoking. These results indicate that the reduction in MAO B in smokers probably occurs gradually and requires chronic tobacco smoke exposure.

Review : Effects of Environmental Tobacco Smoke Exposure on Pulmonary Function and Respiratory Health in Adults: Update 1997

Eighteen epidemiology studies have examined the relationship between chronic environmental tobacco smoke (ETS) exposure and pulmonary func tion. A statistically significant relationship between chronic ETS exposure and a specific spirometric endpoint was reported in 5 of 17 studies that measured forced expiratory volume in 1 s (FEV1), 2 of 9 studies that measured forced vital capacity (FVC) and 3 of 5 studies that measured mean forced expiratory flow during the middle half of the FVC. Fourteen of 24 epidemiological stud ies report a statistically significant association between chronic ETS exposure and a clinical endpoint, although there is little consistency from one report to the next when a specific endpoint is considered. A statistically significant asso ciation was reported in 2 of 9 studies for cough, 3 of 9 studies for phlegm and expectoration, 6 of 10 studies for dyspnea and shortness of breath, 3 of 6 stud ies for bronchitis, and 8 of 18 studies dealing with asthma incidence, exacerba tion, or symptoms. The inconsistency of association in the foregoing function al and clinical epidemiology studies could either reflect absence of such an association or methodology problems such as reliability of spirometric mea surement, lack of verification of clinical endpoint, errors in classification of smoking and ETS exposure status and inappropriate control of confounding variables. The effects of acute ETS exposure (at levels equivalent to or exceed ing real-life smoke-polluted environments) have been examined in experimen tal studies in which spirometric measures were obtained prior to, during, and after exposure of subjects to machine-generated tobacco smoke. Six of seven studies suggest that acute ETS exposure, while serving as an irritant to the upper respiratory tract, fails adversely to affect pulmonary function of normal adults. The effect of acute ETS exposure in asthmatic subjects has been exam ined in 15 studies. These studies suggest that acute exposure to ETS does not consistently evoke adverse pulmonary effects in most asthmatics. Several studies from a single research group suggest that a small sub-set of asthmatics may respond to acute ETS exposure with a ≥20% decrement in FEV1 as well as an increased responsiveness to bronchoconstrictors. The mechanism for this responsiveness does not appear to be allergic in nature and is subject to speculation.

Depression of hepatic cytochrome P450 monooxygenases after chronic environmental tobacco smoke exposure of young ferrets

Six-week-old ferrets were exposed head-only to clean air or environmental tobacco smoke (ETS) for 2 h/day, 5 days a week for a total of 8 weeks. Exposure to ETS caused a significant reduction in the levels of hepatic microsomal cytochrome P450 and P450 reductase activity in both the male and female ferrets. The content of cytochrome b 5 and the activity of its reductase were significantly reduced in the hepatic microsomes of female ferrets. 7-Ethoxycoumarin O- deethylase activity and cytochrome P450 (CYP) 1A protein were markedly decreased in the hepatic microsomes of both the male and female ferrets after ETS exposure. In accord with the downregulation of P450, total metabolites formed from benzo[ a] pyrene were significantly reduced in the liver homogenates of ETS-exposed animals. Similarly, sum total of free (+)- anti- benzo[ a] pyrene-7,8- dihydrodiol-9,10- epoxide, glutathione conjugates and DNA-bound metabolites formed from precursor (−)-7 R- trans- benzo[ a] pyrene-7,8- dihydrodiol showed marked reduction in both the male and female ferrets after ETS exposure in a dose-response manner. This is the first report showing downregulation of hepatic P450 and accompanying benzo[ a] pyrene metabolism after tobacco smoke exposure which apparently occurred after an initial upregulation of these parameters (Rasmussen et al. (1994) FASEB J. 8, A122).

Effect of chronic tobacco smoke exposure on the function of alveolar macrophages in mice.

We evaluated the effect of chronic tobacco smoke exposure on the function of the alveolar macrophage (AM) in mice. Tumor necrosis factor-alpha production of the AM triggered by lipopolysaccharides was smaller in smoke-exposed mice as compared to control mice but did not reach statistical significance (27.3 +/- 4.0 vs. 34.8 +/- 4.9 U/ml). The percentage of AM which did not phagocytize latex particles in the smoke-exposed mice was significantly larger than that in control mice (33.9 +/- 2.3 vs. 20.8 +/- 2.1%; p < 0.05). Ia antigen expression of the AM was significantly larger in smoke-exposed mice (cytotoxicity index: 0.180 +/- 0.033 vs. 0.038 +/- 0.0118; p < 0.01). The asialo-GM1 antigen expression was similar in both groups (0.949 +/- 0.007 vs. 0.961 +/- 0.011). Although the precise mechanisms of these functional changes of the AM by tobacco smoke exposure are not clear, they may have some immunological effects on the alveolar space.

Time-dependent changes in cardiovascular regulation caused by chronic tobacco smoke exposure

The purpose of this study was to determine whether chronic tobacco smoke exposure for less than 2 mo alters cardiovascular regulation. One group of male Sprague-Dawley rats was administered tobacco smoke from low-nicotine cigarettes (group A, 1 mg/cigarette) for 4-6 wk, while a second group (B) served as a sham control by receiving only puffs of room air. Reflex adjustments in mean arterial blood pressure (MAP) after bilateral common carotid occlusion (BCCO) were compared between the two groups. In the anesthetized control state, no significant difference existed for the cardiovascular parameters measured in the two groups. However, MAP increases after BCCO were significantly greater in the smoke-treated animals (P less than 0.05) compared with the sham-treated group. At 10, 20, 30, and 40 s after BCCO, MAP increases above preocclusion values were 66, 45, 42, and 38% for group A and 35, 26, 24, and 22% for group B, respectively. Additionally, the time required to reach maximum MAP after BCCO was significantly less (P less than 0.05) for the smoke-treated vs. sham-treated animals (8.5 +/- 0.2s for group A, 11.2 +/- 0.3s for group B). MAP changes during BCCO were significantly different (P less than 0.05) between the treatment groups after cervical vagotomy. It is concluded that chronic tobacco smoke exposure in experimental animals for periods as short as 4-6 wk alters the reflex regulation of the cardiovascular system.

Tolerance to tobacco smoke- and nicotine-induced analgesia in rats

Acute exposure of male Sprague-Dawley rats to either nicotine or tobacco smoke results in analgesia as measured by tail-flick latencies. A second treatment, 24 hr after the first, failed to produce analgesia, thereby demonstrating the rapid development of tolerance. The restraint which was a necessary part of the tobacco smoke exposure also produced analgesia, although of a more transient nature and lesser magnitude than the resulting from tobacco smoke exposure. Tolerance also developed to restraint stress-induced analgesia. The long-term (43 weeks) daily exposure of rats to tobacco smoke or restraint stress resulted in the development of cross-tolerance, suggesting that these two procedures share, at least in part, a common mechanism. Additionally, long-term tobacco smoke exposure resulted in an increased tail-flick latency when the animals had been withdrawn from tobacco smoke for 24 hr, suggesting the development of tolerance. The data also suggest a differential time course for the development of tolerance and dependence. This is the first report that addresses the effect of acute and chronic tobacco smoke exposure on pain sensitivity.

Ultrastructure and distribution of intracellular spicules in rat lung following chronic tobacco smoke exposure

Ultrastructure and distribution of intracellular spicules in rat lung following chronic tobacco smoke exposure

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Factors that contribute to the induction of lung tumors in F344 rats by chronic tobacco smoke exposure were studied. Previous studies had shown that tobacco smoke exposures of 1-2 years duration induced only one major type of lesion involving the respiratory airways, i.e., fibrotic and cellular enlargement of peribronchiolar alveolar septa. The airway epithelium in these areas was metaplastic and in some of the lesions, the airway lining epithelium advanced out onto the surfaces of adjacent alveoli. Epithelial cells in these lesions frequently contained elongated cytoplasmic inclusions which were oriented with their long dimensions roughly in the same plane as the long axis of the cell. Macrophages contained similar but larger inclusions. Because the composition of the inclusions could be indicative of their origin, we subjected samples of treated and control lung tissues concurrently to transmission electron microscopy and energy-dispersive X-ray fluorescence spectrometry. Spectra from inclusions of macrophages indicated the presence of the elements sulfur, phosphorus, aluminum, silicon, and iron. Spectra from type II cells, however, which did not contain inclusions, showed a different elemental composition. The results suggested that spicules were present in epithelial cells throughout the airways. Minor lesions corresponding to "microinvasion" of epithelium into the lamina propria and of capillaries into the epithelial layer were also found in the trachea.

Effects of chronic tobacco smoke exposure on arterial blood pressure regulation.

The purpose of this study was to determine the effects of long-term consumption of tobacco smoke on arterial blood pressure regulation. Male Sprague-Dawley rats were administered tobacco smoke for 6-8 mo. Two groups of animals (A and B) received tobacco smoke containing different levels of nicotine (group A: high nicotine, 4 mg/cigarette; group B: low nicotine, 1 mg/cigarette), while a third group (C) served as a sham control by receiving only puffs of room air. Reflex adjustments in mean arterial blood pressure (MAP), heart rate (HR), lower body blood flow, and lower body vascular resistance were compared between the three groups. In the anesthetized control state, no significant difference existed for the cardiovascular parameters measured in the three groups. However, perturbating the cardiovascular system by reducing central blood volume via a 60 degrees head-up tilt elicited less of a fall in MAP in the two smoke groups compared with the sham group. Percent decreases in MAP follow: group A, 23%; group B, 22%; and group C, 48%. Increasing MAP with phenylephrine elicited a significantly greater (P less than 0.05) reduction in HR in groups A and B (smoke treated) compared with group C (sham treated). Finally, varying carotid sinus pressure elicited significantly greater (P less than 0.01) changes in MAP in the smoke-treated animals (A and B) compared with the sham group (C). It is concluded that chronic tobacco smoke administration to laboratory rats increases the sensitivity of the reflex control of the cardiovascular system.

The effects of chronic tobacco smoke exposure from high-tar cigarettes on the phagocytic and killing capacity of polymorphonuclear cells of mice

Mice were exposed to high-tar (HT) (16 mg tar/cigarette) filtered cigarettes for up to 32 weeks. Intraperitoneal caseinate induction of polymorphonuclear (PMN) cells in both tobacco smoke (TS)-exposed and age-matched control mice provided the source of cells which enabled an assessment to be made in vitro of both their phagocytic and degradative properties. Radioactive Staphylococcus aureus were opsonized with either immune serum or heat-inactivated (complement deficient) immune serum for the tests. Two strains of mice were used in all trials. The PMN cells from BALB c strain mice were less affected by TS exposure than those of C57 Black mice in both phagocytic and degradative capacities when the S. aureus were opsonized with immune serum. However, heat inactivation of complement within the serum reduced the differences between TS-exposed animals and age-matched controls in both strains of mice. The treatment effects were seen at all times tested from 3 days to 32 weeks of TS exposure. The results suggest that fc-receptor site activity of PMN cells is not significantly affected by TS exposure but that complement interactions within the phagocytic process are significantly suppressed. Whether this is due directly to complement receptors or metabolic associations of phagocytosis of the complement/opsonin/antigen complex is unclear.

Pathogenesis of Lesions Induced in Rat Lung by Chronic Tobacco Smoke Inhalation23

Lesions were induced in the lungs of specific-pathogen-free F344 rats by chronic tobacco smoke exposure. Animals exposed to 7 cigarettes/day were killed after 1, 1.5, or 2 years of exposure. Parallel lifetime exposures induced pulmonary tumors in 9% of the animals. In serially killed animals, four types of lesions were found: 1) perivascular or peribronchiolar accumulation of lymphoreticular cells, 2) fibrotic and cellular enlargement of peribronchiolar septa, 3) type II cell hyperplasia with septal fibrosis, and 4) air-space enlargement (emphysema). However, emphysema occurred only in animals exposed to a higher (10 cigarettes) dose of tobacco smoke. Ultrastructural studies showed all of the focal lesions to be infiltrated by cells typical of the inflammatory response. The type II hyperplastic and peribronchiolar alveolar lesions involved larger portions of the parenchyma in fibrotic changes but differed in structure, location, and frequency. The incidence of the peribronchiolar alveolar lesions was temporally related to tumor incidence.

Effects of chronic tobacco smoke exposure on immune responses in aged mice.

Balb/c mice were exposed to fresh smoke, equivalent to 30 high-tar filtered cigarettes/day, for 83 wk or less. After groups of mice were subjected to 56, 64, 72, and 80 wk of tobacco smoke (TS) exposure, serum antibody responses to both T-dependent and T-independent antigens, numbers of plaque-forming cells, spleen cell and lymph node PHA responses, and systemic clearance of normal and opsonised antigen were investigated. Aged TS-exposed mice showed some deterioration of immune responsiveness with age, but results varied; in extreme old age the immunological responsiveness of TS-exposed mice was similar to that of age-matched controls. In addition, groups of mice inoculated with fibrosarcoma cells after 78 wk TS-exposure did not show significantly greater susceptibility to the early development of pulmonary metastases.

Aspects of the immunotoxicity of chronic tobacco smoke exposure of the rat

One hundred and eighty Wistar-strain rats were exposed to differing concentrations of tobacco smoke, for periods of up to 20 months, in order to examine the response of the pulmonary immune system. The amount of bronchus-associated lymphoid tissue (BALT) in the lungs of exposed rats increased initially over the first 5 weeks of exposure, subsequently falling to below control levels by the fourteenth week and eventually increasing again to a level slightly higher than that of the controls by the twelfth month, at which level it was maintained until the twentieth month. Quantitative immunohistochemical assay of bronchial immunoglobulin levels (only assessed over the initial 14 weeks of exposure) revealed a transitory enhancement of levels followed by a depression, the speed of response being apparently dose-related. Alveolar macrophage activity, indicated by lysosomal enzyme activity, increased relative to the control animals over the same 14-week exposure period. The significance of these observations is discussed and a tentative explanatory hypothesis is advanced.

Effects of chronic tobacco smoke exposure from high-tar or low-tar cigarettes on the systemic clearance mechanisms of mice

Mice were exposed to high-tar (HT) (16 mg tar/cigarette) or low-tar (LT) (5 mg tar/cigarette) filtered cigarettes for 8 min per day for up to 30 weeks. Phagocytic and degradative properties of the liver and spleen were assessed using unopsonized and opsonized radioactive sheep erythrocytes (SRBC) inoculated intravenously into naive or immune animals. Initially phagocytosis of unopsonized SRBC was shown to be compromised in HT-tobacco smoke-exposed animals of both the Balb c and C57Black strains of mice but not for LT-exposed animals of the BALB c strain of mice. Later phagocytosis was also affected in some instances with opsonized SRBC. Degradation of phagocytosed material did not appear to be compromised until after 18 weeks of chronic exposure. There was clear evidence of the C57Black strain of mice being more generally affected by tobacco smoke exposure than the BALB c strain of mice.

Early effects of tobacco smoke exposure on vascular dynamics in the microcirculation.

The purpose of these studies is to examine the early effects of chronic tobacco smoke exposure on vascular dynamics in the mesenteric microcirculation. Female rats were exposed daily to tobacco smoke from five reference cigarettes for a period of 2 mo. At the end of this period the smoke-treated rats had gained 12 g less than sham-treated controls, and arterial blood pressure in the smoke-treated animals was slightly less than pressure in the sham-treated animals. These are characteristic effects of tobacco smoke exposure on rats. Following the treatment period, red blood cell (RBC) velocity in single mesenteric capillaries and microvascular pressures in arterioles and venules were measured in accordance to established methods. There was no significant difference in pressure distribution on the arterial side of the mesenteric vascular network, but pressure in the venules of the smoke-treated animals was significantly higher than that of the sham-treated group. In association with the higher venular pressure in the smoke-treated animals, capillary RBC velocity (an index of capillary flow) was significantly lower. The reduction in velocity was in proportion to the decrease in pressure drop (arteriole-venule) across the capillary network.