<p><font face="TimesNewRomanPSMT"> <p align="left">Nicotine exposure to the fetus through tobacco smoking or nicotine replacement therapy during the whole period of gestation and lactation causes diverse effects on fetal and neonatal lung development, integrity and maturation which compromise the gas exchange function of the lungs and renders this vital organ susceptible to gradual damage and different diseases in latter life. Maternal nicotine exposure during gestation and lactation results in gradual destruction of the lung parenchyma, and this leads to the combination of many small air sacs in one bigger alveoli which is a sign of emphysema. Many researchers speculated that the way in which, nicotine causes emphysema and other damage, is by inducing the formation of many reactive oxygen species (ROS), and creating an imbalance between the oxidants and the antioxidants of the body, which is termed oxidative stress. The aim of this study was to assess the effects of nicotine exposure on the lung of the fetal and neonate rat during gestation and lactation as gas exchanger, and also to see whether the supplementation of tomato juice containing lycopene, a powerful carotenoid antioxidant could protect the lungs against these effects of maternal nicotine exposure.</p> </font></p>

<p>Nicotine exposure to the fetus through tobacco smoking or nicotine replacement therapy during the whole period of gestation and lactation causes diverse effects on fetal and neonatal lung development, integrity and maturation which compromise the gas exchange function of the lungs and renders this vital organ susceptible to gradual damage and different diseases in latter life. Maternal nicotine exposure during gestation and lactation results in gradual destruction of the lung parenchyma, and this leads to the combination of many small air sacs in one bigger alveoli which is a sign of emphysema. Many researchers speculated that the way in which, nicotine causes emphysema and other damage, is by inducing the formation of many reactive oxygen species (ROS), and creating an imbalance between the oxidants and the antioxidants of the body, which is termed oxidative stress. The aim of this study was to assess the effects of nicotine exposure on the lung of the fetal and neonate rat during gestation and lactation as gas exchanger, and also to see whether the supplementation of tomato juice containing lycopene, a powerful carotenoid antioxidant could protect the lungs against these effects of maternal nicotine exposure. In this study pregnant rats have been divided into 4 groups: a group which received nicotine (1mg/kg body weight/day) subcutaneously, a group that received the tomato juice only (6mg/kg body weight/day per os), a third group that received the combination of tomato juice ( 6mg /kg body weight/ day per os) and nicotine (1mg/kg body weight /day subcutaneously ) . The control group that received saline (1mg/kg body weight /day) subcutaneously and water. The injections were done during pregnancy and lactation until weaning at postnatal day 21. The results showed that maternal nicotine exposure during gestation and lactation leads to a gradual damage of the lung parenchyma and slower formation of the alveoli during the equilibrated phase of the lung growth leading to a decrease in the internal surface area required for gas exchange. Supplementation with tomato juice during gestation and lactation prevents all the adverse effects of maternal nicotine exposure on the lungs of the offspring. Since nicotine induce an increase in the oxidant levels of the mother and the fetus, my results imply that lycopene protected the lungs of the offsprings against the oxidants and thus against changes in the program that controls lung development as the animals age. This is supported by the observation that at postnatal day 84 the antioxidant.</p>

<p>Tobacco smoking remains one of the leading causes of death worldwide. Despite all the efforts made by governments, researchers and communities to educate women about the dangerous effects of tobacco smoke and nicotine, smoking during pregnancy continues to be a common habit and accounts for a significant percentage of fetal morbidity and mortality. The offspring is, as a result, exposed to nicotine through the blood and the milk of the mother. Nicotine is therefore expected to interact with the developing fetus and the offspring of mothers who smoke or use Nicotine Replacement therapy for smoking cessation, resulting in the interference with normal fetal lung development. Maternal cigarette smoke or nicotine exposure produces adverse effects in the lungs of offspring, these include / intrauterine growth retardation, low birth weight, premature birth, reduced pulmonary function at birth, and a high occurrence of respiratory illnesses after birth. The main objectives of this study were to determine: 1) the effects of maternal nicotine exposure during gestation and lactation on lung development in the offspring, 2) if there is evidence of premature aging of the lungs of the lungs of the nicotine exposed offspring, and 3) whether tomato juice can have protective effects on the fetal lung development and function in the offspring. From the study, it was established that maternal nicotine exposure had no significant effect on the growth parameters of the offspring. However, it results in the late onset of gradual parenchymal damage which resembles premature aging. The study also found that the consumption of tomato juice may have protective effects on the premature aging of the lungs of the offspring.</p>

<p>Tobacco smoking during pregnancy and lactation is a common habit and accounts for a significant percentage of fetal morbidity and mortality worldwide. The offspring is as a result exposed to nicotine through the blood and the milk of the mother. Nicotine is thus expected to interact with the developing fetus and the offspring of mothers who smoke or use NRT for smoking cessation, resulting in the interference with normal fetal and neonatal lung development. Maternal cigarette smoke or nicotine exposure produces adverse effects in the lungs of offspring, these include / intrauterine growth retardation, low birth weight, premature birth, reduced pulmonary function at birth, and a high occurrence of respiratory illnesses after birth. This study aimed at investigating&nbsp / the effects of maternal nicotine exposure during gestation and lactation on lung development in the offspring / to establish whether tomato juice can have protective effects on the fetal lung&nbsp / development and function in the offspring / and to determine if nicotine cases premature aging of the lungs of the offspring. It was therefore shown that maternal exposure to nicotine during&nbsp / gestation and lactation ad no significant effect on the growth parameters of the offspring. Maternal nicotine exposure during gestation and lactation had no effect on the growth parameters of&nbsp / the offspring, but resulted in compromised lung structure and function. The morphometric results demonstrated decrease in alveolar number, increase in alveolar size, and decrease in lung&nbsp / parenchyma of the nicotine exposed animals showing a gradual deterioration of the lung parenchyma. Structural alterations include emphysematous lesions, where the latter was&nbsp / accompanied by an increase in alveolar size (Lm), and a decrease in the tissue volume of the lung parenchyma. Thickening of alveolar walls was also evident and serves as an indication of&nbsp / remodeling of the extracellular matrix, also a characteristic of emphysema. A consequence of the gradual deterioration of the lung parenchyma is a decrease in the alveolar surface area available for gas exchange. The present study showed that the emphysematous lesions were conceivably a result of a reduced rate of cell proliferation accompanied by the increase in&nbsp / senescent cells numbers in the alveolar walls of the exposed offspring. The data of this study suggests that maternal nicotine exposure during gestation and lactation induces premature&nbsp / aging of the lungs of the offspring rendering the lungs of the offspring more susceptible to disease later in life. Since these structural changes occurred later in the life of the offspring and long&nbsp / after nicotine withdrawal, it is suggested that it is programmed during gestation and lactation. Smoking and NRT result in an increased load of oxidants in the mother and fetus. It also reduces&nbsp / the level of anti-oxidants and thereby compromising the ability of the mother to protect the fetus. It is hypothesized that this oxidant-antioxidant imbalance will program the lungs to age&nbsp / prematurely. The supplementation of the mother&rsquo / s diet with tomato juice, rich in lycopene, other anti-oxidants such as vitamin C, as well as phytonutrients protected the lungs of the offspring&nbsp / against the adverse effects of maternal nicotine exposure. This supports the hypothesis mentioned above. The study further showed that the effects of grand-maternal nicotine exposure during gestation and lactation on the lungs of the F1 offspring is also transferred to the F2 offspring. This is most likely via the paternal and maternal germ line. Since tomato juice supplementation of the mother&rsquo / s diet with tomato juice prevented&nbsp / the adverse effects of maternal nicotine exposure on the lungs of the offspring, it is conceivable that it will prevent transfer of these changes to the F2 generation.&nbsp / </p>

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

<p>In this manuscript I seek to demonstrate the importance of gene-environment interactions in cardiovascular disease. This manuscript contains five studies each of which contributes to our understanding of the joint impact of genetic variation and environmental exposures to cardiovascular disease: a candidate gene study for gene-smoking interactions associated with early-onset coronary artery disease, an epidemiology study of the association between traffic-related air pollution and cardiovascular disease, a Genome-Wide Interaction Study for gene-by-traffic related air pollution interactions associated with peripheral arterial disease, a Genome-Wide Interaction Study for gene-by-traffic related air pollution interactions on coronary atherosclerosis burden, and a method for analyzing associations between high-dimensional genomics datasets.</p><p> Smoking is a strong risk factors for coronary artery disease, and may play a causative role in the incidence of coronary artery disease. Smoking had been implicated as a reason for heterogeneity observed in associations between genetic variants on chromosome three and coronary artery disease. I used a family-based early-onset coronary artery disease cohort (GENECARD) to study gene-smoking interactions. I also used data from the three independent cohorts to perform a meta-analysis of gene-smoking interactions focusing on the KALRN gene and Rho-GTPase pathway. I found significant evidence for gene-smoking interactions associations involving variants in KALRN and other Rho-GTPase pathway genes on chromosome 3. </p><p> Though the estimated increase in incident cardiovascular disease or cardiovascular events due to air pollution exposure is modest at 3-5%, the ubiquitous nature of air pollution exposures means it has a substantial population-level impact on cardiovascular disease. Historically genome-wide interaction studies with air pollution have not yielded genome-wide significant interactions, however by implementing statistical tools novel to this field I have discovered significant interactions between genetic variants and traffic-related air pollution that are associated with cardiovascular diseases. </p><p> I studied interactions associated with peripheral arterial disease and the number of diseased coronary vessels (an indicator for coronary artery disease burden) using race-stratified cohort study designs. With peripheral arterial disease I observed that variants in both BMP8A and BMP2 showed evidence for interactions in both European-American and African-American cohorts. In BMP8A I uncovered the first genome-wide significant interaction with air pollution associated with cardiovascular disease. BMP2 gene expression is upregulated after exposure to black carbon, a major component of diesel exhaust, and coding variants within this gene showed evidence for interaction. With the number of diseased coronary vessels I observed that variants in PIGR showed significant evidence for involvement in gene-traffic related air pollution interactions. I observed that coding variation within PIGR was associated with coronary artery disease burden in a gene-by-traffic related air pollution interaction model. As PIGR is involved in the immune response it represents a strong candidate gene discovered via an unbiased genome-wide scan.</p><p> The use of high dimensional data to study chronic disease is becoming commonplace. In order to properly analyze high-dimensional data without suffering from high false-discovery rate penalties, the data is often summarized in a way that takes advantage of the correlation structure. Two common approaches for this are principal components analysis and canonical correlation analysis. However neither of these approaches are appropriate when one preferentially desires to preserve structure within the data. To address this shortcoming I developed constrained canonical correlation analysis (cCCA). With cCCA one can evaluate the correlation between two high dimensional datasets while preferentially preserving structure in one of the datasets. This has uses when studying multi-variate outcomes such as cardiovascular disease using multi-variate predictors such as air pollution. Additionally cCCA can be used to create endophenotype factors that specifically explain the variation within a high-dimensional set of predictors (such as gene expression or metabolomics data) with respect to potential endophenotypes for cardiovascular disease, such as cholesterol measures.</p> / Dissertation

In a case-control study comprising 589 cases of male lung cancer in northern Sweden longitudinal data concerning occupations, employments and smoking habits were collected by questionnaires. Pipe smoking was as common as cigarette smoking and gave very similar relative risk. The pipe smoking cases, however, had significantly higher mean age and mean smoking years at the time of diagnosis than the cigarette smoking cases. In ex- smokers, the relative risk gradually decreased from 5 years after smoking cessation but this decrease was much less pronounced in ex-pipe smokers than in ex-cigarette smokers. High relative risks were obtained for small cell and squamous cell carcinomas. For adenocarcinoma the relative risk was considerably lower but still significantly increased. The population etiologic fraction attributable to smoking was about 80% in this series. Some occupational groups (underground miners, copper smelter workers, electricians and plumbers) exposed to previously known lung carcinogenic agents had considerably increased odds ratios, which persisted after adjustment for smoking. A slightly elevated odds ratio was observed in a group of blue collar workers potentially exposed to lung carcinogenic agents but this elevation generally disappeared after adjustment for smoking. For two specific subgroups, asphalt and concrete workers and pulp workers, the overrisk persisted after adjustment for smoking. Farmers and foresters had strikingly low odds ratios, which could only partly be explained by their more moderate smoking habits. The population etiologic fraction attributable to occupation was in the reported material assessed to 9 per cent. Professional drivers had higher average tobacco consumption than non-drivers, which explained the slightly increased crude odds ratio found for the occupational group as a whole. Smoking drivers in an upper age group (70 and over), however, had a high relative risk of lung cancer, while in a lower age group (under 70) no significant increase was found. The results in the older age group suggested a multiplicative effect between smoking and the occupational exposure. The study clearly verified the increased lung cancer risk in underground miners. An obvious dose-response relation was found with high risk after long time exposure. All analyses concerning underground miners suggested an interaction of a multiplicative type between underground mining and smoking in the causation of lung cancer. The cases of small cell carcinoma among the underground miners had shorter average latency time and in contrast to the other part of the material, shorter average age than the cases with epidermoid cancer. / <p>S. 1-40: sammanfattning, s. 41-136: 6 uppsatser</p> / digitalisering@umu

Bronchoalveolar lavage (BAL) is an established method providing diagnostic support and evaluation of disease activity in interstitial lung disease (ILD). The aims of the present investigation were 1) to study the inflammatory response in pneumonitis evoked by irradiation. 2) to evaluate how well lung tissue inflammation is reflected in BAL findings. 3) to study the effect of smoking on radiation-induced pneumonitis. BAL was performed in 21 patients (11 smokers, 10 non-smokers) who were treated for breast cancer, stage 1 (TjMaNq) by post-surgery irradiation to an accumulated target dose of 56 Gy. It was founa that irradiation induced an alveolitis in the non-smoking patient group while the smoking patients did not differ from their smoking controls. The alveolitis in non-smokers was characterized by an increase in lymphocytes, mast cells and elevated concentrations of hyaluronan (HA), and fibronectin (FN). Three of the non-smoking patients had chest X-ray infiltrates indicating the presence of pneumonitis. An animal experimental model for radiation-induced pneumonitis and fibrosis was established in rats, allowing comparative analysis of BAL fluid and morphology. In the rat model a divergence was noted between the differential cell counts in BAL and cells observed in the interstitial tissue, which was most notable for neutrophils (PMN) and mast cells whereas there was a good correlation between HA content in BAL and HA deposition in the lung tissue. A marked infiltration of intraseptally-located mast cells occurred during the pneumonitis-phase, and this increase was paralleled by a deposition of HA in the interstitial tissue. Histochemical fixation and staining properties of the mast cells revealed that the majority of these cells were of connective tissue mast cell type (CTMC). Compound 48/80, a mast cell secretagogue, significantly altered the HA content both in BAL and in lung tissue in the irradiated animals. Regular treatment throughout the whole experimental period induced depletion of mast cell granules and a decrease in HA deposition whereas 48/80 treatment during the pneumonitis phase enhanced HA deposition. A rat model with smoke exposure was developed, and the effect of cigarette smoke on radiation-induced inflammation was studied. Rats that smoked 3 weeks prior to irradiation and continued to smoke throughout the observation period (7 weeks) had a significantly reduced inflammatory response compared to irradiated non-smoking rats. The most prominent BAL findings in the smoke-exposed rats were a decrease in PMN, mast cells and a decrease in HA. In conclusion, irradiation induces an alveolitis characterized mainly by mononuclear cells. Mast cells seem to be of importance in the remodelling of the connective tissue in the radiation-induced inflammatory response. Hyaluronan is an important component in the early connective tissue response preceding later collagen deposition, and its interstitial deposition is very well reflected in BAL. Moreover, tobacco-smoke suppresses the radiation-induced inflammation with a decreased recruitment of effector cells including mast cells. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1992, härtill 5 uppsatser.</p> / digitalisering@umu

There is a robust evidence base for the negative health effects from smoking. Smoking is linked to severe morbidity and to mortality, and kills up to half of its regular users. Tobacco use and production also bring other negative consequences such as economic loss for countries, poverty for individuals, child labour, deforestation and other environmental problems in tobacco growing countries.  A combination of comprehensive interventions at different levels is needed to curb the tobacco epidemic. Tobacco control strategies at national levels in the western world often include components of information/education, taxation, legislative measures and influencing public opinion. Two approaches have dominated at the meso and micro levels: cessation support for tobacco users and prevention activities to support young people refraining from tobacco use. Smoking uptake is a complex process that includes factors at the societal level as well as social and individual characteristics.  At national level, taxation and legislation can contribute to a societal norm opposing tobacco and creating a context for primary prevention aimed at tobacco free youth.  There is no magic bullet in primary prevention.  At the meso and micro levels, a continued development of knowledge on the underlying mechanisms and primary prevention methods is essential to prevent young people from starting to use tobacco.  The overall aim of this thesis was to gain knowledge about factors that influence young people’s use of tobacco and of preventive mechanisms.  The specific aims included to study the relation between Tobacco Free Duo, an intervention program targeting youth in Västerbotten County, and tobacco use prevalence.  A specific interest was to explore the role adults can play in supporting young people to refrain from tobacco use.  The thesis is based on four studies with three separate sets of data, two were quantitative and one was qualitative. The studies were conducted among adolescents (aged 13-15 yr) in Västerbotten County and on national level in Sweden (aged 13, 15 and 17 yr).  Tobacco Free Duo is a school-based community intervention that started in 1993. An essential component of the intervention was to involve adults in supporting adolescents to stay tobacco free. Results showed decreased smoking in adolescents among both boys and girls in the intervention area during the study period of seven years.  There was no change in a national reference group during the same time period. A bonus effect was a decrease in adult tobacco use in the intervention area. One out of four adults who supported a young person taking part in the intervention stopped using tobacco. In a qualitative assessment of young smokers, starting to smoke was described as a means of gaining control of their feelings and their situation during early adolescence. They expected adults to intervene against their smoking and claimed that close relations with caring adults could be a reason for smoking less or trying to quit smoking.  In a quantitative study that used three decades of national data, over time adolescents became more positive toward parental action on children’s smoking. The adolescents strongly supported the idea of parental action, regardless of whether or not they themselves smoked. Adolescents preferred that actions from parents were dissuading their children from smoking, not smoking themselves, and not allowing their children to smoke at home.  These results suggest that the Tobacco Free Duo program contributed to a reduction in adolescent smoking among both boys and girls.  Using a multi-faceted intervention that includes an adolescent-adult partnership can decrease adolescent smoking uptake.  Engaging adults as partners in tobacco prevention interventions that target adolescents has an important tobacco reducing bonus effect in the adults. The intervention has proven sustainable within communities.  A growing majority of adolescents support parental interventions to help them refrain from tobacco.  The findings dismiss the notion that adolescents ignore or even disdain parental practices concerning tobacco. A common and consequent norm against tobacco from both schools and parents using a supportive attitude can prevent tobacco use in young people.

Smoking remains a leading cause of premature, preventable death in South Africa killing 44 000 South Africans each year. Through the introduction of comprehensive tobacco control policies, the South African government has tried to reduce the death toll and a significant reduction in tobacco use has been recorded since its peak in the 1990’s. Smoking among women, however have remained unchanged, which calls for actions. Pregnant mothers are specifically vulnerable as their smoking detrimentally affects their own health as well as the health of their babies. This thesis gives an account of the role the antenatal care system could play in reducing the burden caused by cigarette smoking.   The overall aim was to contribute to an understanding of how a person-centred approach to smoking cessation among disadvantaged pregnant women with high smoking rates may influence smoking behaviour. The specific objectives were to confirm the high smoking rates of the target population, assess their readiness to quit, explore existing barriers and promoting factors towards smoking cessation efforts within the public antenatal health care system, and to qualitatively assess the attitudes and perceptions of disadvantaged pregnant women regarding a personcentred smoking cessation intervention.   The high smoking rates of the target population was confirmed based on a cross-sectional study at antenatal clinics in four main cities of South Africa. It focused on the prevalence of smoking during pregnancy and used the stages of change theory to identify their readiness to quit. Additional questions concerned pregnancy related disease experiences, socio-economic determinants of continued smoking as well as attitudes towards the existing clinic services and its possible role in smoking cessation. A qualitative interview study analyzed more in-depth barriers for two-way communication between pregnant mothers and midwives. Both these studies informed the design and development of a person-centred smoking cessation intervention delivered at four public sector antenatal clinics in Cape Town. The intervention was subjected to a comprehensive evaluation based on a combination of quantitative and qualitative measures. This thesis utilizes data from the qualitative process assessment part, comprising individual interviews and focus group discussions with pregnant women during the implementation period of the intervention.   The survey results pointed out a high prevalence of smoking of 46% amongst disadvantaged pregnant women, with varying readiness for behaviour change. Most women were in the contemplation stage of behaviour change and thus ready to quit. Many of the women felt positive about the role of the midwife as an antenatal care provider, but they did not have confidence in midwives concerning encouraging or supporting women to change addictive behaviour be it smoking, alcohol or other illegal substances. The qualitative research highlighted the need for revised curricula for health education and counselling. The analysis illustrated how the current situation created tension between clinic staff and pregnant women making women feel unworthy and thus leaving little room for changing behaviour. The in-depth interviews and the focus group discussions provided an analytical account of how the person-centred approach in this population was perceived by the women themselves. It illustrated that a multifaceted intervention programme, using peer counselors and educational material designed specifically for a given target population, can successfully bring about behaviour change. The intervention succeeded in shifting women’s perceptions of hopelessness into feelings of being empowered to face their addictions and competent to make a change. Though the intervention meant greater rapport with the midwives, involving peer counsellors was rated highly by the participating women. The women reported having used the educational material and attached a great value to the appropriateness of the material to their life situations, and the effectiveness of having it combined with counselling from a peer counsellor. This qualitative evaluation showed the importance of a multifaceted intervention approach, in helping women identify with their behaviour change.   The thesis highlights the importance of designing smoking cessation interventions that are specific to the needs of target populations. When smoking cessation efforts are included into routine antenatal services it is important that the target group inform the nature and specific components of the intervention.