Smoking Effects

Author: Christian Bertana
Date: 04/03/2009


Cigarette smoke, which can be considered a strong chemical oxidant, has the strongest epidemiological link with Age-Related Macular Degeneration (AMD) ; it is the most important risk factor for pulmonary emphysema and fibrosis as well as is an important risk factor for stroke, mediated in part by accelerated intimal thickening and plaque development. In the Atherosclerosis Risk in Communities Study, active smoking and exposure to environmental tobacco smoke were associated with accelerated progression of intimal/medial thickness of the carotid artery.
In add exposure to secondhand smoke causes 53,000 of the 453,000 deaths caused each year by tobacco use in the United States.


Philip Morris conducted research on tobacco-specific nitrosamines (TSNA) that may explain this phenomenon. TSNAs are a group of highly carcinogenic compounds that are formed exclusively from nicotine and other tobacco alkaloids. They are found in mainstream, sidestream, and secondhand cigarette smoke. Common TSNAs include 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK), N-nitrosonornicotine (NNN), 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol (iso-NNAL), N-nitrosoanabasine (NAB), and N-nitrosoanatabine (NAT). NNK and its metabolic breakdown product NNAL are among the strongest nitrosamine carcinogens
known. NNK causes lung adenomas and adenocarcinomas, whether it is administered p.o., i.p., or via the lung. NNK can also cause cancer of the nasal mucosa and liver. The NNK metabolite NNAL is consistently found in nonsmokers exposed to secondhand smoke. Kinetic studies of TSNAs, done at Philip Morris between 1983 and 1997, show that NNK concentrations in sidestream smoke increase after the smoke is released into room air.

Carotid Artery Intimal Thickening

Increased transcription factor activation, expression of adhesion molecules, and redox gene inducible NO synthase (iNOS) have been demonstrated with exposure to cigarette smoke (CS) and may contribute to increased intimal thickening. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor mediating enzyme induction in response to CS and may have a potentiating effect on CS carcinogenicity. The mouse iNOS promoter13 contains a site that corresponds to the core xenobiotic-responsive element (XRE) to which the AhR binds. Therefore, the AhR may mediate the negative effects of CS on the arterial intima.

Anatomy of airways and transient receptor potential channels

The airways are innervated by branches of the trigeminal and vagal nerves. Among the many classes of nerve fibers are the polymodal nociceptors (PMNs). These unmyelinated neurons send signals that cause the perception of pain in response to potentially damaging thermal, mechanical, and chemical stimuli. Their activation induces protective reflexes and nocifensive behaviors (defensive behavior that is elicited by sensory stimuli that have the potential to cause injury) that include apnea, bradycardia, coughing, mucus secretion, and avoidance behavior. Some well established chemical irritants that activate PMNs include capsaicin (the pungent compound in chili pepper and Mace brand defense sprays), allyl isothiocyanate (present in mustard, wasabi, and horseradish), formaldehyde, nicotine, acid, hydrogen peroxide (H2O2), chlorine, acrolein, and, finally, smoke generated from tobacco. The latter differs from the other compounds in that it comprises at least 5,000 distinct chemicals at varying concentrations. Although there are many types of PMNs, the most common are those that are activated by capsaicin through its receptor, transient receptor potential cation channel, subfamily V, member 1 (TRPV1). TRPV1 is a member of the TRPV subfamily of ion channels that are all inhibited by the polyvalent cationic dye and ion channel blocker ruthenium red, but specific antagonists may exist for individual transient receptor potential channels. For TRPV1, one such antagonist is capsazepine, a synthetic analogue of capsaicin. When capsaicin-sensitive neurons are activated, they transmit nociceptive information to upstream relay centers within the CNS that are associated with pain perception and, importantly, these neurons also release proinflammatory mediators. With respect to cigarette smoke aqueous extract (CSE) as a stimulus, capsaicin-sensitive nociceptors appear to have an important role in physiological changes in airways and afferent control of respiration in response to CSE. Specifically, in rodent neonates, capsaicin pretreatment has been shown to induce degeneration of respiratory tract nociceptors and a longlasting desensitization of the airways to cigarette smoke. In this regard, in rat airways, it was found that capsaicin pretreatment prevented plasma extravasation (a critical component of the inflammatory response that results from the activation of sensory nerve endings and the subsequent release of proinflammatory neuropeptides) in response to exposure to cigarette smoke. Interestingly, plasma extravasation was inhibited by ruthenium red but not by capsazepine. These results indicated that TRPV1 capsaicin receptor–expressing neurons are important in airway sensitivity but that the TRPV1 capsaicin receptor is not the receptor for the majority of chemicals in cigarette smoke.

TRPA1 and cigarette smoke

The Ca2+- permeable transient receptor potential cation channel, subfamily A, member 1 (TRPA1) channel as the receptor for some of the principal components of CSE, namely crotonaldehyde and acrolein. TRPA1, like TRPV1, is expressed by trigeminal and nodose/jugular ganglia neurons and moreover, both channels are most often found in the same neuron. This means that activation of TRPA1 will likely exert effects similar to those observed following the activation of TRPV1.

Using a variety of techniques, Andrè et al. showed that the α,β-unsaturated aldehydes crotonaldehyde and acrolein, the most abundant unsaturated aldehydes in CSE, induce neurogenic inflammation by stimulating TRPA1 channels coexpressed with TRPV1 on capsaicin-sensitive nociceptors. After identifying TRPA1 neurons in guinea pig jugular ganglia, the authors cultured these neurons and used Ca2+ imaging to show that, in capsaicin-sensitive neurons, CSE and both unsaturated aldehydes activated these neurons in a dose-dependent manner. Importantly, the responses were inhibited by HC-030031, but not by capsazepine or a variety of ROS scavengers. They showed that nicotine did not activate TRPA1 and that acetaldehyde, the most abundant saturated aldehyde present in CSE, produced a small response at high concentrations but was not inhibited by HC-030031. Also, they provide evidence that HEK293 cells heterologously expressing TRPA1 were responsive to CSE as well as to the two unsaturated aldehydes. This was true also for dorsal root ganglia (DRG) neurons from Trpa1+/+ but not from Trpa1–/– mice. Using slices of guinea pig airways, they showed that acrolein or crotonaldehyde induced release of the neuropeptides substance P and calcitonin gene–related peptide. This release was reduced when the neurons were desensitized with capsaicin and/or when extracellular Ca2+ was removed, thus showing that CSE and unsaturated aldehydes cause an extracellular Ca2+–dependent release of neuropeptides from capsaicinsensitive airway sensory nerve terminals. In physiological experiments using isolated guinea pig bronchial rings, the authors showed that CSE, as well as acrolein or crotonaldehyde, produced a contraction of the bronchial rings that was inhibited by HC-030031 but not by capsazepine or ROS scavengers. Finally, installation of CSE into the trachea of wild-type and Trpa1–/– mice revealed that plasma extravasation was only observed in wild-type mice. In summary, Andrè et al. showed that cigarette smoke–induced airway neurogenic inflammation is mediated by α,β-unsaturated aldehydes and their activation of the TRPA1 receptor.

Age-Related Macular Degeneration (AMD)

Oxidative stress has long been hypothesized to play a substantive role in the development of AMD due to the high oxidative stress environment of the fundus. The Age Related Eye Disease (ARED) study showed that high dose antioxidant vitamin therapy reduced the advancement of intermediate non-neovascular AMD, and that this benefit was associated with a reduction in plasma glutathione and cysteine oxidation. While the genetic variations of several complement factors have been associated with AMD susceptibility, different studies also have identified a susceptibility locus for AMD may be located in or near the hypothetical LOC387715 gene. Kanda et al have confirmed that this locus was the susceptibility locus for AMD, and that this gene encodes a mitochondrial protein. Interestingly, this locus may be associated with smoking, and the combination of the LOC387715 polymorphismand smoking confers a higher risk for AMD than either factor alone. This finding, along with its identification as a mitochondrial protein, raises suspicion for a role of the oxidative defense response in this disease. Further evidence for genetic susceptibility related to oxidative stress has been provided by Canter et al, who have correlated the mitochondrial DNA polymorphism A4917G with AMD and Kimura et al, who showed that a polymorphism in superoxide dismutase 2 (SOD2) is associated with AMD in a small subset of patients. Cigarette smoke, which can be considered a strong chemical oxidant, has the strongest epidemiological link with AMD.

Cigarette smoking is the most important risk factor for pulmonary emphysema and fibrosis.

In fact, cigarette smoking is thought to be the cause of recurrent epithelial injury and impaired repair. For example, previous studies have shown that CS causes death of alveolar epithelial cells, and that CS inhibits epithelial repair responses, such as chemotaxis, proliferation, and contraction of three-dimensional collagen gels.
The alveolar epithelium is often injured by a variety of inhaled toxins, such as SO2, O3, NO2, and cigarette smoke (CS), and when injured, it initiates repair responses. Appropriate repair responses by alveolar epithelial cells require their integrated ability to migrate, proliferate, and differentiate to cover defects that result from the injury. Failure of the epithelium to repair itself is assumed to be an important cause of chronic lung diseases, such as pulmonary emphysema and fibrosis. Epithelial injury and regeneration are thought to occur continually in such diseases, and the repeated cell cycles of the epithelial cells at the site of injury may shorten the length of telomeres, thereby potentially inducing replicative senescence. Inhaled toxins also generate oxidative stress and DNA damage in epithelial cells, which may cause stress-induced senescence. Once epithelial cells reach the senescence stage, they can no longer proliferate. The repair responses by alveolar epithelial cells may cease as a result, and the cessation of the repair responses may in turn result in architectural and functional disruptions in the alveolar epithelium that may allow lung diseases to progress.
Cellular senescence is a state of irreversible growth arrest induced either by telomere shortening (replicative senescence) or by telomere-independent signals, such as DNA damage and oxidative stress (stress-induced senescence). The state of cellular senescence is accompanied by various phenotypic changes, including a distinct, flat, and enlarged cell morphology, an increase in senescence-associated _-galactosidase (SA _-gal) activity, accumulation of lipofuscin, and the expression of cell
cycle inhibitors, such as p16INK4a and p21CIP1/WAF1/Sdi1. Recent evidence suggests that cellular senescence plays an important role not only in physiologic aging processes, but in pathologic disease states, such as liver cirrhosis and atherosclerosis.
Recent studies have shown that two families of cyclin-dependent kinase inhibitors (CKIs) are involved in the intracellular signaling pathways mediating cellular senescence. The first family, inhibit cyclin-dependent kinase (INK)4, includes p15INK4b, p16INK4a, p18INK4c, and p19INK4d,which bind specifically to cyclin-dependent kinase (CDK) 4 and CDK6 and prevent the formation of cyclin D–CDK complexes. p21CIP1/WAF1/Sdi1, p27KIP1, p57KIP2 form the second family, CIP/KIP, which binds to CDK4-cyclin D, CDK6-cyclinD,CDK2-cyclinE, andCDK6-cyclinDcomplexes.
CS-induced senescence of alveolar epithelial cells is associated with the accumulation of p21CIP1/WAF1/Sdi1 protein (exposure to either CSE or H2O2
increases the level of p21CIP1/WAF1/Sdi1 mRNA).

2012-09-22T10:14:57 - Marco Turco

Maternal smoking during pregnancy and offspring obesity


Despite decades of research, press, counter-advertising, and litigation regarding its adverse effects, tobacco use remains a major cause of preventable morbidity and mortality world-wide.
Although fewer women in the US and Britain now smoke than in past decades, an increasing number of teenage girls are initiating smoking, and smoking rates are declining less rapidly among women than among men, so cigarette smoking remains common among women who are of childbearing age, pregnant, or breastfeeding. In the developing world, a small but rapidly expanding proportion of women smoke.
Exposure to cigarette smoke in utero puts a fetus at increased risk for a number of adverse health outcomes, including growth restriction. Whereas smaller size at birth is generally associated with reduced later risk for overweight, recent research suggests that mothers who smoke during pregnancy have children at increased risk for later obesity. The combination of small size at birth and overweight in later life is not only characteristic of the epidemiologic transition from acute to chronic disease, but also confers a high risk of cardiovascular outcomes in adulthood.
The magnitude of the association between prenatal smoking and childhood overweight and independence from social influences are not clear.

Smoking during pregnancy and the impact on offspring

Smoking during pregnancy puts physiological pressure on the mother’s metabolic system and is significant contributor to adverse pregnancy outcomes, including miscarriage , low birth weight, preterm birth and perinatal death. Moreover, it significantly interrupts fetal development and predicts the future risks for respiratory dysfunction, social behavioral problems, cardiovascular disease, obesity, and type-2 diabetes. Despite the disadvantages of maternal smoking, reports still show that 25–29% pregnant women smoke during pregnancy. Some of these processes along with the underlying neurophysiological changes are shown diagrammatically in Figure1.

Figure 1: Neurophysiological mechanism of how maternal smoking programs metabolic disorders in offspring.

Effects on body weight and eating behavior in offspring

In Western countries, it is maternal smoking during pregnancy rather than poverty that is the major cause of low birth weight. Even maternal obesity cannot counteract the infant growth retardation due to smoking during pregnancy. Studies in humans and other primates suggest that lower birth weight associated with maternal smoking is mainly nicotine-mediated. However,brain weight does not appear to be affected by intrauterine nicotine exposure; an observation that may be due to the redistribution of nutrients to preserve brain growth, at the cost of the development of other organs such as the liver and pancreas. Catch up grow this normally observed in children exposed to intrauterine maternal smoking, and there is evidence linking maternal smoking and childhood obesity in offspring, especially those from the mothers who smoke during early pregnancy. It has been reported that children of mothers who smoked during pregnancy started to display an increased risk of being overweight at 5 years of age. Adolescents who are the offspring of mothers who smoked had an increased risk of being among the highest percentile for body mass index. Interestingly, smoking cessation after the first trimester does not appear to reduce this risk to the offspring, suggesting that the first 3 months of pregnancy are critical for long-term impacts on the well being of the offspring. However, children from former smoking mothers did not show increased risk of obesity. Smoking mothers tend to have a shorter breastfeeding period, which deprives the offspring of the protection provided by breast milk against future eating disorders. On this basis,it can be suggested that the rapid weight gain during the early postnatal period may be due to the effect of nicotine withdrawal,in a similar manner to thei ncreased craving for food and subsequent weight gain seen in smokers after smoking cessation. Furthermore,as children also tend to copy the eating habits of their parents, this will be detrimental in the children of smokers, as smokers are more likely to choose foods low in fiber, vitamins and minerals,and high in mono-unsaturated fatty acids, starch, as well as sugar-sweetened soft drinks. Indeed, the children of smokers are more likely to be exposed to passive smoking, with on going detrimental effects of the chemicals in the cigarette smoke.

Effects on brain energy homeostatic regulators

"Nicotine": can have a profound impact on the developing fetal brain, via its ability to rapidly and fully pass across the placenta, with fetal concentrations 115% of maternal levels. When the fetus leaves the womb, the supply of nicotine is removed, and the impact of nicotine withdrawal can be observed in these newborns, as they show increased signs of stress and dysregulation of the hypothalamic-pituitary-adrenalaxis. Studies in humans, other primates,and mice have observed some neuronal abnormalities relevant to feeding regulation that result from maternal smoking or exposure to nicotine. However, the impact of maternal smoking during gestation on brain energy homeostatic pathways in the offspring requires further study. Maternal smoking is clearly linked to abnormal hypothalamic gene expression of appetite regulators,with NPY and POMC gene expression in the arcuate nucleus of the hypothalamus being significantly down regulated in the newborn primate following intrauterine nicotine exposure; a state that may reflect an under-developed brain. This state is similar to observations in adult animals with nicotine or cigarette smoke exposure, as clarified above. Indeed, it can be suggested that without the continuing inhibition of nicotine, NPY, and POMC gene expression can rebound to that equal to an early postnatal age, leading to hyperphagia and future obesity. As yet there is no direct data to date to support this hypothesis. However, studies of mouse models have examined the adult offspring from mothers exposed to cigarette smoke and/or those consuming a high-fat diet during the pregnancy (Chen et al., 2011). Surprisingly, despite increased adiposity in offspring from smoke-exposed mothers, their daily caloric intake was actually lower than the offspring from control mothers, regardless of postnatal diet type. Although the levels of POMC were not different between groups, NPY gene expression was only suppressed by maternal consumption of a high-fat diet,and not intrauterine smoke exposure perse. However, NPY Y1 receptor gene expression was significantly down-regulated by both maternal smoke exposure and a high-fat diet,with this being reflected by reduced food intake in those offspring (Chen et al., 2011) . In addition,other components of cigarette smoke,such as carbonmonoxide and ingredients in tobacco tar, can also directly affect the fetal brain, and there by contribute to the above changes in the fetal brain (Ernst et al., 2001) . It can be suggested that at adulthood,the changes in brain appetite regulators may be an adaptation to increased adiposity, rather than a prolonged impact of intrauterine smoke exposure.
Another important appetite regulator is the adipocyte-derived hormone leptin,which is critical for the development of neurons and neural projections between hypothalamic nuclei involved in appetite control in early life (Bouret et al., 2004) . In mice, a lack of leptin during the early postnatal period results in sparse neuronal projections in the hypothalamus, and later in life,an obese phenotype. Leptin supplementation during this early postnatal period can partially restore the reduced hypothalamic neural projections in the leptin-deficient ob/ob mouse, and partially reverse the hyperphagic phenotype (Bouret et al., 2004) . In humans,cord blood leptin concentrations in both full-term and preterm newborns from smoking mothers are reported to be significantly decreased compared to those from non-smoking mothers.
It has been suggested that smoking might increase the production of catecholamines in the infants leading to lipolysis and fat loss, which can be associated with decreased leptin levels (Ozkan et al., 2005) , as circulating leptin levels are in relative proportion to fat mass.In a similar manner, in primates serum leptin levels are reduced by s50% in newborns from nicotine-treated mothers compared with those from control mothers (Grove et al., 2001) .
One hypothesis that may account for this observation is that reduced leptin in newborns from smoking mothers may interrupt the development of the neurons controlling energy homeostasis, contributing to unhealthy eating behavior at adulthood. As with smokers, it may be that the reward pathways override the energy homeostatic control in such offspring, resulting in a preference for junk foods.
Studies of offspring from nicotine-treated animals show that dopamine receptor binding affinity is increased, despite reduced receptor density; while brain serotonin turnover was reduced, whilst its transporter was increased in such offspring. In the original studies of this topic,this finding was used to explain the abnormal social behavioral problems, such as attention deficit, hyperactivity disorder or addiction, as found in offspring with intrauterine nicotine exposure. However, changes in the reward pathway may also underlie the un healthy eating behavior.


Maternal smoking or nicotine replacement can clearly lead to unhealthy eating habits (such as junk food addiction) and other behavioral disorders in the offspring. Thus, smoking cessation without nicotine replacement during pregnancy is recommended.

2011-09-05T22:12:48 - Gianpiero Pescarmona

Moms' smoking tied to psychiatric meds in kids:study

Moms' smoking linked to psychiatric meds in kids
Aug 29 (Reuters) - Children whose mothers smoked while pregnant were more likely to end up on medications such as antidepressants, stimulants and drugs for addiction, according to a study from Finland that hints at smoking's affect on a baby's developing brain.

While the findings don't prove that cigarette smoking during pregnancy causes changes in children's brains or behavior, they offer one more piece of evidence that should encourage women not to smoke while pregnant, the researchers wrote in the American Journal of Epidemiology.

"The exposure was significantly associated with the risk for all medication use and for both single- and multiple-drug consumption even after adjustment (e.g. mothers' severe psychiatric illnesses," wrote lead researcher Mikael Ekblad, at the Department of Pediatrics at Turku University Hospital.

"These findings show that exposure to smoking during pregnancy is linked to both mild and severe psychiatric morbidity."

Ekblad and his colleagues used Finnish data for 175,000 children born in the country between 1987 and 1989. At that time, midwives had asked all new mothers if they smoked during pregnancy.

The researchers then matched those birth records to a nationwide database of prescription drugs covered by insurance between 1994 and 2007 -- when the children were between five and 20 years old.

One in 11 children was prescribed a psychiatric medication at some point during that period, including anti-anxiety drugs, antipsychotics, antidepressants, stimulants and drugs for addiction.

Of children and teens whose mothers didn't smoke during pregnancy, 8 percent were on at least one of those drugs during the study period. That compared to 11 percent of those whose mothers smoked fewer than 10 cigarettes per day, and close to 14 percent whose mothers had lit up more than 10 times a day.

The link remained when researchers left out babies who were born early or very small, which are other factors that could affect future mental health.

It also stuck when they looked at each class of drugs on its own, and was strongest for stimulant drugs that target attention problems and hyperactivity, and drugs for addiction.

The study is "entirely consistent with a large and still-growing research literature on the effects of prenatal and secondhand smoke exposure on the mental ealth of children," said Michael Weitzman, who studies that topic at New York University Medical Center and was not involved in the study.

"I find it very interesting and very important."

Exactly how smoking may change a growing baby or child's brain is unclear. It's possible that nicotine could affect brain development, or that access to oxygen during pregnancy might be reduced when the mothers smoke, the researchers said.

Weitzman, who said he thought the research was the first he knew of that looked specifically at the use of psychiatric medications in children whose mothers smoked, added that he thought it was "new and intriguing" that depression medications were also linked to smoking.

But the study had its limitations. Ekblad and his colleagues couldn't take into account whether the mothers had been on psychotropic medications themselves, or if they used alcohol or illicit drugs during pregnancy.

They also didn't know which fathers smoked while the children were in the womb, or if either parent smoked after the babies were born, when their brains would still have been developing.

Weitzman added that it can be hard to disentangle the effects of parental smoking during pregnancy from smoking when children are growing up.

"Very few women smoke just during pregnancy," he added. SOURCE: (Reporting by Genevra Pittman at Reuters Health; editing by Elaine Lies)

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