ByFatma hussien fahmy

• What is cigarette smoke ??• Constituents of cigarette smoke• examples on harmful effects of some Constituents• Oxidants in the Cigarette Smoke• membrane lipid peroxidation• Cigarette Smoke Constituents and Cardiovascular Disease• Case study ” Oxidative Stress Bio Markers and Antioxidant

Status in Cigarette Smokers Compared to Nonsmokers”• The effect of smoking on the body • What are the risks of tobacco smoke to nonsmokers?• What are the immediate benefits of quitting smoking?

• Cigarette smoking is a serious health problem and most important avoidable causes of death in world .

• Smoking has been strongly implicated as a risk factor for chronic obstructive pulmonary disease, cancer and atherosclerosis etc .

• Three million deaths annually because of smoking – means one death after every 8 seconds.

• Ten million deaths annually expected by 2020 - means one death after every three seconds.

• Developed countries have reduced smoking by 10% while developing countries have increased by 60% after 1970.

• Cigarette smoke is a complex mixture of chemicals containing more than 4000 different constituents. Some of the compounds identified include

1. different pyridine alkaloids such as nicotine.

2. Ammonia, Acrolein, phenols, acetaldehyde, N-nitrosamine;

3. polycyclic aromatic hydrocarbons such as benzopyrine;

4. combustion gases such as carbon monoxide, nitrogen oxides, hydrogen cyanide;

5. trace metals, lead,iron, cadmium, and mercury

6. radioactive elements such as polonium, radium, and thorium .

• Ammonia: Household cleaner

• Arsenic: Used in rat poisons• Benzene: making dyes, synthetic rubber• Butane: Gas; used in lighter fluid• Carbon monoxide: Poisonous gas•

Cadmium: Used in batteries•

Cyanide: Deadly poison• DDT: A banned insecticide

•Ethyl Furoate: Causes liver damage in animals

•Lead: Poisonous in high doses

•Formaldehiyde: Used to preserve dead specimens

•Methoprene: Insecticide

•Napthalene: Ingredient in mothballs

•Polonium: Cancer-causing radioactive element

• Two major phases were identified in cigarette smoke: • a tar phase and a gas phase; both phases are rich in

oxygen-centered, carbon-centered and nitrogen-centered free radicals as well as non-radical oxidants.

• From the analysis of each phase, it was estimated that a single cigarette puff contains approximately, 1014 free radicals in the tar phase, and 1015 radicals in the gas phase.

• These include various compounds, which are capable of causing an increase in the generation of various reactive oxygen species (ROS) like superoxide (O2• ‾) hydrogen peroxide (H2O2), hydroxyl (OH• ) and peroxyl (ROO•) radicals.

These reactive oxygen species in turn are capable of initiating and promoting oxidative damage in the form of lipid peroxidation

The free radicals in cigarette smoke can be classified into two categories:

• (1) free radicals that form during the burning of tobacco and the smoking process,it includes the radicals in the TPM and the gas phase

• (2) free radicals that are not initially present in the smoke, but are generated either when the gas phase or the TPM constituents are oxidized in the smoke aerosol, or when they dissolve in oxygenated aqueous solutions or biological media , it includes semiquinone radicals, ROS, and RNS.

• Oxidation of hydroquinone (QH2) by molecular oxygen in aqueous solution generates the semiquinone (Q– ・ ) and superoxide radicals following reaction 1:

QH2 + O2→ Q–• + O2–• + 2H+ (1)• Spontaneous disproportionation of the superoxide radical

anion, or catalytic disproportionation in vivo by SOD, generates H2O2 (reaction 2). In the presence of transition metal ions, H2O2 can undergo disproportionation to generate hydroxyl radical, a powerful oxidant (reaction 3).

O2–• + 2H+→ H2O2 (2) H2O2 + Fe²+→ •OH + OH– + Fe³+ (3)• Superoxide and hydroxyl radicals have been shown to form

in aqueous extracts of cigarette smoke

• NO ・ and peroxynitrites are the major reactive nitrogen species derived from cigarette smoke. The yields of NO ・from 49 commercial cigarettes smoked on a smoking machine under ISO conditions were reported to be 78–487 μg per cigarette .

• NO ・ forms in the cigarette gas phase from the burning of different tobacco constituents showed that NO ・ from heated tobacco is produced in two distinct temperature ranges,

• a low-temperature range (275–375 °C) in an oxygen-free atmosphere, and

• a high-temperature range (425–525 °C) that requires an oxygen-containing atmosphere.

• Nitrates were determined to be the source of NO ・ formation in the low-temperature ranges, and amino acids and proteins were suggested to be the sources of NO ・ at the higher-temperature ranges.

• Peroxynitrite forms by the reaction of NO ・ and superoxide radicals.

• Alkyl peroxynitrites can also form by reaction of NO ・ and peroxyl radicals, which are presumed to form in the gas phase of cigarette smoke .

• Peroxynitrite in cigarette smoke extract has been shown to react with and inactivate the α1-proteinase inhibitor.

• Peroxynitrite has also been identified as an oxidative stress-inducing constituent of aqueous cigarette smoke fractions.

• After depletion of intracellular GSH by electrophilic aldehydes, peroxynitrite interferes with specific target molecules, resulting in the activation of stress signal transduction and stress gene expression in cigarette smoke-treated cells in vitro

• Glutathione is abundant in cytoplasm, nuclei, and mitochondria and is the major water- soluble antioxidant in these cell compartments at millimolar concentrations.

• High levels of GSH are found in the extracellular lung lining fluid (about 100 μmol/l), but not in blood plasma, where concentrations are very low (<1 μmol/l).

• Among the intracellular nonprotein thiols such as cysteine, homocysteine, α- lipoic acid, and coenzyme A, GSH accounts for more than 90% of the total thiols.

• GSH and other thiols react more easily with α,β-unsaturated aldehydes (acrolein and crotonaldehyde ) at the β-carbon than at the carbonyl carbon.

• Modifications of intracellular GSH by electrophiles in the gas phase of cigarette smoke were first reported decades ago reported that the concentration of protein sulfhydryl groups in blood plasma is about 500 μM.

• After exposure to cigarette smoke, the concentration of protein sulfhydryl groups was reduced by ca. 60%.

• NO ・ , which is abundant in the cigarette smoke gas phase, can react with GSH to form S-nitroso-GSH (GSNO)

• Quinones form covalent bonds with essential biological molecules (especially molecules containing thiol groups).

• redox-inactive metals such as lead, cadmium, and mercury can deplete cells of thiol-containing antioxidants

• Quinones are readily formed from cigarette smoke constituents that can undergo autooxidation.

• Benzoquinone, for example, forms by the autooxidation of hydroquinone or by oxidation in vivo in living organisms..

• In general, the toxicity of quinones is believed to occur by two mechanisms,

1. the redox cycling mechanism, which generates excess ROS as byproducts, and

2. the formation of covalent bonds with essential biological molecules (especially molecules containing thiol groups).

• The reduction of quinones by NADPH or ascorbate regenerates the parent quinols, thereby creating the redox cycle.

• Redox cycling of xenobiotic quinones can significantly increase the cellular burden of ROS and deplete their antioxidant defenses.

• Tobacco plants transport metal ions from the soil through the roots into the leaves .Trace amounts of heavy metals accumulate in the leaves

• Many investigations have suggested that metal-induced oxidative stress can be partially responsible for the toxicity of these metals.

• Redox-active metals, such as iron, copper, nickel, and chromium, can undergo redox cycling in oxygenated aqueous solutions, with the concomitant formation of ROS,

• whereas redox-inactive metals such as lead, cadmium, and mercury can deplete cells of thiol-containing antioxidants and reduce the activity of antioxidant enzymes.

• Heavy metals can exert other molecular effects such as inhibition of DNA repair and activation of cellular signaling .

• Thus, both redox-active and redox-inactive metals can potentially cause an increase in ROS in smokers.

O2● − and OH● generated and released by activated immune and inflammatory cells are highly cytotoxic and when generated in close proximity to a cell, oxidize membrane phospholipids (lipid peroxidation), which may initiate a chain reaction.

A direct result of such a process is the generation of toxic downstream lipid peroxidation products, such as malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE),and acrolein, The peroxidative alteration of polyunsaturated fatty acids severely impairs functions of the membrane, membrane-bound receptors, enzymes, and receptor/enzyme translocation. In addition,there is increased tissue permeability because of loss of membrane fluidity, which has been implicated in the etiogenesis of diverse lung injuriesLipid peroxidation may also have a role in the signaling events in the molecular mechanisms involved in the lung inflammation observed in COPD.

Three constituents of cigarette smoke have received the greatest attention as potential contributors to CVD: nicotine, carbon monoxide (CO), and oxidant gases.

Nicotine is a sympathomimetic drug that releases catecholamines both locally from neurons and systemically from the adrenal gland and thus it increase the heart rate.

Nicotine may also contribute to endothelial dysfunction, lipid abnormalities, and insulin resistance.

• CO is a major constituent of cigarette smoke. • CO binds avidly to hemoglobin, reducing the amount of hemoglobin available to carry oxygen and impeding release of oxygen by hemoglobin. • CO exposure can aggravate ischemia and worsen symptoms in persons with vascular disease

• A reactive aldehyde produced by endogenous lipid peroxidation, is present at high levels in cigarette smoke.

• Acrolein binds covalently to form protein adducts, and acrolein-induced modification of proteins has been implicated in atherogenesis.

• It modifies apolipoprotein A-I (APO A-I), the major protein in HDL. • Acrolein also oxidized thioredoxins 1 and 2 in endothelial cells.

• . In addition, acrolein induces production of the enzyme cyclooxygenase-2 (COX-2) in human endothelial cells in vitro .

• . Acrolein may contribute to thrombogenicity in smokers by inhibiting antithrombin activity

• Finally, acrolein induces hypercontraction in isolated human arteries and could contribute to smoking-induced coronary vasospasm .

Study populationThe study population consisted of 200 male (age-matched)

subjects divided into two groups viz. 100 smokers and age- and sexmatched non-smokers (healthy volunteers) 100 subjects were selected.

Blood collection and hemolysate preparationBlood samples were collected by venous puncture in

heparinized tubes and the plasma was separated by centrifugation at 1000 g for 15 min. After centrifugation, the buffy coat was removed and the packed cells were washed three times with physiological saline.

Blood analysis 1. Estimation of lipids and cardiac markers2. Estimation of lipid peroxidation3. Assay of enzymatic antioxidants4. Estimation of non-enzymatic antioxidants

• Your body has a stress hormone called corticosterone, which lowers the effects of nicotine. If you’re under a lot of stress, you’ll need more nicotine to get the same effect.

• Physical withdrawal from smoking can impair your cognitive functioning and make you feel anxious, irritated, and depressed. Withdrawal can also cause headaches and sleep problems.

•One of the ingredients in tobacco is a mood-altering drug called nicotine. Nicotine reaches your brain in mere seconds. It’s a central nervous system stimulant, so it makes you feel more energized for a little while. As that effect subsides, you feel tired and crave more. Nicotine is habit forming.•Smoking increases risk of cataracts and poor eyesight.• It can also weaken your sense of taste and sense of smell

• Smokers have a higher risk of respiratory infections, colds, and flu.• In a condition called emphysema, the air sacs in your lungs are

destroyed. In chronic bronchitis, the lining of the tubes of the lungs becomes inflamed.

• Over time, smokers are at increased risk of developing these forms of chronic obstructive pulmonary disease (COPD). Long-term smokers are also at increased risk of lung cancer.

•When you inhale smoke, you’re taking in substances that can damage your lungs. Over time, your lungs lose their ability to filter harmful chemicals. Coughing can’t clear out the toxins sufficiently, so these toxins get trapped in the lungs.

• Smoking damages your entire cardiovascular system. When nicotine hits your body, it gives your blood sugar a boost. After a short time, you’re left feeling tired and craving more. Nicotine causes blood vessels to tighten, which restricts the flow of blood (peripheral artery disease). Smoking lowers good cholesterol levels and raises blood pressure, which can result in stretching of the arteries and a buildup of bad cholesterol (atherosclerosis). Smoking raises the risk of forming blood clots.Blood clots and weakened blood vessels in the brain increase a smoker’s risk of stroke. Smokers who have heart bypass surgery are at increased risk of recurrent coronary heart disease. In the long term, smokers are at greater risk of blood cancer (leukemia).

• Some of the more obvious signs of smoking involve the skin.

• The substances in tobacco smoke actually change the structure of your skin.

• Smoking causes skin discoloration, wrinkles, and premature aging.

• Your fingernails and the skin on your fingers may have yellow staining from holding cigarettes.

• Smokers usually develop yellow or brown stains on their teeth.

• Hair holds on to the smell of tobacco long after you put your cigarette out. It even clings to nonsmokers.

• Smokers are at great risk of developing oral problems. Tobacco use can cause gum inflammation (gingivitis) or infection (periodontitis). These problems can lead to tooth decay, tooth loss, and bad breath.

• Smoking also increases risk of cancer of the mouth, throat, larynx, and esophagus. Smokers have higher rates of kidney cancer and pancreatic cancer.

• Smoking also depresses appetite, so you may not be getting all the nutrients your body needs. Withdrawal from tobacco products can cause nausea.

You're more likely to get type 2 diabetes if you smoke. The risk of developing type 2 diabetes is 30 to 40 percent higher for smokers than non-smokers.

Additionally smoking increases the risk of complications once diagnosed with diabetes, such as heart and kidney disease, poor blood flow to legs and feet

(which leads to infections and possible amputation),

• blindness and nerve damage.

• Both men and women who smoke are at higher risk of infertility.

• Women who smoke may experience menopause at an earlier age than nonsmoking women.

• Smoking increases a woman’s risk of cervical cancer.

• Smokers experience more complications of pregnancy, including miscarriage, problems with the placenta, and premature delivery.

• Pregnant mothers who are exposed to secondhand smoke are also more likely to have a baby with low birth weight. Babies born to mothers who smoke while pregnant are at greater risk of low birth weight, birth defects, and sudden infant death syndrome (SIDS).

• Secondhand smoke (also called environmental tobacco smoke, involuntary smoking, and passive smoking) is the combination of “sidestream” smoke (the smoke given off by a burning tobacco product) and “mainstream” smoke (the smoke exhaled by a smoker)

•The U.S. Environmental Protection Agency has classified secondhand smoke as a known human carcinogen (cancer-causing agent) .

•Inhaling secondhand smoke causes lung cancer in nonsmoking adults. Approximately 7,300 lung cancer deaths occur each year among adult nonsmokers in the United States as a result of exposure to secondhand smoke . •The U.S. Surgeon General estimates that living with a smoker increases a nonsmoker’s chances of developing lung cancer by 20 to 30 percent .•Exposure to secondhand smoke may increase the risk of heart disease by an estimated 25 to 30 percent .(34,000 deaths from heart disease each year )

• Exposure to secondhand smoke also increases the risk of stroke by 20 to 30 percent .

• Pregnant women exposed to secondhand smoke are at risk of having a baby with low birth weight .

• Children exposed to secondhand smoke are at an increased risk of SIDS, ear infections, colds, pneumonia, and bronchitis.

•  It can also increase the frequency and severity of asthma symptoms among children who have asthma.

• Being exposed to secondhand smoke slows the growth of children’s lungs and can cause them to cough, wheeze, and feel breathless 

• Heart rate and blood pressure, which are abnormally high while smoking, begin to return to normal.

1. Within a few hours, the level of carbon monoxide in the blood begins to decline. (Carbon monoxide reduces the blood’s ability to carry oxygen.)

2. Within a few weeks, people who quit smoking have improved circulation, produce less phlegm, and don’t cough or wheeze as often.

3. Within several months of quitting, people can expect substantial improvements in lung function .

4. Within a few years of quitting, people will have lower risks of cancer, heart disease, and other chronic diseases than if they had continued to smoke.

• In addition, people who quit smoking will have an improved sense of smell, and food will taste better.