1. PATHOPHYSIOLOGY of TOBACCO-RELATED DISEASE
This module reviews the known and hypothesized mechanisms by which tobacco use or exposure results in disability and disease.
♪ Note to instructor(s): This module is considered optional.

2. 2004 SURGEON GENERAL’s REPORT: THE HEALTH CONSEQUENCES of SMOKING
ADVERSE HEALTH EFFECTS ASSOCIATED with SMOKING
Cancer
Cardiovascular disease
Respiratory disease
Reproductive complications
Osteoporosis
Periodontitis
Cataract
Postoperative complications
In 2004 the U.S. Surgeon General released a comprehensive report delineating the numerous health consequences associated with smoking (USDHHS, 2004). A major conclusion of the report was that smoking harms nearly every organ of the body, causes many diseases, and reduces smokers’ health in general.
Although many adverse health effects are associated with tobacco use, this module addresses the conditions for which plausible biological mechanisms exist for these associations, including
Cancer
Cardiovascular disease
Respiratory disease
Reproductive complications
Osteoporosis
Periodontitis
Cataract
Postoperative complications
♪ Note to instructor(s): For more detailed information and literature citations regarding risks for these tobacco-related illnesses, refer to the Surgeon General’s Report at
U.S. Department of Health and Human Services (USDHHS). (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.
USDDHHS. (2004). The Health Consequences of Smoking: A Report of the Surgeon General.

3. TOBACCO and CANCER: CANCERS CAUSED by TOBACCO
Lung
Larynx
Oral cavity and pharynx
Esophagus
Pancreas
Bladder and kidney
Cervix
Stomach
Bone marrow (acute myeloid leukemia)
Tobacco use is a major risk factor for the development of many forms of cancer. As stated in the 2004 Surgeon General’s Report, the evidence is sufficient to infer a causal relationship between smoking and cancers of the lung, larynx, oral cavity, pharynx, esophagus, pancreas, bladder, kidney, cervix, and stomach. Additionally the data are sufficient to conclude that smoking increases the risk of developing acute myeloid leukemia (USDHHS, 2004). While not conclusive, the evidence suggests that a causal relationship may exist between smoking and the development of colorectal and liver cancers.
♪ Note to instructor(s): Although data reviewed in the 2004 Surgeon General’s Report were insufficient to infer a causal relationship between active smoking and breast cancer, a recent report from the California Environmental Protection Agency suggests that exposure to second-hand smoke is causally related in the development of breast cancer among premenopausal women. The full report, Proposed Identification of Environmental Tobacco Smoke as a Toxic Air Contaminant, is available at
U.S. Department of Health and Human Services (USDHHS). (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.
USDHHS. (2004). The Health Consequences of Smoking: A Report of the Surgeon General.

4. TOBACCO and CANCER: CARCINOGENS in TOBACCO PRODUCTS
Polycyclic aromatic hydrocarbons (PAHs)
Benzopyrene
Benzanthracene
Tobacco-specific nitrosamines (TSNAs)
Aromatic amines
Formaldehyde
Benzene
Vinyl chloride
Cadmium
Radioactive polonium-210
Tobacco smoke and smokeless tobacco products contain numerous cancer-causing substances. Of the more than 4,000 known compounds present in tobacco smoke, more than 60 are known carcinogens (IARC, 2004). Some of these carcinogens are naturally present in tobacco (e.g., heavy metals) or are formed during the tobacco-curing process (e.g., nitrosamines, aldehydes), but the majority are generated during the combustion of tobacco (e.g., PAHs) (Hecht, 2003). Although smokeless tobacco products (snuff, chewing tobacco) contain fewer carcinogens than tobacco smoke, at least 16 carcinogens have been identified in unburned tobacco, including very high levels of nitrosamines (Wogan et al., 2004).
Compounds present in tobacco or tobacco smoke that are proven human carcinogens include the following (EPA, 1992; Hecht, 2003):
Polycyclic aromatic hydrocarbons (PAHs): includes benzopyrene, benzanthracene
Tobacco-specific nitrosamines (TSNAs)
Aromatic amines: includes 4-aminobiphenyl, 2-naphthylamine
Formaldehyde
Benzene
Vinyl chloride
Cadmium
Radioactive polonium-210
All of these compounds have been found in mainstream smoke (the aerosol fraction inhaled by the smoker), and most are present in sidestream smoke (the fraction released into the air directly from the burning tobacco and the primary source of most environmental tobacco smoke). In general, the more potent carcinogens (e.g., PAHs, nitrosamines, aromatic amines) are present in lower concentrations than weaker carcinogens (e.g., acetaldehyde) (Hecht, 2003).
Hecht SS. (2003). Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 3:733–744.
International Agency for Research on Cancer (IARC). (2004). Tobacco Smoke and Involuntary Smoking (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans; Vol. 83). Lyon (France): IARC.
U.S. Environmental Protection Agency (EPA). (1992). Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders (EPA Publication No. EPA/600/6-90/006F). Washington, DC: EPA, Office of Air and Radiation. Retrieved December 31, 2006, from
Wogan GN, Hecht SS, Felton JS, Conney AH, Loeb LA. (2004). Environmental and chemical carcinogenesis. Semin Cancer Biol 14:473–486.

5. TOBACCO and CANCER: CARCINOGENS (cont’d)
Cancer site
Likely carcinogen(s)
Lung
PAHs, nitrosamines, aldehydes, benzene, heavy metals
Larynx
PAHs
Oral cavity
Nitrosamines
Esophagus
Pancreas
Cervix
PAHs, nitrosamines
Bladder/kidney
Aromatic amines
Bone marrow (AML)
Benzene
This slide summarizes the carcinogens likely involved in tobacco-related cancers. Likely carcinogens have been identified based on animal studies, biochemical evaluations of human tissues, and epidemiologic data (Hecht, 2003).
Hecht SS. (2003). Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 3:733–744.
Adapted from Hecht. (2003). Nat Rev Cancer 3:733–744.

6. TOBACCO and CANCER: MECHANISM of CARCINOGENESIS
Compounds in tobacco function as
Carcinogens
Initiate tumor growth
Tumor promoters
Stimulate the development of established tumors
Co-carcinogens
Enhance the mutagenic potential of carcinogens; possess little or no direct carcinogenic activity
Irritants
Induce inflammation and compromise tissue integrity
Tobacco contains compounds that may induce or promote carcinogenesis in the following ways (Hecht, 2003; Levitz et al., 2004):
Carcinogens are mutagens that stimulate or initiate the growth of tumors.
Tumor promoters are compounds that stimulate excessive cellular proliferation and the growth of previously initiated tumors.
Co-carcinogens are compounds that increase the carcinogenic activity of carcinogens. In general they possess little or no direct carcinogenic activity. They enhance the effects of carcinogens but are not essential to the carcinogenic process.
Irritants are compounds that may enhance the carcinogenic process by inducing tissue inflammation and compromising the integrity of normal tissues.
Hecht SS. (2003). Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 2003;3:733–744.
Levitz JS, Bradley TP, Golden AL. (2004). Overview of smoking and all cancers. Med Clin N Am 88:1655–1675.

7. TOBACCO and CANCER: CELL DIVISION
This image demonstrates cancer cell division. The chromosomes, shown in white, are dividing into two new cells.
A cancer cell dividing its chromosomes (shown in white) into two new cells
Image courtesy of Dr. Paul D. Andrews / University of Dundee

8. TOBACCO and CANCER: MECHANISM of CARCINOGENESIS (cont’d)
Formation of DNA adducts
Covalent binding product of carcinogen (or its metabolite) to DNA
Leads to miscoding and point mutations
Mutations of oncogenes or tumor suppressor genes can lead to uncontrolled cellular growth and development of cancer
The mechanisms of tobacco-induced carcinogenesis are complex, but the formation of DNA adducts appears to play a significant role in the development of cancer (Hecht, 2003; USDHHS, 2004).
Similar to the processes associated with drug metabolism, many carcinogens (including PAHs and TSNAs) undergo a series of enzymatic reactions yielding compounds that are excreted more readily. The initial metabolic processes usually involve oxidative (phase I) enzymes, the most important of which include the microsomal cytochrome P450 isozymes. The cytochrome P450 enzymes (particularly CYP2D6 and CYP1A1) are responsible for the formation of highly reactive compounds that serve as substrates for inactivating (phase II) enzymes. Phase II enzymes convert these highly reactive intermediates to inactive, water-soluble conjugates that are more readily eliminated from the body. Reactive metabolites formed by phase I enzymes that are not appropriately inactivated may form a covalent (irreversible) bond to cellular DNA, forming DNA adducts. These bulky DNA adducts, if not repaired by normal cellular homeostatic processes, can lead to miscoding and permanent cellular mutations. In some cases, cells with damaged DNA undergo apoptosis or programmed cellular destruction, arresting the development of cancer. In other instances, permanent mutations may lead to activation of oncogenes and inactivation of tumor suppressor genes, resulting in unregulated cellular growth and, ultimately, cancer (Hecht, 1999, 2003).
Hecht SS. (1999). Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 14:1194–1210.
Hecht SS. (2003). Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 3:733–744.
U.S. Department of Health and Human Services (USDHHS). (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

9. TOBACCO and CANCER: MECHANISM of CARCINOGENESIS (cont’d)
Nicotine
addiction
PAHs, TSNAs,
other carcinogens
Tobacco use
Metabolic
detoxification
Excretion
Metabolic activation
This slide depicts the role of nicotine addiction in the development of tobacco-induced carcinogenesis. Although nicotine itself is not carcinogenic, nicotine addiction is responsible for chronic tobacco use and exposure to carcinogenic substances. Many carcinogens, including PAHs and TSNAs, appear to cause cancer following metabolic activation. Cancer does not develop in all tobacco users because numerous detoxification and repair pathways alter the risk of malignant progression. The balance between metabolic activation and various detoxification and repair processes appears to influence an individual’s risk of developing cancer (Hecht, 1999).
Hecht SS. (1999). Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 14:1194–1210.
DNA
adducts
Repair
Normal DNA
Persistence/miscoding
Apoptosis
Mutations,
other changes
Cancer
Adapted with permission. Hecht. (1999). J Natl Cancer Inst 91:1194–1210.

10. TOBACCO and CANCER: SUMMARY
Tobacco products cause a variety of cancers
Carcinogens present in tobacco are responsible for these cancers
Carcinogenesis likely involves a multistep process:
Formation of DNA adducts
Permanent cellular mutations
Unregulated cellular growth
To summarize the role of tobacco exposure and cancer:
Tobacco products cause a variety of cancers
Carcinogens present in tobacco are responsible for these cancers
Carcinogenesis likely involves a multistep process:
Formation of DNA adducts
Permanent cellular mutations
Unregulated cellular growth

11. SMOKING and CARDIOVASCULAR DISEASE
Coronary heart disease
Angina pectoris, ischemic heart disease, myocardial infarction
Cerebrovascular disease
Stroke, transient ischemic attacks
Abdominal aortic aneurysm
Peripheral arterial disease
A wealth of evidence suggests that tobacco smoking is a major risk factor for the development of cardiovascular disease. Cardiovascular disease ranks second behind cancer as the leading cause of smoking-attributable mortality among U.S. adults. Each year an estimated 137,979 adults (84,367 males and 53,612 females) die prematurely from smoking-induced cardiovascular disease (CDC, 2005). Smoking is known to accelerate the process of atherosclerosis, leading to coronary heart disease (angina pectoris, ischemic heart disease, myocardial infarction), cerebrovascular disease (stroke, transient ischemic attacks), abdominal aortic aneurysm, and peripheral arterial disease (USDHHS, 2004).
Centers for Disease Control and Prevention (CDC). (2005). Annual smoking-attributable mortality, years of potential life lost, and productivity losses—United States, 1997–2001. MMWR 54:625–628.
U.S. Department of Health and Human Services (USDHHS) (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

12. SMOKING and CARDIOVASCULAR DISEASE: POSTULATED MECHANISMS
Smoking-induced atherogenesis and thrombosis
Endothelial injury/dysfunction
Thrombosis
Inflammation
Lipids/lipid metabolism
Toxins present in tobacco smoke interact with blood constituents and the vascular endothelium to promote atherosclerosis, the primary pathophysiologic feature of cardiovascular disease. Atherosclerosis is characterized by deposition of lipid in the arterial wall, fibrosis, and vascular thickening. Smoking can accelerate atherosclerosis and promote thrombosis by multiple mechanisms, including (Benowitz, 2003; USDHHS, 2004)
Endothelial injury/dysfunction: Damage to the vascular endothelium is the pivotal event in the development of atherosclerosis. Tobacco smoke is hypothesized to accelerate this process by inhibiting the release of endothelium-derived relaxing factor (nitric oxide), a mediator with numerous beneficial cardiovascular effects. Nitric oxide regulates platelet function (decreases aggregation and adhesiveness) and maintains a state of vascular relaxation. Impaired release of nitric oxide results in coronary vasoconstriction, platelet aggregation, smooth muscle proliferation, and adherence of monocytes to the endothelium, resulting in an environment favorable for the development of atherosclerotic plaque.
Inflammation: Smoking induces a systemic inflammatory response characterized by increased circulating leukocytes, C-reactive protein (an acute phase protein that serves as a marker for systemic inflammation), and fibrinogen. The components of tobacco smoke responsible for the inflammatory process are not known, but oxidant gases are thought to play a role.
Thrombosis: Smoking may promote thrombosis by multiple mechanisms. Smoking activates platelets and increases platelet aggregation. Smokers exhibit impaired release of tissue plasminogen activator, which may play a key role in coronary thrombosis. Smokers are known to have elevated fibrinogen levels and red blood cell concentrations as a consequence of long-term carbon monoxide exposure. This leads to increased blood viscosity and thrombosis.
Lipids/lipid metabolism: Smokers tend to have serum lipid profiles associated with increased cardiovascular risk (lower HDL cholesterol levels and higher LDL, VLDL, and triglyceride levels) compared to nonsmokers. Data suggest that, as a consequence of exposure to oxidant gases in tobacco smoke, smokers typically have higher levels of oxidized LDL, a lipoprotein known to be highly atherogenic.
Benowitz NL. (2003). Cigarette smoking and cardiovascular disease: Pathophysiology and implications for treatment. Prog Cardiovasc Dis 46:91–111.
U.S. Department of Health and Human Services (USDHHS). (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

13. SMOKING and CARDIOVASCULAR DISEASE: POSTULATED MECHANISMS (cont’d)
Adverse effects on cardiovascular function
Increased oxygen demand
Decreased oxygen delivery
Further exacerbating the atherogenic and thrombotic effects of smoking on the vascular system are the physiologic demands on myocardial tissue resulting from an imbalance of oxygen supply and demand. Smoking may contribute to ischemia and precipitate acute events (myocardial infarction, unstable angina, sudden death) in patients with atherosclerosis via the following mechanisms (Benowitz, 2003; USDHHS, 2004):
Increased myocardial workload: Long-term smoking increases average heart rate and blood pressure throughout the day. Additionally, smoking increases myocardial contractility and acutely increases the stiffness of the large peripheral arteries. The net effect is an increased myocardial workload.
Reduced oxygen-carrying capacity of blood: Tobacco smoke contains carbon monoxide, which binds to hemoglobulin, forming carboxyhemoglobin, a complex with reduced oxygen-carrying capacity. The compensatory physiologic response is an increase in erythropoiesis, which increases blood viscosity, further increasing the risk of thrombosis. Additionally, animal data suggest that carbon monoxide may lower the ventricular fibrillation threshold, increasing the risk of sudden death.
Coronary vasoconstriction: Smoking leads to constriction of epicardial arteries and increases coronary vascular resistance. This coronary vasoconstriction reduces myocardial blood supply, leading to ischemia or arrhythmias.
Catecholamine release: Smoking stimulates catecholamine release (epinephrine, norepinephrine), leading to increased heart rate and myocardial contractility. Smoking-induced catecholamine release also leads to decreased coronary blood flow via constriction of epicardial arteries. Catecholamines may also contribute to the development of arrhythmias leading to sudden death.
Benowitz NL. (2003). Cigarette smoking and cardiovascular disease: Pathophysiology and implications for treatment. Prog Cardiovasc Dis 46:91–111.
U.S. Department of Health and Human Services (USDHHS). (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

14. SMOKING and RESPIRATORY DISEASE
Acute respiratory diseases
Upper respiratory tract
Rhinitis, laryngitis, pharyngitis, sinusitis
Lower respiratory tract
Bronchitis, pneumonia
Chronic respiratory diseases
Reduced lung function in infants
Respiratory symptoms in children & adults
Cough, phlegm, wheezing, dyspnea
Poor asthma control
Chronic obstructive pulmonary disease
Smoking has significant adverse health effects on the upper and lower respiratory tract system. The 2004 Surgeon General’s Report has divided smoking-induced respiratory disease into two categories: acute (predominantly caused by infections) and chronic (disorders of the conducting airways and alveoli) (USDHHS, 2004).
Acute Respiratory Diseases
Exposure to tobacco smoke incudes a variety of acute respiratory diseases affecting both the upper and lower respiratory tracts. Toxins (particularly carbon monoxide) present in tobacco smoke paralyze cilia on columnar respiratory epithelium and compromise protective mucociliary transport host defenses. Additionally, tars in smoke concentrate in pulmonary alveolar macrophages and inhibit the phagocytic activity of these cells. The net effect is reduced host defenses against infections caused by respiratory pathogens (Kamholz, 2004). Clinically, smokers have a higher incidence of acute respiratory tract infections of the upper airways (rhinitis, laryngitis, pharyngitis, and sinusitis) and lower airways (bronchitis and pneumonia), compared to nonsmokers (USDHHS, 2004).
Chronic Respiratory Diseases
Infants exposed to maternal smoking in utero are more likely to have measurable evidence of impaired lung function, although the mechanism for this impairment is not known (USDHHS, 2004). Likewise, children, adolescents, and adults exposed to tobacco smoke are more likely to experience chronic respiratory symptoms (cough, increased phlegm production, wheezing, and dyspnea) (USDHHS, 2004). Individuals with asthma who smoke are more likely to have poor asthma control, compared to nonsmoking asthmatics. Irritants and oxidant gases present in tobacco smoke are believed to worsen airway inflammation and exacerbate bronchial hyperresponsiveness (USDHHS, 2004). Some data suggest that asthmatic smokers have a reduced therapeutic response to inhaled corticosteroids, compared to nonsmokers (Tomlinson et al., 2005). Finally, smoking is the single most important cause of chronic obstructive pulmonary disease. This topic is addressed in greater detail in subsequent slides.
Kamholz SL. (2004). Pulmonary and cardiovascular consequences of smoking. Med Clin North Am 88:1415–1430.
Tomlinson JE, McMahon AD, Chaudhuri R et al. (2005). Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax 60:282–287.
U.S. Department of Health and Human Services (USDHHS). (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

15. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
Characterized by airflow limitation (not fully reversible)
Progressive airflow limitation associated with abnormal inflammatory response of the lungs to noxious particles or gases
Characteristic symptoms (cough, sputum production, dyspnea)
Prevalence increasing worldwide
Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases (NHLBI/WHO, 2005). The characteristic symptoms of COPD are chronic cough, sputum production, and dyspnea on exertion. Cough and sputum production may manifest years before the development of measurable airflow limitation (NHLBI/WHO, 2005).
COPD is the fourth leading cause of death in the United States (Jemal et al., 2005). If global tobacco use patterns remain unchanged, the World Health Organization (WHO) predicts that by 2020, COPD will be the fifth most common cause of death in the world (NHLBI/WHO, 2005).
Cigarette smoking is by far the single most important risk factor for the development of COPD. Although the vast majority of patients with COPD are current or former tobacco smokers, only a fraction of smokers (15–20%) develop clinically significant COPD. This finding suggests an underlying genetic predisposition for the disease (NHLBI/WHO, 2005). The WHO cautions that the percentage of smokers who develop COPD is likely an underestimate because COPD is often underdiagnosed (NHLBI/WHO, 2005).
Jemal A, Ward E, Hao Y, Thun M. (2005). Trends in the leading causes of death in the United States, 1970–2002. JAMA 294:1255–1259.
National Heart, Lung, & Blood Institute/World Health Organization (NHLBI/WHO). (2005). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Workshop Report, Global Initiative for Chronic Obstructive Lung Disease (GOLD). Retrieved December 31, 2005, from
The single most important risk factor for COPD is
tobacco smoking.

16. SMOKING and COPD: POSTULATED MECHANISMS
Tobacco smoke induces inflammation and damage to pulmonary tissue through
Release of inflammatory cells and mediators
Imbalance between proteases and antiproteases
Oxidative stress
Constituents in tobacco smoke are believed to induce lung inflammation and impair normal host defense mechanisms, leading to damage of pulmonary tissues. Pathologic changes in the lung include airway narrowing and fibrosis, parenchymal destruction (emphysema), and thickening of the pulmonary vasculature. Several mechanisms are postulated to explain the pathology associated with COPD (NHLBI/WHO, 2005; USDHHS, 2004). Tobacco smoke is thought to induce inflammation and cause direct damage to pulmonary tissue through the following mechanisms:
Release of inflammatory cells and mediators: Tobacco smoke appears to activate a variety of inflammatory cells including macrophages, T lymphocytes, and neutrophils. Following activation, macrophages and neutrophils release proteases that break down lung tissue. Macrophages also release mediators, including leukotriene B4 and interleukin-8, which further recruit neutrophils from the blood into the airways. The interplay of these inflammatory cells and mediators leads to the hypersecretion of mucus and destruction of lung tissue.
Imbalance between proteases and antiproteases: Proteases are enzymes released from neutrophils and macrophages that cleave elastin in lung parenchymal tissue, leading to emphysema. Normally these proteases are held in check by antiproteases present in the lung, the most important of which is 1-antitrypsin. In the majority of smokers, increased levels of proteases are effectively neutralized by antiproteases, preventing lung damage. However, in a small minority of susceptible smokers, the production of antiproteases may be insufficient and COPD develops.
Oxidative stress: Increasing evidence suggests that oxidative stress might play a role in the pathogenesis of COPD. Reactive oxygen species such as superoxide anion, hydrogen peroxide, hydroxyl radical, and peroxynitrate from tobacco smoke or inflammatory cells can promote inflammation and proteolysis in pulmonary tissue.
National Heart, Lung, & Blood Institute/World Health Organization (NHLBI/WHO). (2005). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Workshop Report, Global Initiative for Chronic Obstructive Lung Disease (GOLD). Retrieved December 31, 2005, from
U.S. Department of Health and Human Services (USDHHS). (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

17. SMOKING and REPRODUCTIVE HEALTH
Reduced fertility in women
Pregnancy and pregnancy outcomes
Placenta previa
Placental abruption
Preterm premature rupture of membranes
Preterm delivery
Low infant birth weight
Infant mortality
Sudden infant death syndrome (SIDS)
Tobacco use is associated with numerous reproductive-related complications, including effects on fertility, pregnancy and pregnancy outcomes, and infant mortality (USDHHS, 2001, 2004). Women who smoke are more likely to experience problems with delayed conception and infertility. Although the mechanisms by which smoking affects female fertility are not definitively known, animal studies suggest that tobacco smoke inhibits the release of gonadotropins, causes fallopian tube dysfunction, and impairs implantation of fertilized ova (USDHHS, 2001).
Placenta previa is a pregnancy complication whereby the placenta implants in the lower part of the uterus and obstructs the cervical opening to the vagina. Although the cause of placenta previa is not known, this condition is observed more frequently in smokers (USDHHS, 2004). Placental abruption is the premature separation of the placenta from the uterus. It has been hypothesized that smoking-induced vasoconstriction and hypoperfusion at the site of placental implantation leads to necrosis, hemorrhage, and separation (USDHHS, 2004). Preterm premature rupture of membranes (PROM) occurs when the amniotic sac ruptures before 37 weeks gestation and prior to the onset of labor. The role of smoking and preterm PROM is not established, but components in tobacco smoke might disrupt the cytokine system, impair reproductive tract immune function, or promote inflammatory processes (USDHHS, 2004). A dose-dependent increase is seen in the risk for preterm delivery in pregnant smokers. Nicotine-induced vasoconstriction in the placenta may induce labor. Additionally, catecholamine release (stimulated by tobacco smoke) may precipitate premature labor (USDHHS, 2001). Finally, women who smoke during pregnancy are more likely to deliver low-birth-weight infants (i.e., less than 2.5 kg). Smoking is hypothesized to reduce birth weight through several mechanisms: 1) smoking may cause premature birth, 2) nicotine and carbon monoxide may cause fetal growth retardation, 3) the vasoconstrictive effects of nicotine may decrease uteroplacental circulation, leading to fetal hypoxia and reduced nutrition, and 4) pregnant smokers may gain less weight than nonsmokers (USDHHS, 2001).
The risk for sudden infant death syndrome (SIDS) is increased among infants with mothers who smoked during pregnancy and among those exposed to environmental tobacco smoke after birth. It is hypothesized that constituents in tobacco smoke interfere with the neuroregulation of breathing, precipitating apneic spells that lead to sudden infant death (USDHHS, 2001).
U.S. Department of Health and Human Services (USDHHS). (2001). Women and Smoking. A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.
U.S. Department of Health and Human Services. (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

18. SMOKING and OSTEOPOROSIS
Smoking causes
Low bone density
Postmenopausal women
Hip fractures
Observed in women and men
Osteoporosis, a condition characterized by decreased bone density and a propensity for bone fracture, is an important skeletal complication associated with smoking. Considerable epidemiologic evidence suggests that postmenopausal women who smoke have lower bone density than women who do not smoke. Furthermore, epidemiologic evidence consistently demonstrates an increased risk for hip fracture among both women and men who smoke (USDHHS, 2001, 2004).
U.S. Department of Health and Human Services (USDHHS). (2001). Women and Smoking. A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.
U.S. Department of Health and Human Services. (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

19. SMOKING and OSTEOPOROSIS: POSTULATED MECHANISMS
Direct toxic effect on osteoblasts
Increased bone resorption
Smokers have decreased parathyroid, vitamin D levels
Reduced calcium absorption
Early menopause
Decreased weight-bearing forces:
Lower body weight
Less physical activity
Vascular insufficiency
There are many postulated mechanisms by which smoking contributes to the development of osteoporosis. Nicotine or cadmium in tobacco smoke might be directly toxic to osteoblasts, the cells responsible for bone formation (USDHHS, 2004). Smokers have decreased parathyroid hormone levels and vitamin D3, leading to reduced calcium absorption. The combination of these two factors might lead to increased bone resorption (USDHHS, 2001). In general, smokers tend to have lower body weight; this weight difference itself might lead to lower bone density and a higher incidence of fracture (USDHHS, 2001). Women who smoke are more likely to experience earlier menopause; this increases the risk of osteoporosis, because bone mass decreases markedly in the postmenopausal period (USDHHS, 2004). In general, most smokers are less physically active compared to nonsmokers, and this relative reduction in the degree of weight-bearing forces that stimulate bone growth may contribute to an increased risk of fracture (USDHHS, 2004). Finally, tobacco-induced vascular insufficiency might have adverse effects on bone (USDHHS, 2001).
U.S. Department of Health and Human Services (USDHHS). (2001). Women and Smoking. A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.
U.S. Department of Health and Human Services. (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

20. SMOKING and DENTAL DISEASE
Smoking causes periodontitis.
Possible mechanisms:
Alterations in oral microbial flora
Compromised oral immune function
Impaired tissue regeneration and repair
Periodontitis, or inflammation of the gingiva and connective tissue supporting the teeth, is a dental disease commonly observed in smokers. Clinical manifestations of periodontitis include edema, erythema, gingival bleeding following probing, and ultimately tooth detachment from the jaw bone resulting from the destruction of the periodontal ligament and loss of supporting bone structure (USDHHS, 2004).
Mechanisms believed to contribute to the increased risk for periodontal disease among smokers include alterations in oral microbial flora, compromised oral immune function, and impaired tissue regeneration and repair processes (USDHHS, 2004).
U.S. Department of Health and Human Services (USDHHS). (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.
Image courtesy of Dr. Sol Silverman / University of California San Francisco

21. SMOKING and OCULAR DISEASE
Smoking causes cataract.
Possible mechanisms:
Oxidation and precipitation of lens proteins
Tobacco smoke may alter plasma concentrations of nutrients/antioxidants essential for lens transparency
Cataract (i.e., opacification of the crystalline lens of the eye) is an important cause of blindness and disability worldwide. Smoking is a well-established risk factor for the development of nuclear cataract, and possibly posterior subcapsular cataract, with heavy smokers up to three times as likely as nonsmokers to develop cataracts (USDHHS, 2004; Weintraub et al., 2002). The mechanisms by which smoking increases the risk of cataract are not established definitively, but some experts believe that heavy metals and aromatic compounds and free radicals produced by the combustion of tobacco may directly damage lens tissue. Tobacco smoke also might alter plasma concentrations of nutrients or antioxidants that are essential for maintaining lens transparency (USDHHS, 2004).
U.S. Department of Health and Human Services (USDHHS). (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.
Weintraub JM, Willett WC, Rosner B et al. (2002). Smoking cessation and risk of cataract extraction among US women and men. Am J Epidemiol 155:72–79.

22. SMOKING and POSTOPERATIVE COMPLICATIONS
Surgical wound complications
Delayed healing
Wound dehiscence
Infection
Scarring
Respiratory complications
Pneumonia
Respiratory failure
Numerous studies suggest that smokers experience a greater incidence of postoperative complications (wound and respiratory complications), compared to nonsmokers (USDHHS, 2004). Surgical wound complications include delayed healing, wound dehiscence, infections, and scarring. Constituents in tobacco smoke (e.g., carbon monoxide, hydrogen cyanide, acrolein, nicotine) are believed to contribute to poor wound healing through impaired wound epithelialization; thrombosis; decreased oxygen delivery; direct microvascular injury; and dysfunction of leukocytes, macrophages, fibroblasts, and platelets (Krueger & Rohrich, 2001). Respiratory complications (pneumonia, respiratory failure, and death due to pulmonary disease) are believed to be more common among smokers, because toxins in tobacco smoke are known to impair respiratory immune function. Furthermore, many smokers have preexisting compromised respiratory function secondary to underlying COPD; this further increases the risk for respiratory complications (USDHHS, 2004).
Krueger JK, Rohrich RJ. (2001). Clearing the smoke: The scientific rationale for tobacco abstention with plastic surgery. Plast Reconstr Surg 108:1063–1073.
U.S. Department of Health and Human Services (USDHHS). (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

23. PATHOPHYSIOLOGY of TOBACCO- RELATED DISEASE: SUMMARY
Tobacco use harms nearly every organ of the body and is associated with a variety of adverse health outcomes resulting in significant morbidity and mortality.
Mechanisms for disease have not been definitively established, but constituents of tobacco and smoke disrupt many normal cellular processes.
Tobacco cessation efforts are essential to arrest or prevent disease progression.
In summary, tobacco use harms nearly every organ of the body and is associated with a variety of adverse health outcomes, resulting in significant morbidity and mortality (USDHHS, 2004). The causal mechanisms for the development and progression of disease have not been established definitively, but constituents of tobacco and smoke are known to disrupt many normal cellular processes. Tobacco cessation efforts are essential to arrest or prevent disease progression.
U.S. Department of Health and Human Services (USDHHS). (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.