Smoking and the Lung - Murray & Nadel's Textbook of Respiratory Medicine

1. Epidemiology

2. Toxicology of Cigarette Smoke

• Nicotine
• Benzo(a)pyrene and polycyclic hydrocarbons
• 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
• N-nitrosonornicotine (NNN)
• β-naphthylamine
• Polonium-210, nickel, cadmium, arsenic, lead

• Carbon monoxide, acetaldehyde, acetone, methanol
• Nitrogen oxides, hydrogen cyanide, acrolein
• Ammonia, benzene, formaldehyde, nitrosamines, vinyl chloride

3. Smoking-Related Lung Diseases

A. Lung Cancer

• Smoking carries a relative risk of 15.0 to 30.0 for lung cancer - the highest of all smoking-related cancers.
• Smoking accounts for approximately 30% of all cancer deaths and is the largest preventable cause of cancer.
• Lung cancer remains the most common cause of cancer death worldwide, with ~1.7 million deaths/year (projected to rise to 3 million/year by 2035).
• Mechanism: Tobacco carcinogens (polycyclic hydrocarbons, nitrosamines) form DNA adducts, inducing specific patterns of p53 gene mutations. Chemicals act as tumor initiators, co-carcinogens, tumor promoters, or complete carcinogens.
• Dose-response relationship: There is a strong correlation between the amount smoked (pack-years) and lung cancer risk.
• The 1964 US Surgeon General's Report formally established the causal link between cigarette smoking and lung cancer.
• 5-year survival remains poor (~20%), since most cases are diagnosed at advanced stages.

B. COPD: Chronic Bronchitis and Emphysema

• Smoking is the dominant cause of COPD (chronic obstructive pulmonary disease).
• It causes both chronic bronchitis (productive cough for ≥3 months/year for ≥2 consecutive years) and emphysema (permanent enlargement of air spaces distal to the terminal bronchioles with destruction of walls).
• Mechanism:
  • Epigenetic reprogramming of airway basal cells (BCs): Smoking causes BC hyperplasia, goblet cell hyperplasia, squamous metaplasia, dropout of ciliated and secretory cells, and cilia damage. These changes precede inflammatory cell infiltration, suggesting they are necessary but insufficient for COPD progression.
  • Oxidative stress induces EGF production, EGFR activation, and amphiregulin-driven epithelial hyperplasia even after cessation of oxidative stress.
  • Loss of CC16/SCGB1A1 (the most abundant protein in normal distal airway secretions), which blocks NF-kB activation and phospholipase A2, contributes to small airways disease (SAD).
  • Loss of secretory IgA (sIgA) due to impaired polymeric immunoglobulin receptor expression leads to bacterial invasion of small airways.
  • Protease-antiprotease imbalance: Smoking activates macrophages and neutrophils releasing elastase, MMP-9, MMP-12; these overwhelm α-1 antitrypsin defenses, destroying alveolar walls.
• Small airways (respiratory bronchioles lack basal cells) are uniquely susceptible to inhalational damage and are the initial site of centrilobular emphysema (CLE) development.

C. Interstitial Lung Diseases (Smoking-Associated)

• Desquamative Interstitial Pneumonia (DIP)
• Respiratory Bronchiolitis-ILD (RB-ILD)
• Pulmonary Langerhans Cell Histiocytosis (PLCH)
• Association with idiopathic pulmonary fibrosis (IPF) is well recognized.

D. Asthma

• Smoking is a risk factor for the development of asthma and worsens asthma control. It increases airway hyperresponsiveness and reduces corticosteroid responsiveness.

E. Increased Risk of Infections

• Risk for pneumococcal disease declines to nonsmoker levels 10 years after cessation.
• Many immunologic disturbances resolve within 6 weeks of smoking cessation.
• Smoking increases incidence and severity of influenza (more cough, phlegm, breathlessness, wheezing, more lost workdays). Influenza vaccination is less effective in smokers.
• Smoking is strongly associated with increased incidence and severity of pulmonary tuberculosis (OR 4.5).
• Smoking increases the risk of COVID-19 progression (meta-analysis).

4. Other Systemic Effects of Smoking Relevant to Pulmonary Practice

5. Nicotine Dependence - Mechanism

6. Passive (Secondhand) Smoking

• Passive smoke exposure also increases risk for pneumococcal invasive disease (OR 2.5) and community-acquired pneumonia.
• Children exposed to environmental tobacco smoke have increased respiratory infections, wheezing, asthma exacerbations, and impaired lung development.
• Maternal smoking during pregnancy is associated with impaired fetal lung development, premature birth, low birth weight, and sudden infant death syndrome (SIDS).

7. Smoking Cessation

Benefits

• Reduced rate of FEV₁ decline (the Lung Health Study showed cessation slowed the accelerated FEV₁ decline in smokers)
• Reduced lung cancer risk (though risk never returns to that of a lifelong never-smoker)
• Reduced cardiovascular risk (drops rapidly within 1-2 years)
• Immunologic improvements within 6 weeks
• Reduced infection risk (pneumococcal risk returns to baseline after 10 years)

Pharmacotherapy for Smoking Cessation (from Murray)

1. Nicotine Replacement Therapy (NRT): Available as patch, gum, lozenge, nasal spray, inhaler. Doubles cessation rates compared to placebo. Can be combined (patch + short-acting form).
2. Bupropion (Zyban): An antidepressant that reduces nicotine craving and withdrawal. Doubles cessation rates.
3. Varenicline (Champix/Chantix): Partial agonist at α4β2 nAChRs - reduces craving and withdrawal while also blocking the rewarding effects of nicotine. Most effective single agent; approximately triples cessation rates vs placebo.

• A randomized trial (Hajek et al., NEJM 2019) showed e-cigarettes were more effective than NRT for smoking cessation, though long-term safety data remain limited.

The "5 A's" Framework

Summary Box (High-Yield for Exams)