lecture 23: smoking and lung health Flashcards
What are current global smoking rates?
- smoking rates on the increase in some developing countries
- rates in excess of 40-50% of adult population in western pacific regions (thailand, vietnam, malaysia, nauru…)
- india has lower
- greece and russia still high
What is smoking consumption over past century in US?
- depicts the national history of smoking consumption in US
- rapid uptake of smoke exposure
- peaking in 60s and 70s
- since 70s gradual downturn
- associated with introduction of government initiatives
- tax
- awareness/education
What is the variable decline in global smoking rates (1990-2010)?
- importance of increased taxes and public health awareness
- past two decades
- high degree of variability
- reflects where different countries are at in terms of government initiatives
- in contrast to other countries where the message of smoking cessation is yet to have an impact
What does smoking result in?
- long disease latency
- stage I:
- low smoking prevalence (below 20%), generally limited to males and little increase in tobacco-caused chronic illness. Sub-sarahan africa
- stage II:
- smoking rates are greater than 50% in men and women’s smoking rates increasing
- some evidence of smoking related illness BUT support for tobacco control initiatives still not widespread
- southeast asian, latin american and north african regions and china
- stage III:
- smoking prevalence begins to decline, however deaths increase because of earlier high smoking rates
- health education programmes better developed
- smoking becomes less socially acceptable and the climate is increasingly conductive to the introduction of tobacco control policies
- eastern and southern europe, latin america
- stage IV:
- marked by continuing downturn in smoking prevalence
- male deaths from smoking begin to decline
- but female deaths continue to rise, reflecting later smoking patterns
- parts of western europe, the UK, the US, canada, NZ, australia
What are challenges to reducing the burden of cigarette smoke?
- large proportion of global population still in Stage I-II
- current global smoking trends in developing countries will impact on death rates for over 50-80 years…
- can smoking rates be reduced to below 10% in developed countries?
- consider new phase of anti-smoking education programmes
- further restrict sophisticated, cynical marketing targeting the young
Why are 10-15% of adult population still smoking in Australia?
- nicotine is highly addictive affecting CNS dopamine pleasure/reinforcement and executive centres
- addiction and smoking behaviours may have a genetic basis: where nicotinic acetylcholine receptor genetic variants govern smoking dose
- nicotine is a major appetite suppressant and many smokers continue to smoke in order to control body weight
- therapeutic intervention to combat nicotine addiction:
- nicotine replacement therapy (patches, sprays), nicotine receptor blockers (bupropion) and partial agonists (Varencline) increase probability of quitting by 2-fold
- quitting is the only intervention to reverse health consequences of smoking
What are the consequences of chronic smoke exposure?
- premature death
- cigarette use is the leading preventable cause of death in the US
- cigarette smoking causes about one of every five deaths in the US each year
- more than 450,000 deaths annually:
- 278,544 deaths annually among men
- 201,773 deaths annually among women
What are causes of smoking related deaths?
- cancers
- oropharynx
- larynx
- oesophagus
- trachea, bronchus and lung
- acute myeloid leukaemia
- stomach
- liver
- pancreas
- kidney and ureter
- cervix
- bladder
- colorectal
- chronic diseases
- stroke
- blindness, caratacts, age-related macular degeneration
- congenital defects - maternal smoking: orofacial celfts
- peridontitis
- aortic aneurysm, early abdominal aortic atherosclerosis in young adults
- coronary heart disease
- pneumonia
- atherosclerotic peripheral vascular disease
- chronic obstructive pulmonary disease, tuberculosis, asthma, and other respiratory effects
- diabetes
- reproductive effects in women (including reduced fertility)
- hip fractures
- ectopic pregnancy
- male sexual function-erectile dysfunction
- rheumatoid arthritis
- immune function
- overall diminished health
What are major causes of smoking related deaths?
- about 443,000 US deaths attributable each year to cigarette smoking
- lung cancer: 128,900, 29%
- ischemic heart disease: 126,000 (28%)
- chronic obstructive pulmonary disease: 92,000 (21%)
- other diagnoses: 44,000 (10%)
- stroke: 15,900 (4%)
- other cancers: 35,300 (8%)
What is a leading cause of cancer directly related to smoking?
- lung cancer has highest mortality rates from selected cancers among men in the US 1930-2008
- clearly increased with development and increased use of cigarettes
- other cancers have relatively similar or decreasing levels since onset of smoking
- 80-90% of lung cancer cases are due to long-term exposure to tobacco smoke
- over 50% patients have metastatic disease at diagnosis
- only 20-25% have localised tumour that is potentially resectable for cure
- 60% patients die within first year of diagnosis
- 15% survival rates over 5-years
What initiates lung cancer in high risk smokers?
- role of nicotine in lung cancer
- not directly mutagenic but:
- genetic loci most strongly associated with lung cancer include genes that regulate acetylcholine nicotinic receptors members
- these gene variants are strongly associated with nicotine dependence
- smoking behaviour driven by genetics will causes an increased uptake of nicotine in smoke AND consequently a greater presence of lung carcinogens
- mainstream smoke contains over 4000 chemicals:
- contains over 50 known carcinogens that can covalently bind to DNA to form DNA adducts:
- polycyclin aromatic hydrocarbons (PAH) likely mutatio GC → AT
- N-nitrosamines (e.g. NNK) → GC → TA, GC → AT
- contains over 50 known carcinogens that can covalently bind to DNA to form DNA adducts:
- cigarette smoke is a potent source of free radicals that induce oxidative damage:
- superoxide + nitric oxide → peroxynitrite (ONOO-)
- all → DNA adducts (G, 8-oxo-G)
- peroxynitritie → lipid peroxidatio: end products are reactive aldehydes: malondialdehude (MDA) and 4-hydroxynonenal (HNE)
- → tumour initiation
What are types of smoking related lung cancer?
- non-small cell lung cancer (NSCLC) accounts for about 70-80% of cases and is divided roughly equaly into two main histological types;
- 30-40% adenocarcinomas
- historically orginates in peripheral airway
- significant proportion of non-smokers (15%), female, asian background
- recent smoking-related shift in rate (change in tobacco composition?)
- 30-40% squamous cell carcinomas
- historically originates in central airway
- strongly associated with smoking history
- slowly declining in developed countries such as Australia and US
- likely to increase in developing countries where smoking has just peaked
Are smoking and non-smoking related lung cancers the same?
- lung cancers relating to smoking have a different mutation profile to non-smoking related lung cancers
- in this study looked at mutation frequency in non-smoking adenocarcinomas and smoking related squamous cell carcinomas
- adenocarcinoma: high proportion of mutations in EGFR, ALK pathway, k-RAS pathway
- rate of mutations in these pathways much lower in smoking related cancers
What is the implication of different driver mutations?
- implications for current treatments
- adenocarcinoma
- K-RAS (activating mutation 20%)
- EGFR (20%)
- EML4-ALK translocation (5%)
- contribute to cell growth and survival
- squamous carcinoma
- FGF?
- SOX2 gene amplification (20%)
- FGFR1 gene amplification (20%)
- need new targets to treat squamous cell carcinoma
- FGFR1 inhibitors are currently being assessed in SCC patients that are positive for FGFR1 amplification
- Gefitinib (Iressa) and Eriotinib (Tarceva) inhibit EGFR in adenocarcinoma
What else may cigarette smoke drive?
- tumour promoting inflammation and avoidance of immune destruction
- emerging hallmarks of cancer:
- avoiding immune destruction (adaptive arm)
- cigarette smoke inhibits the function of NK cells
- cytotoxin CD8+ T cells also accumulate in response to smoke exposure and their function may be compromised
- deregulating cellular energetics
- avoiding immune destruction (adaptive arm)
- enabling characteristics:
- genome instability and mutation
- tumour-promoting inflammation
- inflammatory cells can release ROS, that are actively mutagenic for nearby cancer cells, accelerating their malignancy potential
- M2 macrophages accumulate in chronic smokers and release mediators that promote tumour growth (e.g. angiogenic factors) and invasion (e.g. MMP-9)