lecture 23: smoking and lung health Flashcards
1
Q
What are current global smoking rates?
A
- 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
2
Q
What is smoking consumption over past century in US?
A
- 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
3
Q
What is the variable decline in global smoking rates (1990-2010)?
A
- 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
4
Q
What does smoking result in?
A
- 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
5
Q
What are challenges to reducing the burden of cigarette smoke?
A
- 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
6
Q
Why are 10-15% of adult population still smoking in Australia?
A
- 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
7
Q
What are the consequences of chronic smoke exposure?
A
- 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
8
Q
What are causes of smoking related deaths?
A
- 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
9
Q
What are major causes of smoking related deaths?
A
- 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%)
10
Q
What is a leading cause of cancer directly related to smoking?
A
- 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
11
Q
What initiates lung cancer in high risk smokers?
A
- 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
12
Q
What are types of smoking related lung cancer?
A
- 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
13
Q
Are smoking and non-smoking related lung cancers the same?
A
- 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
14
Q
What is the implication of different driver mutations?
A
- 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
15
Q
What else may cigarette smoke drive?
A
- 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)
16
Q
What is a primary cause of COPD?
A
- cigarette smoke
- 10-15% of smokers develop COPD
- risk of developing COPD increases with age (up to 60% in older cohorts)
- currently affects 65 million people worldwide
- with high smoking rates in developing countries, COPD estimated to become third leading cause of death by 2030
- COPD = umbrella term encompassing small airways disease (obstructive bronchiolitis), emphysema and chronic bronchitis
- outcome is fixed airways disease that is poorly responsive to currently used anti-inflammatory and bronchodilator agents
- chronic inflammation → oxidative stress → chronic inflammation
- GOLD stage 0, 1, 2, 3, 4
- inflammatory profile
- increase in neutrophils and macrophages in tissues of patients
- increases with disease severity
- eosinophilic inflammation not prominent (unlike asthma, except one subtype)
- adaptive component, accumulation of CD8 cytotoxic t cells → proteolytic destrcution
- accumulation of tertiary lymphoid organelles
- autommune component of disease?
- innate and adaptive both involved
- multifactorial
- one of the early patterns of disease is narrowing of terminal bronchioles , due to inflammatory or fibrotic process, restricts airway flow to airway sac
- pressure and tethering
- release of proteases → proteolytic destruction
- dramatically reduces surface or air exchange
- excessive mucus hypersecretion
- fixed airway obstruction that is poorly responsive to current airway treatments
- inflammation drives excessive oxidative stress and vice versa
17
Q
What does smoke-induced NFkB control?
A
- inflammatory gene programmes
- → inflammatry gene transcription
- → innate inflammation
- → protease induction
18
Q
What is the impact of smoking on pathogen clearance and colonisation?
A
- smoking impairs pathogen clearance and promotes colonization in COPD
- 30-50% of COPD patients chronically colonised with PPMs in lower airways
- haemophilus influenzae
- streptococcus pneumoniae
- moraxella catarhellis
- presence associated with
- lower lung function
- poorer health status
- increased neutrophilic inflammation
- increased IL-8 and IL-6
- increased endotoxin levels
19
Q
By what is COPD worsened?
A
- acute infective exacerbations
- detection of newly acquired pathogens at exacerbation onset (n=78)
- colonisations
- very susceptible
- causes of these exacerbations
- majority usually end up in hospital → high rates of mortality
- pathogen induced infective
- half viral, half bacteria
- serious is both
- big increase in both local and systemic inflammation
- rapid decline in lung function in those who exacerbate more frequently
- drive disease progression
20
Q
How does smoking compromise essential host immunity?
A
- impaired mucociliary clearance (through direct damage to airway wall)
- no effective clearance of airborne particulates
- defective innate immunity
- normal function of phagocytic leukocytes
- chronically colonised
- airway injury (DAMPS)
- recurrent exacerbations
- triggered by virus and bacteria
- increased proteases, free radicals → contribute to airway injury (which in itself can perpetuate inflammation)
- the british hypothesis
21
Q
How does smoke impair host immunity?
A
- oxidants in smoke impair alveolar macrophage responses
- more than 4500 components in gas and particulate phase
- superoxides
- hydroxyl radicals
- stable NO derivatives
- oxidants will generate reactive:
- aldehydes
- keto-aldehydes
- DNA damage
- lipid peroxidation
- protein oxidation:
- protein carbonylation
- nitrosylation/nitration
- modify function/activity of key proteins
- more than 4500 components in gas and particulate phase
22
Q
By what is carbonylation markedly induced?
A
- CSE exposure
- metal catalysed oxidation of susceptible proteins
- 10% proteome prone during ageing
- attacks the amino acid side chain of Pro, Lys, Arg and Thr residues
- typically irreversible reaction removed by degradation
- detected by derivatization with 2,4 dinitrophenol hydrazone
23
Q
What is the role of pseudopodia?
A
- heavily carbonylated and associated with reduced phagocytosis
- known carbonylation targets:
- actin (disrupts cytoskeleton)
- SP-A/D (increased susceptibility to pneumonia)
- alpha1-antitrypsin (protease/anti-protease imbalance)
- carbonylation related to impaired pathogen clearance
24
Q
What is defective macrophage function?
A
- impaired efferocytosis and resolution of inflammation
- normal recruitment from blood stream
- maturation of monocyte derived macrophages, clear exhausted neutrophils
- one of the important findings is that patients with COPD have a reduced ability to clear apoptotic cells
- outcome of this is that reduced ability to clear apoptotic cells → go down necrosis pathway → release cell contents → normally maintained in discrete compartments w/i the cell e.g. neutrophil elastase
25
Q
What does neutrophil degranulation do with severity?
A
- increase
- increases in a steroid resistant manner
- releases other mediators that further drive inflammation
- viscious cycle
26
Q
What are the effects of second hand smoke?
A
- immunosuppressive effects not confined to active smokers
- children
- middle ear disease
- lower respiratory illness
27
Q
What is the impact of second hand smoke on children?
A
- worldwide, 40% of children were exposed to second-hand smoke in 2004
- 603,000 deaths were attributable to second-hand smoke in 2004, which was about 1.0% of worldwide mortality
- 28% of deaths occurred in children less than 5 years of age
- this exposure was estimated to have caused 165,000 deaths from lower respiratory infections in children less than 5 years of age
- smoke exposure and early life respiratory infections are major risk factors for developing asthma later in life
28
Q
What is the impact of smoke on the immune system?
A
- cigarette smoke is pro-inflammatory; promotes activation of inflammatory transcription factors to initiate recruitment of leukocytes into the airways
- alters normal functioning of mucosal immune cells
- M2 skewing of alveolar macrophages (alternative phenotype)
- suppress NK cells function required for efficient tumour clearance
- cigarette smoke physically damages mucosal lining leading to impaired mucociliary clearance → bacterial colonisation
- macrophages and important defence molecules are susceptible to oxidative modification in the form of protein carbonylation
- impaired macrophage function leads to deficient microbial clearance and impaired efferocytosis → increased inflammation and damage
29
Q
What are systemic effects of cigarette smoke?
A
- primary cause of cardiovascular disease
- cigarette smoking is causally related to CVD
- associated with accelerated atherosclerosis and increased risk of acute myocardial infarction (AMI), stroke and peripheral artery disease (PAD)
- oxidizing chemicals in smoke are absorbed systemically, increase lipid peroxidation to promote endothelial dysfunction, inflammation, and platelet activation
- carbon monoxide reduces oxygen delivery to heart, which can aggravate PAD
- formation of atherosclerotic plaques appear to be particularly important in smokers, where clots can embolise in narrowed vessels (stroke, heart attack)
- weakened vessels (due to inflammatory elastolysis) can also blow-out (aneurysm) or rupture (bleeding stroke)
30
Q
summary
A
- summary rates continue to rise in developing countries including the Western pacific region. death rates attributable to smoke exposure have yet to peak in these regions
- very difficult to reduce smoking rates in developed countries below 10%. genetic polymorphisms in CHRA5 nicotinic receptor linked to nicotine addiction
- smoking directly causes numerous diseases and cancers. leading causes of smoke-related deaths include lung cancer, COPD, and CVD
- 40% children worldwide are exposed to second-hand smoke and these children are at increased risk of developing a serious lower respiratory infection
- toxic chemicals, oxidants and mutagens present in vapour and particulate phases damage tissue, damage DNA to initiate cancer, promote inflammation and damage essential host immunity
- cessation (quitting) rapidly reduces risks. no other known preventions (other than cessation which is aided by medicines) or cure
