Lecture 23 - Smoking and Lung Health Flashcards
Describe the current global smoking rates
Smoking rates and increasing in developing countries
Rates at 40-50% in western Pacific regions:
• Thailand, Vietnam, Indonesia, Malaysia
Decline in smoking rates is variable between countries:
• Great decline in Denmark
• Small decline in Ireland
• Increase in Russia
- United states data –
1900: rates were very low
- United states data –
1960:
• Smoking rates peaked
• Release of Surgeon General’s report on smoking and oral health
After 1960: • Rates steadily dropping • Further reports: SG on second hand smoke • Nonsmokers rights movement • Doubling of federal tax on cigarettes
Outline the various stages of the proposed model of the cigarette epidemic
Give examples of countries that are in each stage
Stage I
• Low smoking rates (20%)
• Little increase in tobacco related illness
• e.g. Sub-saharan Africa
Stage II
• Increasing rates of smoking
• Little support for public health measures against smoking
• e.g. China, Southeast Asia
Stage III
• Smoking rates beginning to decline
• Tobacco related deaths still prevalent
• Better organisation of health education programmes
• e.g. Eastern and Southern Europe
Stage IV
• Smoking rates have been declining for a while
• Rates of tobacco related illness declining in males
• In females, rates of tobacco related illness still increasing, reflecting later smoking patterns
• Northern and Western Europe, US, Australia, Canada
What are smoking rates in Australia?
10-15%
Why are smoking rates in Australia still up around 10-15%?
- Nicotine is highly addictive
- Addiction and smoking behaviours may have a genetic basis
- Nicotine is an appetite suppressant; used to control body weight
What is the efficacy of pharmacological intervention to aid quitting smoking?
2-fold increase in success in quitting
Describe the contribution of cigarette smoking to mortality burden in the US
Smoking is the leading cause of preventable death
1 in every 5 deaths is attributable to smoking
List diseases that are causally related to smoking
Cancer:
• Colorectal cancer
• Lung cancer
Chronic diseases: • COPD • Ischemic heart disease • Diabetes • Ectopic pregnancy • Rheumatoid arthritis • Immune dysfunction
Compare the mortality rates of different cancers
In the US, lung cancer is the leading cause of death from cancer
Lung cancer is widely attributable to smoking
Does smoking always cause cancer?
No, however 80-90% of lung cancer cases are attributable to long term exposure to tobacco smoke
When is lung cancer usually diagnosed?
Lung cancer is usually diagnosed after metastasis has already occurred (50%)
In only 25% of cases is the tumour localised and potentially resectable
What is the prognosis after diagnosis of lung cancer?
60% of patients die within the first year
Describe how the various substances in cigarette smoke contribute to the development of lung cancer
- Nicotine
Nicotine is not directly mutagenic, but variants in the nAChR governs how much an individual smokes
- Genetic loci most strongly associated with lung cancer are those that regulate nAChRs
- Gene variants of these loci can lead to altered smoking behaviour (enhanced addiction)
- This leads to more cigarettes being smoked, and so more exposure to the noxious agents (lung carcinogens) in the smoke
- Carcinogens
• Cigarette smoke contains 50 known carcinogens
• Carcinogens bind DNA to form DNA adducts
• Accumulation of mutations can lead to GC → AT transition
3. Free radicals • Cause oxidative damage: - Lipid peroxidation - DNA adducts - Defective proteins • Superoxide and nitric oxide → Peroxynitrite (more stable)
The accumulation of mutation, especially in the respiratory epithelium, is an essential trigger for tumour initiation
- Agents that disrupt the immune system
a. Inflammation
b. Disruption of adaptive immune mechanisms that mediate tumour recognition and destruction
How do carcinogens cause harm?
Carcinogens bind DNA and form DNA adducts
Outline the various types of lung cancer
A. Non-small cell lung cancer (NSCLC) (70-80%)
1. Adenocarcinoma (30-40%)
• Typically originates in peripheral airway
• Associated with non-smokers (15%)
- Squamous cell carcinomas
• Typically originates in central airways
• Strongly associated with smoking history
Compare the genetic mutation profiles of lung cancers in smokers and non-smokers
Different mutation profiles in smokers and non-smokers
Compare driver mutations of adenocarcinoma and squamous cell carcinoma
What is the implication of this?
These two types are caused by different driver mutations
The implication is that these two different types of cancer will respond to different therapeutic approaches
Driver mutations are more common in adenocarcinoma compared to SCC
Adenocarcinoma:
• K-RAS activating mutation
• EGFR activating mutation
Squamous cell carcinoma:
• FGFR1 gene amplification
• SOX2 gene amplification
How is adenocarcinoma therapeutically targeted?
NB EGFR activating mutation is common in adenocarcinoma
Gefitinib & Erlotinib:
• EGFR blockers
How is squamous cell carcinoma therapeutically targeted?
NB FGFR gene amplification is common in SCC
FGFR inhibitors are currently being trialled in SCC patients positive for FGFR gene amplification
Describe the effects of cigarette smoke on the immune system
- Adaptive immune system
• Inhibition of NK cell function
• CTL effector function is compromised
• Immune destruction of tumour cells is important in preventing cancer - Innate immune system
a. Promotion of inflammation
• ROS: mutagenic
• M2 macrophages: stimulate angiogenesis, release GFs and MMPs (tissue destruction)
• Tumour promoting inflammation is an enabling feature of cancer
b. Impaired mucociliary escalator
• Leads to bacterial colonisation
c. Impaired alveolar macrophage responses
• M2 skewing
• Oxidants (such as in smoke) impairs the alveolar macrophage function
• Protein carbonylation –> dysfunctional phagocytosis and thus pathogen clearance
• Impaired efferocytosis
What is the importance of cigarette smoking for COPD?
Cigarette smoking is the primary cause of COPD in most developed countries
10-15% of smokers develop COPD
Describe the pathogenesis of COPD
- Chronic exposure to noxious stimuli (cigarette smoke)
- Chronic, abnormal inflammatory response to the smoke
• Infiltration of PMNs, Macrophages
• Oxidative stress on lungs - Destruction of lung parenchyma, fibrosis, mucus hyper secretion
- Fixed airway disease:
• Diameter of airways is reduced, and can not be reversed with bronchodilators
• Destruction of alveoli means loss of elastic recoil of bronchi
Which diseases are encompassed in COPD?
Emphysaema
Chronic bronchitis
Describe the effect of cigarette smoke on inflammation
- Smoke induces NFKB
- NFKB turns on transcription of inflammatory cytokines
• TNF
• GM-CSF - Induction of innate inflammation
• Production of ROS, MMPs that damage host tissue
Describe the effect of cigarette smoke on pathogen clearance
What is observed in COPD patients?
Smoking impairs pathogen clearance and promotes colonisation
30-50% of COPD sufferers have colonisation with H. influenzae and S. pneumoniae
What is the clinical implication of microbial colonisation in COPD?
↓ Lung function ↓ Health status ↑ Neutrophilic inflammation ↑ IL-6, IL-8 ↑ Endotoxin levels
What is the effect of infective exacerbations on COPD?
Exacerbations result in a worsening of COPD
• Demonstrated by accelerated decrease in FEV1 in those with frequent infective exacerbations
• Due to the considerable increase in local and systemic inflammation during infection
Infective exacerbations result in release of:
• Proteases
• Free radicals
These result in further tissue injury, which further impairs innate immunity, increasing susceptibility to infection
This creates a vicious cycle
What are the implications of tissue injury due to cigarette smoke
Tissue injury results in the release of DAMPs which exacerbate the inflammation
Describe the role of Carbonylation in smoking
What are the targets of carbonylation?
What does this lead to?
Agents in cigarette smoke promote an oxidising environment, which promotes carbonylation of proteins
Target of carbonylation
• Attack of specific amino acids (Pro, Arg etc)
• Actin → disrupts phagocytosis
• Anti-trypsin → disrupts protease / anti-protease balance
Effect:
• Profound carbonisation of pseudopodia seen in smoking
• Pseudopodia are important for sensing and phagocytosing pathogens
• Thus, clearance of bacteria is disrupted
• Balance tipped in favour of proteases → tissue damage
Describe what happens to efferocytosis in COPD
Cigarette smoke impairs efferocytosis
Efferocytosis is especially important in removing dead neutrophils from the system
If efferocytosis is impaired, neutrophils will undergo necrosis instead of apoptosis
The necrosis of neutrophils results in release of toxic granules:
• Neutrophil elastase especially
• This contributes to the progression of the disease
Neutrophil elastase is markedly elevated in COPD
Describe the effect of second hand smoke
Give examples in adults and children
Immunosuppressive effects of cigarette smoke are also caused by passive smoke inhalation
Children:
• Middle ear disease
• Lower respiratory illnesses
• Early smoke exposure and lower respiratory infections are strong risk factors for development of asthma
Adults:
• Stroke
• Lung cancer
• Coronary heart disease
What is the global disease burden of second hand smoke?
600 000 deaths attributable to second hand smoke in 2004
165 000 deaths from lower respiratory infections in children under 5 due to second hand smoke
Is smoking pro- or anti-inflammatory?
Pro-inflammatory, but immunosuppressive
Describe the role of cigarette smoke in CVD
Oxidants in smoke are rapidly absorbed into the systemic compartment
Smoking is a primary cause of CVD, through: • Accelerated atherosclerosis • AMI • Peripheral artery disease • Aneurysm
Mechanism:
• Smoking → chronic inflammation
• ROS → lipid peroxidation → atherosclerosis
• Endothelial dysfunction, platelet activation
• Inflammatory elastolysis → aneurysm
How can smoking contribute to risk of aneurysm?
- Smoke exposure
- Inflammatory elastolysis of vessel walls
- Weakening of vessels
- Aneurysm
How can risk of disease due to tobacco be removed?
Cessation of smoking is the only way
NB pharmacological intervention can aid cessation
What is efferocytosis?
Removal of dying and dead cells by phagocytosis
What is the role of M2 macrophages in smoking?
Smoking stimulates M2 macrophages
Release:
• Angiogenic factors → vascularisation of tumour
• GFs → tumour growth
• MMPs → tissue destruction and tissue remodelling
• ROS (superoxide, hydroxyl radicals, NO)
Describe the immune dysfunction in COPD
- Innate
• Overexpression of NFKB induced by cigarette smoke
• Accumulation of innate inflammatory cells (PMNs, macrophages, eosinophils)
• Chronic inflammation (cytokines TNF and GM-CSF)
• Induction of proteinases → remodelling of tissue matrix - Adaptive
• Accumulation of CTLs which cause tissue damage through the release of perforin and granzyme
Also:
• Mucociliary disfunction due to cigarette smoking
What is the role of proteases in COPD?
Proteases are released by inflammatory cells
These result in tissue damage and remodelling (i.e. contributing to the disease)
What is the effects of oxidants in the lung?
Suppress alveolar macrophage function
In addition to the tissue, molecule, & DNA damage
Is carbonylation reversible?
It’s typically irreversible
The only way it can be reversed is ubiquitin dependent degradation of the protein in the proteasome
