Lecture 23 - Smoking and lung health Flashcards
Smoking rates are ___ in some countries
increasing
Smoking results in long diease latency:
What are the challenges of reducing the burden of Cigarette smoke?
Large proportion of the golbal population is still in early stages of smoking epidemic (i.e education and government intervention are not yet established)
Current golbal smoking trends in developing countries will impact on dealth reates for over 50-80 years…
Can smoking reates be reduced to below 10% in developed countries?
Consider New phase of anti-smoking educational programs
Further restrict sophisticated, cynical marketing targeting the young
Why are 10-15% adult population still smoking in Australia?
nicotine is highly addictive affeting CND dopamine please/reinforcement and executuve centres
Addition and smoking behavious may have a genetic basis: where nicotinic Ach receptor genetic variants govern smoking dose
Nicotine is a major appetite suppresant - people use it for weight loss
What are the therapeutic intervention to combat nicotine addiciton?
nicotine replacement therapy, nicotine receptor blockers and partial agonists
true or false
Cigarette use is the leading preventable cause of death in the US
true
What cancers other than lung can be caused by smoking?
Liver, rectum and stomach
COPD, ischemic heart disease and lung cancer are each what percentage of smoking related deaths?
25%
so the remaining quarter is made up of other cancers, stroke and other stuff
What percentage of lung cancer cases are due to long-term exposure to tobacco smoke?
80-90%
What percentage of patients have metastatic disease at lung cancer diagnosis?
over 50% - majority will die in the first year of diagnosis
What is the role of nicotine in lung cancer?
Not directly mutagenic BUT
The gene variants of the Ach receptor are strongly associated with nicotine dependence
So smoking behaviours is driven by genetic and will cause an increased uptake of nicotine in smoke AND consequently a greater present of lung carcinogens
smoke contains __ known carcinogens that can covalently bind to DNA to form DNA adducts
50
Cigarette smoke is also a contains ___
ROS
What are the types of non-small cell lung cancers (which account for 70-80% of cases)
30-40% - Adenocarcinomas - originate in peripheral airway (associated with non-smokers, particularly female asians)
30-40% Squamous cell carcinomas - originate in central airways - strongly associated with smoking history (so declining is AUS, but increased amounts in developing countries
Lung cancers relating to smoking have a different mutation profile to…
non-smoking related lung cancers
We need therapies/targets to treat squamous cell carcinoma because…
Alternative FGFR1 gene amplication pathways are moreso responsible
This is in contrast to adenocarcinomas which rely on activating mutations in K-RAS signalling molecules
FGFreceptor1 inhibitors are currently being assessed in SCC patients that are positive for FGFR1 amplification
Cigarette smoke may also drive tumour promoting..
inflammation and avoidance of immune destruction:
- This inflammation can be tumour promoting
inflammatory cells can release ROS, meaning…
they are actively mutagenic for nearby cancer cells, accelerating their malignancy potential
Cigarette smoke also drives lung inflammatio that causes the developmnt of____
COPD
10-15% smokers develop COPD
risk of developing COPD increase with age, and is an issue in developing countries in the future
Chronic inflammation can cause ___ ______ in the same way ___ ______ causes chronic inflammation
oxidative stress
increase in neutrophils, macropaghes - innate immunity is exaggerated in COPD as well as adaptive
Smoke-induced NFkB controls inflammatory gene programs
How does NFkB contribute to smoking pathology
NFkB can be activated by cigarette smoke
It then drives expression of inflammatory mediators including TNF-a and GM-CSF
Also induces protease expression - promotes further recruiting of inflammatory cells by remodelling the matrix
COPD exacerbations are very related to…
bacterial and viral infections - this really drives disease progression
How does smoking contribute to COPD exacerbations via infections
Defective innate immunity - Smoking damages the mucosal linging, leading to imapied muco-ciliary clearance
Can also directly interfere with the function of phagocytic leukocytes (so the pathogen sticks around)
this then causes increased expression of Protases and ROS, causes airways injury and the cycle continues
Carbonylation is markedly induced in Cigarette smoke exposure - what does this mean?
metal catalysed oxidation of susceptible proteins
attacks the amino acid side chain of Pro, Lys Arg and Thr residues
Typically irreversible reaction removed by degradation
Pseodopdoai are important in Macrophage fucntion, it means…
sensing the pathogen
carbonylated macrophages don’t do this as well - can be prevented using anti-oxidants
What are some known carbonylation targets?
Actin - disrupts cytoskeleton
Sp - A/D 9increase susceptiility to pneumonia)
a1-antitrypsin (anti-protease, so can lose the protease balance)
A reduced ability to clear apoptotic cells what will happen
will go down the necrotic pathway and release contents unsafely (including protease)
Whats are the efects of secondary smoke?
especially bad for children
40% of chilren worldwide were exposed to second hand smoke in 2004
Smoke exposure and early life respiratory infections are major risk factors for developing asthma
Cigarette smoking is pro-____: promotes activation of inflammatory transcription factors to initiate recruitment of ______ into the airway
Cigarette smoking is pro-inflammatory: promotes activation of inflammatory transcription factors to initiate recruitment of leukocytes (macrophages) into the airway
How does smoking alter 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 linging leading to…
impaired mucociliary clearance = bacterial colonisation
Macrophages and important defense molecules are susceptible to oxidative modificaion in the form of ____ _______
protein carbonylation
impaired macrophage fucntion leads to deficient microbial clearance and impaired efferocytosis (safe clearance of damaged tissue, necrotic pathways instead), which leads to….
increase inflammation and damage
How is cigarette smoking causally related to CVD?
Associated with acelerated atherosclerosis and increased risk of acute myocardial infarction, stroke and peripheral artery disease
oxidising chemicals in smoke are systemically absorbed, increasing lipid peroxidation which promotes endothelial dysfunction, inflammation and platelet acivation
Carbon monoxide reduces oxygen delivery to heart
atherosclerotic plaques appear to be important in smokers - where clots can embolise in narrowed vessels
Weakened vessels can also blow-out or rupture
Smoking ____ continue to rise in developing countries including the western pacific region
rate
It is very difficult to reduce smoking rates in developed countries below ___
10%
Genetic polymorphisms of CHRA5 nicotinic receptor linked to…
nicotine addiciton
___% of children worldwide are exposed to second-hand smoke - this increases the risk of…
40%
increases risk of developing a serious lower respiratory infection
What damages tissue, dNA and initiates cancer, promotes inflammation and damages to essential host immunity in smoke?
Toxic chemicals, oxidants and mutagens prsent in vapour
Cessation rapidly reduced risk. Are there any other known preventions or cures?
no
only medicines that aid cessation
