Lecture 23 - Smoking and lung health

Question 1

Smoking rates are ___ in some countries

Answer 1

increasing

Question 2

Smoking results in long diease latency:

What are the challenges of reducing the burden of Cigarette smoke?

Answer 2

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…

Question 3

Can smoking reates be reduced to below 10% in developed countries?

Answer 3

Consider New phase of anti-smoking educational programs

Further restrict sophisticated, cynical marketing targeting the young

Question 4

Why are 10-15% adult population still smoking in Australia?

Answer 4

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

Question 5

What are the therapeutic intervention to combat nicotine addiciton?

Answer 5

nicotine replacement therapy, nicotine receptor blockers and partial agonists

Question 6

true or false

Cigarette use is the leading preventable cause of death in the US

Answer 6

true

Question 7

What cancers other than lung can be caused by smoking?

Answer 7

Liver, rectum and stomach

Question 8

COPD, ischemic heart disease and lung cancer are each what percentage of smoking related deaths?

Answer 8

25%

so the remaining quarter is made up of other cancers, stroke and other stuff

Question 9

What percentage of lung cancer cases are due to long-term exposure to tobacco smoke?

Answer 9

80-90%

Question 10

What percentage of patients have metastatic disease at lung cancer diagnosis?

Answer 10

over 50% - majority will die in the first year of diagnosis

Question 11

What is the role of nicotine in lung cancer?

Answer 11

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

Question 12

smoke contains __ known carcinogens that can covalently bind to DNA to form DNA adducts

Answer 12

50

Question 13

Cigarette smoke is also a contains ___

Answer 13

ROS

Question 14

What are the types of non-small cell lung cancers (which account for 70-80% of cases)

Answer 14

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

Question 15

Lung cancers relating to smoking have a different mutation profile to…

Answer 15

non-smoking related lung cancers

Question 16

We need therapies/targets to treat squamous cell carcinoma because…

Answer 16

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

Question 17

Cigarette smoke may also drive tumour promoting..

Answer 17

inflammation and avoidance of immune destruction:

• This inflammation can be tumour promoting

Question 18

inflammatory cells can release ROS, meaning…

Answer 18

they are actively mutagenic for nearby cancer cells, accelerating their malignancy potential

Question 19

Cigarette smoke also drives lung inflammatio that causes the developmnt of____

Answer 19

COPD

10-15% smokers develop COPD

risk of developing COPD increase with age, and is an issue in developing countries in the future

Question 20

Chronic inflammation can cause ___ ______ in the same way ___ ______ causes chronic inflammation

Answer 20

oxidative stress

increase in neutrophils, macropaghes - innate immunity is exaggerated in COPD as well as adaptive

Question 21

Smoke-induced NFkB controls inflammatory gene programs

How does NFkB contribute to smoking pathology

Answer 21

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

Question 22

COPD exacerbations are very related to…

Answer 22

bacterial and viral infections - this really drives disease progression

Question 23

How does smoking contribute to COPD exacerbations via infections

Answer 23

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

Question 24

Carbonylation is markedly induced in Cigarette smoke exposure - what does this mean?

Answer 24

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

Question 25

Pseodopdoai are important in Macrophage fucntion, it means...

Answer 25

sensing the pathogen carbonylated macrophages don't do this as well - can be prevented using anti-oxidants

Question 26

What are some known carbonylation targets?

Answer 26

Actin - disrupts cytoskeleton Sp - A/D 9increase susceptiility to pneumonia) a1-antitrypsin (anti-protease, so can lose the protease balance)

Question 27

A reduced ability to clear apoptotic cells what will happen

Answer 27

will go down the necrotic pathway and release contents unsafely (including protease)

Question 28

Whats are the efects of secondary smoke?

Answer 28

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

Question 29

Cigarette smoking is pro-____: promotes activation of inflammatory transcription factors to initiate recruitment of ______ into the airway

Answer 29

Cigarette smoking is pro-inflammatory: promotes activation of inflammatory transcription factors to initiate recruitment of leukocytes (macrophages) into the airway

Question 30

How does smoking alter normal functioning of mucosal immune cells

Answer 30

M2 skewing of alveolar macrophages (alternative phenotype) Suppress NK cells function required for efficient tumour clearance

Question 31

Cigarette smoke physically damages mucosal linging leading to...

Answer 31

impaired mucociliary clearance = bacterial colonisation

Question 32

Macrophages and important defense molecules are susceptible to oxidative modificaion in the form of ____ _______

Answer 32

protein carbonylation

Question 33

impaired macrophage fucntion leads to deficient microbial clearance and impaired efferocytosis (safe clearance of damaged tissue, necrotic pathways instead), which leads to....

Answer 33

increase inflammation and damage

Question 34

How is cigarette smoking causally related to CVD?

Answer 34

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

Question 35

Smoking ____ continue to rise in developing countries including the western pacific region

Answer 35

rate

Question 36

It is very difficult to reduce smoking rates in developed countries below ___

Answer 36

10%

Question 37

Genetic polymorphisms of CHRA5 nicotinic receptor linked to...

Answer 37

nicotine addiciton

Question 38

___% of children worldwide are exposed to second-hand smoke - this increases the risk of...

Answer 38

40% increases risk of developing a serious lower respiratory infection

Question 39

What damages tissue, dNA and initiates cancer, promotes inflammation and damages to essential host immunity in smoke?

Answer 39

Toxic chemicals, oxidants and mutagens prsent in vapour

Question 40

Cessation rapidly reduced risk. Are there any other known preventions or cures?

Answer 40

no only medicines that aid cessation