Lung cell biology tutorial

Question 1

Describe the epidemiology of asthma

Answer 1

20% children
10% adults
Global increase

Question 2

Describe the epidemiology of COPD

Answer 2

4th cause of death
5th cause of disability
Global increase

Question 3

Which part of the airway is affected in asthma

Answer 3

Large & small airways
Airway hyper-
responsiveness
Increased mucus production

Question 4

Which part of the airway is affected in COPD

Answer 4

Airways and lung
Very little AHR
iNCREASED  Mucus

Question 5

Which inflammatory cells and mediators are involved in asthma

Answer 5

Eosinophils
Mast cells
Th2 lymphocytes

IL-4, -5, cysLTs

Question 6

Which inflammatory cells and mediators are involved in COPD

Answer 6

Neutrophils
Macrophages
Tc1 lymphocytes

TNF, IL-8, LTB4

Question 7

Describe the treatment of COPD and asthma

Answer 7

Asthma- Bronchodilators -
Corticosteroids -

COPD cannot use these

Question 8

What is the key difference between asthma and COPD

Answer 8

Asthma- reversible

COPD- irreversible

Question 9

Summarise asthma pathology

Answer 9

Bronchoconstriction + mucus
Allergic induced airway inflammation results in:
smooth-muscle constriction
thickening of the airway wall (smooth-muscle hypertrophy and oedema)
basement membrane thickening
mucus and exudate in the airway lumen- mucus plug containing inflammatory cells- makes it hard to breathe.

Question 10

What does the viscid mucous contain in asthma

Answer 10

Desquamated epithelial cells
Whorls of shed epithelium (Curschmann’s whorls)
Charcot-Leyden crystal ( eosinophil cell membrane)
Infiltration of inflammatory cells, particularly CD4+ T lymphocytes

Question 11

Summarise the pathology of COPD

Answer 11

Chronic bronchitis- airway hyper mucous secretion
Tobacco smoke damages the lungs:
Inflammatory cell activation- stimulates epithelial cells, macrophages and neutrophils to release inflammatory mediators and proteases (neutrophil elastase)
oxidative stress- oxidants in cigarette smoke act directly on epithelial cells and goblet cells- causing inflammation
Impaired mucociliary clearance- leading to retained mucus secretions

Question 12

What are the two main pathological processes in COPD

Answer 12

Alveolar destruction (emphysema)
Mucus hypersecretion (chronic bronchitis)

Question 13

Describe emphysema in COPD

Answer 13

Cigarette smoke and other inhaled noxious particles cause inflammatory cell activation within the lungs, inducing cells to release inflammatory mediators and proteases, the most important being neutrophil elastase
Normally, antiproteases will neutralise these proteases, but in COPD the volume of proteases produced is in excess
Unopposed action of neutrophil elastase destroys lung tissue
As the distal airways are held open by alveolar septa- destruction of alveoli causes the airways to collapse- resulting in airway obstruction.

Question 14

Describe the consequences of emphysema

Answer 14

Destruction of parenchyma increases compliance of the lung and causes a V/Q mismatch
Increased compliance (reduced elastic recoil) means that the lungs do not deflate as easily, contributing to air trapping
As more alveolar walls are destroyed- compliance of the lungs increases and bullae (dilate air spaces >10mm) form which can rupture and cause pneumothoraces

Question 15

Describe centriacinar (centrilobular) emphysema

Answer 15

septal destruction and dilation are limited to the centre of the acinus, around the terminal bronchiole and predominately affect upper lobes- seen in smoking
increasing damage further into the alveoli

Question 16

Describe panacinar (panlobular) emphysema

Answer 16

The whole of the acinus is involved distal to the terminal bronchioles, and lower lobes are commonly affected- characteristic of alpha 1- antitrypsin deficiency

Question 17

Describe chronic bronchitis (mucous hypersecretion in COPD)

Answer 17

Cigarette smoke causes hyperplasia and hypertrophy of mucus-secreting glands found in the mucosa of the large cartilaginous airways.
Mucous gland hypertrophy is expressed as gland:wall ratio or by the Reid index (normally <0.4)
Hyperplasia of the intraepithelial goblet cells occurs at the expense of ciliated cells in the lining epithelium and squamous metaplasia may occur
Small airways become obstructed by intraluminal mucus plugs, mucosal oedema, smooth muscle hypertrophy and peribronchial fibrosis.
Secondary bacterial colonization of retained products occurs
The effect of these changes is to cause obstruction, increasing resistance to air flow
mismatch in V/Q occurs- impairing gas exchange

Question 18

Describe small airway disease (bronchiolitis)

Answer 18

Mucosal and peribronchial inflammation and fibrosis (obliterative bronchiolitis)

Question 19

Why do the small airways collapse, become obstructed and stenosed in COPD

Answer 19

a. Collapse – alveolar attachments get digested away.
b. Obstructed – hyperplasia of goblet cells causing excess mucus production.
c. Stenosed – Fibrosis of the small airways.

Question 20

What are the changes in epithelial cell profile and secretions during bronchitis?

Answer 20

a. Profile – hyperplasia of goblet cells and hypertrophy of submucosal glands.
b. Secretions – more mucus produced and cilia become destroyed and beat asynchronously.

Question 21

Describe the proportion of cells in healthy individuals and those with COPD

Answer 21

Healthy
Macrophages- 70
Neutrophils- 30

COPD- reverses
mucociliary escalator not working- lots of dead neutrophils- macrophages come to clear these away- numbers still increase but neutrophils have a larger increase- mucous- infection- therefore increase

Question 22

Describe the proportion of cells in the alveoli in healthy individuals and compare that to COPD patients

Answer 22

Healthy:
Macrophages- 90
Neutrophils- 10
COPD- same ratio but numbers increase- 5-10 fold increase
problem when pathogens enter the peripheral lungs- an increase in neutrophils by greater than 30% is problematic

Question 23

Describe the bronchiolar lavage

Answer 23

inspects activity of the proteases in the lavage, need to see if the drug is effective
uses saline to wash mucus, cells and proteases away for sampling
mucus should decrease in response to treatment

Question 24

What should be found in the lavage in response to the drugs (It can inhibit the activity of serine proteinases as well as matrix metalloproteases)

Answer 24

less IL-8, IL-1, TNFa

More defensins, anti-proteases and IL-10 as these are anti-inflammatory and so will put inflammation in balance

Question 25

Describe the use of CT scanning

Answer 25

COPD lungs- full of gas and air- hyperinflated lungs
gas looks black on the X-ray- lungs look very dark- but won’t see much change
CT- contrast can differentiate between different types of tissue more easily- different shades of white to black
CT- pixels- measure the number and size of holes in the lungs to measure the level of emphysema.

Question 26

Do drugs reduce the number of holes

Answer 26

No- destruction is an irreversible process

Question 27

Compare neutrophil elastase and metalloproteinases

Answer 27

NE- active enzymes in storage granules- released upon recruitment, hydrolyses elastin
MMP- metal ion (zinc) as its active site- released in latent form- Zn releases/frees active site- MMPs can then break down connective tissue and collagen (cement of lungs)- which are not healed properly

Question 28

Compare the activities of the different anti-proteases

Answer 28

AAT; also called alpha-1 proteinase inhibitor- inhibits NE

tissue inhibitor of metalloproteases (TIMP)- INHIBIT MMPS

Question 29

What is important to remember about the proteases

Answer 29

NEs degrade TIMPS
MMPs degrade AATs
So we get a protease soup- imbalance in proteases- walls dissolve- alveolar destruction

MMPs and NEs activate growth factors and other molecules- important in homeostasis of tissues

Question 30

Describe AATs

Answer 30

acute phase protein- irreversibly inactivate NEs
Neutrophils make free radicals which activate NEs
Cigarette smoke has millions of free radicals

Question 31

Summarise small airway disease

Answer 31

Elastic walls disappear- mucous builds up- stenosis

Fibrosis adds to the stenosis

Question 32

Why do we need to inhale the drugs

Answer 32

Deactivated by free radicals and the proteases themselves

Thus we need to inhale the drug to get it directly to where it is needed

Question 33

Why do we need a dual inhibitor

Answer 33

Two classes of proteases

But inhibiting MMPs increases the risk of cancer- thus we need to deliver the drug locally

Question 34

Why is it hard to deliver the drug

Answer 34

Lungs are blocked and stenosed- can be hard to inhale

Give mucolytic which is coughed up- freeing the airways

Question 35

Describe the use of bronchodilators in COPD patients

Answer 35

a. Not really as COPD doesn’t affect bronchoconstriction. If he has a co-morbidity of asthma, it might affect him.- if they feel better- keep them on it

Question 36

Describe the asthma- COPD overlap

Answer 36

Asthma-COPD overlap (ACO): smokers with asthma leading to wheezy bronchitis - overlap of two conditions

Question 37

Describe a schema for the pathophysiology of COPD

Answer 37

Epithelial cells producing TGBbeta to activate fibroblasts leading to fibrosis and chronic bronchiolitis
Smoke activates macrophages- autocrine effect of MCP-1, activation of proteases, Neutrophil chemo-
tactic factors
(eg IL-8, LTB4)
and activating CTLs
Neutrophils release oxidants and proteases
CTLs lead to alveolar destruction

Oxidants lead to mucous hypersecretion and alveolar destruction, proteases have the same effect
Antioxidants inhibits oxidants
Anti-proteases inhibit proteases

Question 38

Describe the findings from Flethcher et al

Answer 38

lung function measured in people >25 till age 80 to study how changes over lifetime; identified non-smokers had limited decline (~25%), and non-susceptible smokers had an almost identical decline; susceptible smokers had a much more severe decline that led to symptoms, disability and then death; if stopped smoking then led to reduced rate of decrease so longer prognosis, but older you stop the less the recovery

Function in terms of FEV1 (% predicted at age 25)
Symptoms at 50% predicted
Disability at around 30%
Death- 15%