lecture 10

Question 1

What are the pathways air travels through to get to the lung?

Answer 1

Airways are a series of branching tubes.

• upper airways
• trachea
• bronchi
• bronchioles
• terminal bronchioles
• respiratory bronchioles
• alveolar ducts
• alveoli

Question 2

What is the acinus?

Answer 2

Where the main action of the lung (gas exchange) occurs.

• respiratory bronchioles
• alveolar ducts
• alveolar sacs
• alveoli

raspberry shaped

Question 3

How does the development of the lung occur?

Answer 3

5 stages of lung development.

1. embryonic: 0-6 weeks gestation
   - lung bud appears day 26-28
   - ventral outpouching of the primitive foregut
   - endodermal origin
   - proximal branching of the airways into surrounding mesoderm
2. pseudoglandular: 6-16 weeks gestation
   - lungs start to form an early pattern that is a little more recognisable to the airway patterns seen in baby/adult
   - airways develop (branch) to the level of the terminal bronchioles (pre-acinar bronchi)
   - by the time you get to the terminal bronchioles you have 16 divisions/generations of airways that have developed
3. Canalicular: 16-26 weeks gestation
   - acinar region develops
   - thinning of the peripheral epithelium
   - Type I and II pneumocytes develop
4. sacular/alveolar: 26-36 weeks gestation
   - sacules form into the alveolar ducts and alveoli start to be developed
   - marked decrease in interstitial tissue
   - sacules become thin walled (as recognised in postnatal lungs)
   - sacules and alveoli form further generations of alveoli by septation
   - by the time a baby is born there are 100 x 10^6 (on average) alveoli in a baby (1/3 of those present in adults)
   - surface area at birth 4m^2 (in adult 10m^2)
5. postnatal: birth to ? (2 years to adult)
   - lungs continue to develop afterbirth but unclear when it finishes. Used to be thought to end at 2 but now at least into teenage years. Good news for young children with lung disease.

Question 4

What are some of the functions of the lung?

Answer 4

• gas exchange
• defence
• acid-base balance
• metabolic
• heat exchange
• water balance
• phonation

Question 5

What are the lung defence mechanisms?

Answer 5

Physical (airway)

• upper airway filter
• reflexes (sneeze, cough)
• mucociliary escalator

Cellular (alveolar)

• phagocytes e.g. alveolar macrophages
• immunological

Question 6

What is the mucociliary escalator?

Answer 6

• airway surface liquid (ASL) has 2 layers
• • periciliary layer (quite thin)
• • mucus gel layer (thicker)
• mucus produced by secretory cells include Goblet cells
• mucus propelled by cilia
• • beat 12-15 times per second
• • 1mm per minute
• • beat the mucus from the distal ends of the airways upwards through to the back of your throat –> constantly swallowing mucus (around 30ml per day in a normal person)
• • impurities in the air get trapped in the mucus and this escalator prevents them from reaching the rest of the body

Question 7

How does gas exchange occur in the lung?

Answer 7

• in the acinus which is the portion of the lung that includes the alveoli
• o2 in co2 out
• type II cell are what produce the surfactant
• type I where gas exchange occurs - form the walls of the alveoli - very thin layer so that oxygen can easily diffuse across the membrane of the alveolar wall and the capillary (CO2 diffuses in opposite direction

Question 8

How do we measure lung function?

Answer 8

• volume (litres)
• flow (l/sec) = volume over time
• pressure

Question 9

What are the different lung volumes and capacities?

Answer 9

• tidal volume: small volume, normal restful breathing, amount of air you’re breathing at any one time
• inspiratory reserve volume: take a deep breath to fill your lungs as much as possible
• expiratory reserve volume: expelling as much air as you can
• total lung capacity: complete amount of air in the lungs
• residual volume: you can never breath all the air out of your lungs, this represents what is left of total capacity when you breathe out as much as possible

Question 10

What is forced expiration?

Answer 10

• measure with spirometer
• maximal inspiration followed by fast exhalation to residual volume
• forced expiratory volume (FEV1): volume exhaled in first second
• forced vital capacity (FVC): total volume exhaled

Question 11

What does a normal flow-volume curve look like?

Answer 11

• initally the flow is very fast and as the volume drops off the flow reduces

Question 12

What happens to the flow/volume curve when you have CF/severe asthma etc?

Answer 12

• fast initial flow
• v. quickly drops off
• someone with obstruction of airways can take a long time to blow out all the air because of narrow tubes –> total amount of air in the lungs is the same but thinner passages make it harder to breathe out

Question 13

What is the role of pulmonary disease in CF?

Answer 13

• lung disease is associated with a significant amount of morbidity and mortality in CF: 90% of people with CF will die because of a lung disease
• pulmonary exacerbations
• • increased cough and sputum production
• • increased dyspnoea
• • lethargy/poor appetite
• • reduced lung function
• • can lose weight
• progressive decline in lung function
• respiratory failure
• death/transplantation

Question 14

How is CFTR associated with lung disease?

Answer 14

• CFTR mutations –> lung disease: exact mechanism unknown
• complex relationship between host defense and airway microbiology that impacts on sputum production and airflow obstruction
• viral infections may play a role in the initiation of these events (also bacterial, probably also fungal)

CFTR expressed on several cell types

• apical plasma membrane of ciliated epithelial cells in airways; regulates ion transport – chloride, bicarbonate
• serous cells of submucosal glands
• alveolar epithelial type II cells
• cells of the immune system
• • alveolar macrophages
• • neutrophils

Question 15

What does CFTR do in airway epithelial cells?

Answer 15

Coordinates modulation of ASL (airway surface liquid) by

1. Na+ absorption Epithelial Na+ channel (ENaC) (in lungs, usually inhibits)
2. Cl- secretion

2 functions of CFTR lost in CF:
1. ENaC not inhibited: therefore increased sodium absorption (water follows sodium)
2. Cl- ions not secreted
therefore increased Na+, Cl- and H2O absorption
therefore decreaseed ASL volume

Question 16

How is the relationship between CFTR and Airway Surface Liquid important?

Answer 16

ASL volume hyperabsorption has important consequences for both the PCL and the mucus layer:

• volume depletion of PCL –> failure of ciliary beating
• absence of lubrication –> adherent mucus plaque

–> promotes chronic infection

Question 17

What is the anaerobic milieu?

Answer 17

Thick mucus plaques adherent to epithelial surface AND increased oxygen consumption by CF epithelia –> anaerobic environment

• ideal environment for growth of certain bacteria
• Pseudomonas converts to anaerobic biofilm mode of growth

Question 18

What are some other ions associated with CF lung/CFTR?

Answer 18

• studies in pigs with CF show that deficiency of CFTR-mediated transport of bicarbonate and regulation of the pH of airway surface liquid inhibits antimicrobial function in the cystic fibrosis airways
• CFTR has an important role in the maintenance of glutathione and thiocyanate concentrations in the fluid of the epithelial lining
• • glutathione deficiency in ASL of patients with CF might contribute to lung inflammation and oxidative stress

Question 19

How does inflammation affect CF?

Answer 19

• CFTR dysfunction promotes chronic airway infection
• results in exaggerated, predominantly neutrophilic inflammation
• CFTR dysfunction may also directly affect airway immunity
• • (probably) increased production of proinflammatory mediators

Neutrophils are predominant inflammatory cells in CF airways
- play central role in the ensuing tissue damage and disease progression
- possess an array of mediators, oxidants and proteases, critical for response against infection
- large amounts of these enzymes escape from neutrophils in cell death and during phagocytosis
Antiprotease defences in the airways overwhelmed by the protease burden in the lung

CF airways are exposed to oxygen radicals derived from environmental oxygen and bacterial products and also fromt he host immune response

• oxidative stress exacerbates pulmonary deterioration and advances brionchiectasis in patients with CF
• growing evidence that oxidative stress leads to oxidation of airway proteins e.g. SP-A (surfactant proteins)
• may further augment cytokine release and airway inflammation

Question 20

What are extracellular triggers of inflammation in CF?

Answer 20

Variety of extracellular factors present in CF airways continuously trigger the airway epithelial innate and adaptive immune cells to produce excessive pro-inflammatory cytokines

• bacteria, viruses, fungi, GER (gastric esophageal reflux), ROS/antioxidants balance, Protease/anti-protease balance
• as a result of these you get production of a whole range of cytokines/chemokines including CXC, ICAM-1. IL-8

Question 21

What are the intracellular triggers of inflammation in CF?

Answer 21

• In CF there is increasing evidence of increased cellular response to inflammatory triggers
• Proinflammatory property of CF airway epithelium may be due to dysregulated activity of transcription factors (e.g. increased nuclear factor-kappa B
• evidence coming out that people with CF have an exaggerated inflammatory response in their lung airways
• accumulation of abnormally folded CFTR in ER results in unfolded protein responses that trigger ‘cell stress’ and apoptosis
• ceramide accumulation may further augment pulmonary inflammation by inducing apoptosis with subsequent deposition of DNA in airways
• ceramide is breakdown product of sphingomyelin found in plasma membrane and in endolysosomal compartments
• inherent abnormal intracellular pathways, primarily in airway epithelial cells, lead to apoptosis on the one hand and to cell stress and excessive cytokine production on the other, perpetuating the inflammatory response in the airways
• abnormal TLR signalling e.g. leading to increase in pro-inlammatory cytokines
• increasing interest in the role of CFTR in pulmonary inflammation via interaction between organisms and epithelial cells e.g. : pseudomonas stimulates formation of lipid rafts containing CFTR and caveolin-1 which facilitates organism entry into epithelial cells to be destroyed

Question 22

What is bronchiectasis?

Answer 22

Infection, inflammation and obstruction of airways leading to dilation and damage of airways –> once visualised by taking slices of lung, now with CT scans. Pathologic

Question 23

What is the histology of a lung with CF?

Answer 23

• lots of neutrophilic inflammation

Question 24

What are some of the infections that trouble people with CF?

Answer 24

• haemophilus influenzae (v. common even in non-CF)
• staphylococcus aureus (young children with CF)
• pseudomonas aeruginosa (usually older CF patients)
• burkholderia cepacia
• stenotrophomonas maltophilia
• Non-tuberculous myobacteria (concerning - quite resistant to antibiotics currently available)

Question 25

Does FEV1% change overtime with CF patients?

Answer 25

Yes - declines with age
Modern therapies have improved this though rate of decline has not change the initial lung health has, therefore altering how low their lung function becomes over time

Question 26

What does the % of FEV1 represent?

Answer 26

Normal range of lung function is between 80 and 120 % - can be over 100. 100 represents average

100% lung function could represent a significant loss if your original lung function was 120%

When FEV1 reaches ~30% patient is recommended for lung transplant –> 50% chance of death within 2 years w/o transplant therefore justifying risks of transplant