Biochemistry of Lung surfactant

Question 1

Which law consititutes the area/depth of the lungs?

Answer 1

Fick’s Law

Question 2

what is the function of all the ‘splitting’ in lung airways?

Answer 2

the volocity of air falls rapidy as it moves down into the lung

Question 3

What are the two major alveolar cells?

Answer 3

Type 1 = all about transfer of oxygen and good connections with blood flow 95% of the alveolar cells

Type 2 = 5% secrete pulmonary surfactant - a phsopholipid protein complex which facilitates lung expansion

Question 4

What do the smooth muscle cells do in the bronchi?

Answer 4

They control the diameter and tension of the bronchi - amount decreases deeper in the lung - involved in asthma (chronic asthma can have increased bronchial smooth muscle content) - produces cytokines - IL5 and IL13

Question 5

What is the role of lung macrophages?

Answer 5

• Interspersed – found along length of the respiratory tract
• Particularly important for immune defense in respiratory bronchioles.
• Function through phagocytosis (e.g. soot, spots in smokers lung, clearance of cell turnover)
• Produce potent antimicrobial agents

–Reactive oxygen species

–Proteases

•Antiviral agents

–interferon

Question 6

what antiviral agent is produced by lung macrophages?

Answer 6

interferon

Question 7

What does the release of histamine, prostaglandin D2, and Leukotriene C4D4 by the mast cells lead to?

Answer 7

–Cause: bronchoconstriction & increased mucous production

Question 8

What are the Goblet cells of the lungs?

Answer 8

• Present from bronchioles up
• Located in epithelium
• Function is to secrete mucous
• Density of goblet cells is increased in Cystic Fibrosis

Question 9

what are the pulmonary endothelial cells?

Answer 9

• Environment for alveolar capillaries
• Represents the largest and most dense vascular bed in the human body – approx 140m2
• Produce vasoactive peptides e.g.Tissue Plasminogen Activator (TPA), of ACE I – ACE II, inactivation of bradykinin (vasodilator) (CONSTRICTORS)
• Controlling blood flow, fluidity and pressure & viscosity

Question 10

What are the Flat Alveolar Cell?

Answer 10

•Type 1 = main cells found in the alveoli

Resembles a fried egg - large & thin cells, central nucleus - make up 95% of the epithelial lining of the respiratory zone

• Fusion of type 1 epithelial cells with the pulmonary endothelium
• Responsible for gas exchange. Fusion with pulmonary endothelium results in ultra-thin layer – & diffusion
• Unable to replicate= terminally differentiated - require stem cells under the influence of other mediators to differenciate into this type of alveolar cell

Question 11

What are Alveolar type 2 cells?

Answer 11

Large alveolar cells – Type 2 pneumocytes= stem cell

• Much less numerous than Type 1 pneumocytes- which seems counterintuitive that the cell that produces both Type 1 and Type 2 cells is much less concentrated
• Have large nuclei, microvilli (secrete surfactant) & extensive mitochondria
• Site of synthesis, storage and secretion of surfactant
• Are stem cells – can replace themselves or other pulmonary cell types after injury – can replace damaged type 1 cells

Question 12

What is Surfactant?

Answer 12

• Lines inner surface of alveoli and bronchioles
• Surfactant reduces surface tension, relative to its concentration (otherwise small aveoli would empty in to large!)

They counteract the collapsing force of the water molecules which want to congregate together

Question 13

what is compliance as it relates to the lungs?

Answer 13

•Compliance is the ability of lungs and thorax to expand

Question 14

what is hysteresis?

Answer 14

•Difference in volumes, ‘Hysteresis’ - is due to the air-water surface tension that occurs at the beginning of inflation

Question 15

what law states that the gas pressure needed to keep equilibrium between the collapsing force of surface tension and the expanding force of gas in an alveolus of radius r ?

Answer 15

Law of laplace

Question 16

Increasing compliance by surfactant allows for what ?

Answer 16

allows the lungs to inflate more easily

Question 17

what happens when an alveoli begins to collapse?

Answer 17

•Each alveolus is surrounded by other alveoli and interconnected by connective tissue

•

•If an alveolus starts to collapse, the surrounding alveoli are stretched as their walls are pulled in the direction of the caving alveolus

•

•The distended alveoli re-coil in response and exert an expanding force on the collapsing alveolus

Question 18

what is the strongest surfactant molecule in the pulmonary surfactant mixture?

Answer 18

The DPPC is the strongest surfactant molecule in the pulmonary surfactant mixture. It also has higher compaction capacity than the other phospholipids, because the apolar tail is less bent

Question 19

what cell secretes DPPC?

Answer 19

Type 2 pneumocytes

Question 20

phospholipid synthesis occurs one of two ways - what ways can it occur?

Answer 20

(i) Donation of the phosphatidic acid from cyditine diphosphate (CDP) CDP-diacylglyercol to an alcohol (either attach a CDP to the diacylglyerol)

Or

(ii) Donation of the phosphomonoester of the alcohol from CDP-alcohol to 1,2 diacylglycerol (or attach CDP to alcohol head)

Question 21

what palmates are attached to the molecule surfactant?

Answer 21

DPPC and apolipoproteins *addition of these two molecules make it lung specific molecule - not found anywhere else in the body*

Question 22

What are the four surfactant associated proteins ?

Answer 22

SP-A

SP-B

SP-C

SP-D

•The major surfactant associated proteins SP-A and SP–D are hydrophilic. These are known to play a crucial role in pulmonary immunity

•

•The surfactant proteins SP-B and SP–C are very hydrophobic proteins. They are closely linked to alveolar surface-tension, phospholipid packaging and organization of surfactant structure and also have recently emergent roles in host defence

Question 23

What is neonatal respiratory distress syndrome?

Answer 23

NRDS =

• Rapid, labored breathing in newborn (sternal retraction due to partial collapse of lungs)
• Affects 1-2% of newborn infants, approx 20% of neonatal deaths due to NRDS
• Characterised by insufficient surfactant
• Incidence correlates with degree of prematurity
• the real problem in this is that the babies heart has to work very hard to move the oxygen around the body

Question 24

what can we test for when we test for fetal lung maturity?

Answer 24

• Sampling the amount of surfactant in the amniotic fluid by amniocentesis. Several tests are available that correlate with the production of surfactant.
• Lecithin-sphingomyelin ratio- as the lung matures you have more lecithin than sphingomyelin, therefore it’s a good predictor
• the presence of phosphatidylgycerol (PG) (precursor for the surfactant) and more recently,
• the surfactant/albumin (S/A) ratio-

Question 26

Treatment for NRDS?

Answer 26

• Treat mother with corticosteroids (increase enzymatic activity (of phosphatidic acid phosphatase) to increase surfactant lipid synthesis) to speed fetal lung development
• Treat neonate with exogenous surfactant immediately after birth
• Positive pressure mechanical breathing - Oxygen is given with a small amount of continuous positive airway pressure (“CPAP”), and intravenous fluids are administered to stabilize the blood sugar, blood salts, and blood pressure. If the baby’s condition worsens, an endotracheal tube (breathing tube) is inserted into the trachea and intermittent breaths are given by a mechanical device

Question 27

What enzyme catalyzes the production of phospholipid (phosphatidylcholine)

Answer 27

Phosphatidic acid phosphatase

Question 28

What is elastic recoil?

Answer 28

• the rebound of the lungs after having been stretched by inhalation, i.e. The ease with which the lung rebounds.
• With inhalation, the interpleural pressure (the pressure within the pleural cavity) of the lungs decreases. Relaxing the diaphragm during expiration allows the lungs to recoil and regain the interpleural pressure experienced previously at rest.
• Elastic recoil is inversely related to lung compliance.
• If [elastase] up [elastin] down which results in decreased elasticity of lung & emphysema

Question 29

what is the role of alpha1 antitrypsin?

Answer 29

it is a protease inhibitor which neutralises elastase and trypsin - it prevents the degradation of elastin in the lungs

Question 30

what is alpha 1 antitrypsin deficinecy?

Answer 30

autosomal recessive hereditary disorder = •In all these cause of reduced AAT activity in the lung, increased activity of elastase is seen. The elastase activity causes damage to and reduced elasticity of alveoli and other lung tissue , resulting in difficulty breathing, emphysema, COPD. Disease is progressive, most present in early 50’s, patients can also have liver cirrhosis.

Question 31

where is alpha1 antitrypsin produced?

Answer 31

in the Liver

Question 32

why might pulmonary disease present with liver cirrhosis?

Answer 32

b/c as lung function degenerates, the liver tries to make more alpha 1 antitrypsin to compensate- this causes liver cirrhosis

Question 33

What is the Pittsburgh mutation?

Answer 33

mutated methionine 358 site (where elastase and alpha 1 antitrypsin normally bind) - converts it to arginine - therefore it impairs the ability of alpha 1 antitrypsin to act as a serpin - and instead it is converted to a Thrombin inhibitor - leading to a clotting disorder

Question 34

What is a gain of function mutation of alpha1 antitrypsin

Answer 34

more alpha 1 antitrypsin mutations - buildup levels of these molecules in the lungs and they bring on an immune storm of the region - therefore you get a lot of neutrophil chemotaxis in the lung and leads to vasoconstriction of the lung airways

Question 35

cigarrete smoke can impact what?

Answer 35

it can lead to oxidation of methionine 358 of alpha1 antitrypsin ( which is the binding site between A1AT and elastase)- this is thought to be one of the primary mechanisms by which cigarette smoking can lead to emphysema

Question 36

what is the treatment of patients with A1 AT deficiency?

Answer 36

• Early diagnosis = treatment with purified AAT – before onset of damage
• Augmentation therapy with AAT can restore the anti neutrophil elastase activity within the lung and slow the rate of decline of lung function in ATT deficient patients, it has no known effect on the pulmonary gain of function effects associated with the accumulation of polymerised ZATT in the monocytes and bronchial epithelial cells