Lecture 55

Question 1

(glycero)phospholipid functions

Answer 1

• structural component of: cellular membranes (lipid bilayer), lipoproteins, pulmonary surfactant, bile
• precursors for second messengers: PIP3 and PIP4, diacylglycerol (DAG)

pg 1422

Question 2

(glycero)phospholipids

Answer 2

• glycerol backbone with polar group

4 most common in human body:

• phosphatidylcholine (PC, lecithin)
• phosphatidylethanolamine (PE, cephalin)
• phosphatidylserine (PS)
• phosphatidylinositol (PI)

pg 1423

Question 3

synthesis of phospholipids

Answer 3

uses intermediates from the TAG synthesis pathway as precursors for phospholipids

• lysophosphatidic acid (glycerol-3-P + 1 FA) is precursor for cardiolipin, phosphatidylinositol, and phosphatidylglycerol
• phosphatidic acid (DAG phosphate -> 2 FAs) is precursor for PC, PS and PE

can be produced by all cells as they need to maintain their membranes
synthesis done in smooth ER

pg 1424

Question 4

CDP-DAG pathway

Answer 4

• used for synthesis of PI, PG, and cardiolipin
• reduces phosphatidic acid (using CTP) to CDP-diacylglycerol
• CDP-diacylglycerol undergoes exchange with an alcohol (glycerol/inostiol) to form the glycerophospholipid

pg 1425

Question 5

transfer of activated CDP-choline or CDP-ethanolamine to DAG (Kennedy pathway)

Answer 5

• used for synthesis of PC, PE, PS (PE converted to PS through a base change reaction)
• converts phosphatidic acid to diacylglycerol
• diacylglycerol converted to glycerophospholipid via transfer of activated alcohol (CDP-choline or CDP-ethanolamine)

pg 1426

Question 6

phospholipases

Answer 6

hydrolyze phosphodiester bonds of glycerophospholipids, each type can only cleave particular bonds

Question 7

phospholipase A₁

Answer 7

• can only cleave FA at position 1
• present in many mammalian tissues

pg 1427

Question 8

phospholipase A₂

Answer 8

• can only cleave FA at position 2
• present in many mammalian tissues and pancreatic juice; also in snake and bee venoms
• pancreatic secretions rich in A2 proenzyme, which is activated by trypsin and requires bile salts for activity
• releases arachidonic acid when acting on PI
• inhibited by glucocorticoids (like cortisol)

pg 1427

Question 9

phospholipase C

Answer 9

• cleaves position 3 -> diacylglycerol intermediate
• found in liver lysosomes and the α-toxin of clostridia and other bacilli
• membrane-bound, activated by PIP₂ system and plays a role in producing second messengers

pg 1427

Question 10

phospholipase D

Answer 10

• involved in signal transduction
• generates phosphatidic acid (PA), choline from PC and diacylglycerol from PA

pg 1427

Question 11

alveolar structure

Answer 11

• grape-like sacs with optimal SA for gas exchange
• single layer of type I alveolar cells, scattered type II
• thin epithelium
• type II alveolar cells secrete surfactant
• macrophages present to attack inhaled bacteria/toxins

pg 1429

Question 12

unique properties of water

Answer 12

• large difference between electronegativity of the H and O atoms
• highly polarized bonds in water molecules and partial (+) and (-) charges
• intermolecular hydrogen bonds
• tetrahedral geometry: interaction with up to 4 adjacent water molecules
• high boiling point and surface tension due to strong H bonds

pg 1430-1432

Question 13

surface tension

Answer 13

• a phenomenon in which the surface of a liquid, where the liquid is in contact with a gas (such as the air), acts as a thin elastic sheet
• if the surface is between two liquids (such as oil and water), it is called “interface tension”
• intermolecular attraction between water molecules is greater along the air surface than in the bulk water phase
• almost forms a membrane

pg 1433-1434

Question 14

surface tension and alveolar function

Answer 14

• the alveolus must expand easily upon inhalation and remain open (not collapse!) upon exhalation
• phospholipids (major component of surfactant) penetrate through the air-water interface to reduce intermolecular hydrogen bonding between water molecules and lower surface tension
• surface tension decreases as phospholipid monolayer is compressed (molecules move closer together)
• this prevents collapse upon exhalation and allows for easier re-inflation

pg 1435-1438

Question 15

composition of lung surfactant

Answer 15

• 90% lipids including:
• phospholipids -> 70% PC, other glycerophospholipids, and sphingomyelin
• cholesterol
• 10% proteins:
• SP-A, SP-B, SP-C, SP-D

pg 1439

Question 16

surfactant phosphatidylcholine

Answer 16

• 1/2 dipalmitoyl phosphatidylcholine (DPPC) -> both R₁ and R₂ are palmitate/palmitic acid
• 1/2 unsaturated PC (R₁ and/or R₂ are unsaturated FAs)

pg 1440

Question 17

surfactant proteins (SP)

Answer 17

• minimal component, but important function
• hydrophilic surfactant proteins: SP-A and SP-D, involved in innate host defense, antimicrobial properties, help to regulate inflammation
• hydrophobic surfactant proteins: SP-B (required for life) and SP-C, interact strongly with PLs, adsorption and spreading on surface, prevent collapse of alveolus

pg 1441

Question 18

the life cycle of lung surfactant

Answer 18

• de novo synthesis occurs in ER
• transported to GA for modification
• released as lamelar body particles (LBP)
• can be recycled in lysosomes or degraded by macrophages
• synthesis and recycling both occur in alveolar type II cells

pg 1442

Question 19

genetic disorders of surfactant homeostasis

Answer 19

mutations in genes encoding SP-B and SP-C and the LB-associated lipid transporter protein (ABCA3) are causes of rare, but severe, pulmonary diseases in newborn infants and children

pg 1443

Question 20

neonatal respiratory distress syndrome (RDS)

Answer 20

• names: neonatal respiratory distress syndrome (RDS) or infant respiratory distress syndrome (IRDS) or hyaline membrane disease
• occurrence: most common causes of respiratory distress in preterm infants

pg 1445

Question 21

RDS risk factors

Answer 21

• # 1 is prematurity -> < 28 weeks gestation (~100%), 28-34 weeks (33%), > 34 weeks (5%)
• perinatal depression
• male predominance
• maternal diabetes
• C-section
• multiple birth

pg 1445

Question 22

RDS etiology and results

Answer 22

• etiology: structural and functional immaturity of lungs due to underdeveloped parenchyma and surfactant deficiency
• results: decreased lung compliance, unstable alveoli

pg 1445

Question 23

phospholipid concentration and gestation week

Answer 23

• fetus lung maturity can be gauged by determining the PC (lecithin) to SM (sphingomyelin) ratio in amniotic fluid
• PC/SM (L/S) > or = to 2 reflects lung maturity
• indicates a major shift from SM to PC synthesis in type 2 pneumocytes which normally occurs around 32 weeks of gestation

pg 1446

Question 24

medication for RDS

Answer 24

corticosteroid administration before delivery (if concerned about early delivery) speeds up lung development and surfactant production

pg 1446

Question 25

acute respiratory distress syndrome (ARDS)

Answer 25

• characterized by: hypoxemia, lung edema, increased alveolar-capillary permeability leading to leakage of surface-active blood and serum proteins into air spaces
• lung surfactant function is impaired and exacerbates the work of breathing
• leakage of serum proteins into alveolar spaces leads to: inflammation, edema, and surfactant dilution affecting its microstructure and converting highly packed assemblies into loosely packed membranes

pg 1448