Lecture 55 Flashcards
Glycerophospholipid Synthesis, Degradation, and Role in RDS
(glycero)phospholipid functions
- structural component of: cellular membranes (lipid bilayer), lipoproteins, pulmonary surfactant, bile
- precursors for second messengers: PIP3 and PIP4, diacylglycerol (DAG)
pg 1422
(glycero)phospholipids
- glycerol backbone with polar group
4 most common in human body:
- phosphatidylcholine (PC, lecithin)
- phosphatidylethanolamine (PE, cephalin)
- phosphatidylserine (PS)
- phosphatidylinositol (PI)
pg 1423
synthesis of phospholipids
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
CDP-DAG pathway
- 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
transfer of activated CDP-choline or CDP-ethanolamine to DAG (Kennedy pathway)
- 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
phospholipases
hydrolyze phosphodiester bonds of glycerophospholipids, each type can only cleave particular bonds
phospholipase A1
- can only cleave FA at position 1
- present in many mammalian tissues
pg 1427
phospholipase A2
- 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
phospholipase C
- 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
phospholipase D
- involved in signal transduction
- generates phosphatidic acid (PA), choline from PC and diacylglycerol from PA
pg 1427
alveolar structure
- 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
unique properties of water
- 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
surface tension
- 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
surface tension and alveolar function
- 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
composition of lung surfactant
- 90% lipids including:
- phospholipids -> 70% PC, other glycerophospholipids, and sphingomyelin
- cholesterol
- 10% proteins:
- SP-A, SP-B, SP-C, SP-D
pg 1439
surfactant phosphatidylcholine
- 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
surfactant proteins (SP)
- 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
the life cycle of lung surfactant
- 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
genetic disorders of surfactant homeostasis
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
neonatal respiratory distress syndrome (RDS)
- 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
RDS risk factors
- # 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
RDS etiology and results
- etiology: structural and functional immaturity of lungs due to underdeveloped parenchyma and surfactant deficiency
- results: decreased lung compliance, unstable alveoli
pg 1445
phospholipid concentration and gestation week
- 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
medication for RDS
corticosteroid administration before delivery (if concerned about early delivery) speeds up lung development and surfactant production
pg 1446
acute respiratory distress syndrome (ARDS)
- 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
