Lec1 Phospholipids PDF - MBBS Notes

# Objective - At the end of the session, students of MBBS should be able to discuss phospholipids. - **Phospholipids** - Classification: Glycerophospholipid and Sphingophospholipid - Synthesis and degradation - **Surfactant** - Biosynthesis - Function - Law of Laplace - Respir...

# Objective - At the end of the session, students of MBBS should be able to discuss phospholipids. - **Phospholipids** - Classification: Glycerophospholipid and Sphingophospholipid - Synthesis and degradation - **Surfactant** - Biosynthesis - Function - Law of Laplace - Respiratory Distress syndrome - Neonatal respiratory distress syndrome - Adult respiratory distress syndrome # Case of Neonatal Respiratory Distress Syndrome - A 30-year-old pregnant mother G3P2 is in her 30-weeks gestation delivered 1.5 kg baby girl. Cesarean section done after some complication in pregnancy. The mother received one dose of Betamethasone 10 hours before delivery. - The baby was resuscitated, intubated and had surfactant administered in the delivery room, within 15 minutes of delivery. Apgar scores were two, five and six at 1, 5 and 10 minutes. - The baby was mechanically ventilated for severe respiratory distress syndrome (RDS). # Phospholipids - **Definition**: Phospholipids or Phosphatides are compound lipids, which contain Phosphoric acid group in their structure. - **Structure**: Phospholipids are composed of: 1. Fatty acids (a saturated and an unsaturated fatty acid). 2. Nitrogenous base (Choline, Serine, Threonine, or Ethanolamine). 3. Phosphoric acid. 4. Fatty alcohols (Glycerol, Inositol or Sphingosine). The page contains a diagram which shows Phospholipids classified into two groups: Glycerophospholipids and Sphingophospholipids. These groups are further classified into sub-groups, for example Glycerophospholipids are classified into phosphatidate, Phosphatide, and Lysophospholipid, and Sphingophospholipids are classified into Sphingomyelin and Cerebroside. # Glycerophospholipids - **Type 2 – Lecithin - Phosphatidyl choline** - Fatty Acid + Glycerol)Choline - Most abundant group of phospholipid in cell membrane - Phosphatidic acid + Choline - Storage of body Choline (Donar of Methyl grou in Methylation reactions) - Choline - Acetyl choline nerve impulse transmission - Lysolecithin - Removal of fatty acids from C1 or C2 of Lecthin - **Dipalmitol Lecithin - Maintain Surface Tension - Adherence of inner surface of lungs** - **Deficiency - Respiratory distress syndrome in infants** # The most common Glycerophospholipids are 1. - **Phosphatidic acid**: It is the simplest phospholipid and doesn't have specific functions. 2. - **Lecithin**: It is formed of Glycerol, two fatty acids, Phosphate and Choline which is a nitrogenous base. It is phosphatidic acid – choline so it is called phosphatidylcholine. - It is the most abundant phospholipid in cell membranes and plays a critical role in membrane structure and fluidity. In the lungs, dipalmitoylphosphatidylcholine (DPPC) is a major component of pulmonary surfactant, reducing surface tension. The page contains a diagram showing the chemical structure of Lecithin and Phosphatidic acid. 3. - **Phosphatidyl ethanolamine (Cephalin)**: Its chemical structure is exactly as lecithin but choline is replaced by ethanolamine. - Clotting factor III Thromboplastin - Cephalin - Function helps in clotting of blood. - PE is another major component of cell membranes, particularly in the inner leaflet. It helps maintain membrane curvature and is involved in membrane fusion and fission processes. # Phosphatidyl serine - is an important phospholipid which supports cell integrity. - Found in high concentrations in the brain, levels of which decline with age - It is essential for normal neuron structure and function and may play a critical role in maintaining concentration and memory. - It plays a role in cell signaling, particularly in apoptosis (programmed cell death), where its externalization serves as a signal for phagocytosis. # Phosphatidyl inositol - It is one of cell membrane lipids (but less common). - In addition, it plays a role in cell signaling (a group of events that lead to specific cellular response). - Secondary Messenger for Oxytocin, Vasopressin. The page contains a diagram showing the chemical structure of Phosphatidyl inositol. # Synthesis Of Glycerophospholipids - **Liver** is the site of synthesis. - **(A) Synthesis of lecithin (phosphatidyl choline) and cephalin (phosphatidyl ethanolamine):** - Their synthesis needs: 1. Glycerol activated by ATP (by glycerol kinase) giving glycerol-3-phosphate. 2. Two fatty acids activated by CoA (by thiokinase) giving acyl CoA (active FA). 3. Choline (for synthesis of Lecithin) or Ethanolamine (for synthesis of cephalines) activated by CTP to give CDP choline or CDP ethanolamine. # Synthesis of Phosphatidic Acid/Lecithin/Cephalin The page contains a diagram showing the synthesis of Phosphatidic Acid/Lecithin/Cephalin from the following: 1. Glycerol 2. Two fatty acids 3. Choline or Ethanolamine # Degradation of Glycerophospholipids The page contains a diagram showing the breakdown of Glycerophospholipids with the help of various Phospholipases. The diagram indicates the following: 1. Phospholipase A1 2. Phospholipase A2 3. Phospholipase C 4. Phospholipase D # Degradation of Phospholipids - **Phospholipase A1**: Act on ester bond in position 1: removes the first fatty acid from lecithin or cephalin producing lysolecithin or lysocephalin. - **Phospholipase A2 (PLAZ)**: Act on position 2 removes the second fatty acid from lysolecithin or lysocephalin. - **Phospholipase C (phosphodiesterase)**: Act on linkage between the glycerol and phosphate giving free glycerol and phosphate + base (phosphoryl base). - When PLC act on phosphatidyl inositol 1,5 biphosphate, it release inositol triphosphate (IP3) and DAG which are important second messengers. - **Phospholipase D (phosphatase)**: Act on linkage between phosphate and base giving free phosphate and free base. # Cell Membrane Phospholipid The page contains a diagram showing the breakdown of Cell Membrane Phospholipid with the help of the following enzymes: 1. PLA2 2. Cycloxygenase 3. 5-Lipoxygenase The page contains a table showing the function of the following in terms of Cell Membrane Phospholipid: 1. NSAIDs 2. Glucocorticoids # Functions of Phospholipids - Enter in the structure of cell membranes - Component of lipoproteins - Blood clotting: Cephalins enter in the formation of thromboplastin which is necessary for blood clotting - Phospholipids as a component of bile in bile make cholesterol soluble. Their deficiency leads to cholesterol gallstones. - Dipalmitoyl Lecithin act as lung surfactant, prevent alveolar collapse and allow air passage. - Cardiolipin found in inner mitochondrial membrane, cardiolipin is essential for the optimal function of several enzymes involved in mitochondrial energy metabolism, including those in the electron transport chain. # 2-Sphingophospholipids - **Sphingomyelin**: It is a sphingophospholipid. - Not contain glycerol but contain alcohol called sphingosine. - Fatty acid is attached to amino group of sphingosine and phosphorylcholine (phosphate + choline) is attached to the last OH group. - **Sources**: present in high amount in brain and nerve tissues. - **1. Palmitoyl CoA.** - **2. Combination of Palmitoyl CoA with Serine to form sphingosine derivative (ketosphinganine) which after modification gives sphingosine base.** - **3. Ceramide.** - **4. Ceramide + Lecithin.** The page contains a diagram showing the components of Sphingomyelin: 1. Fatty acids 2. Sphingosine 3. Phosphorylcholine (Phosphate + Coline) # Synthesis of Sphingomyelins - Sphingomyelin is formed of sphingosine base, fatty acyl CoA, phosphate and choline. - **Steps of synthesis**: 1. Palmitic acid is activated by CoA to give palmitoyl CoA. 2. Combination of palmitoyl CoA with serine to form sphingosine derivative (ketosphinganine) which after modification gives sphingosine base. 3. Then sphingosine reacts with acyl CoA to form ceramide. 4. Ceramide then reacts with lecithin (phosphatidylcholine) to form sphingomyelin and diacylglycerol. # Degradation of Sphingomyelins - Sphingomyelinase of lysosomes hydrolyses sphingomyelins to ceramide & phosphoryl choline. - Ceramide is further degraded to sphingosine & free fatty acid. The page contains a diagram showing the degradation of Sphingomyelin with the help of the following: 1. Sphingomyelinase 2. Ceramidase # Degradation of Sphingomyelin: - Sphingomyelinase enzyme in lysosome giving ceramide and phosphatidyl choline. - **Niemann-Pick disease: in children** - Niemann-Pick disease results from genetic absence of *sphingomvelinase* enzyme (the enzyme that breakdown excess sphingomyelin). The absence of this enzyme leads to accumulation of sphingomyelin in liver and spleen leading to enlargement of these organs and may cause reduced appetite, abdominal distension and pain, and the enlarged spleen may trap platelets and other blood cells, leading to reduced numbers of these cells in the circulation. - The disease is fatal in early life. - Sphingomyelin accumulation in the brain results in unsteady gait (ataxia), slurring of speech and difficult swallowing (dysphagia). More widespread disease involving the cerebral cortex cause dementia and seizures. # Lysosomal Storage Disorders The page contains a diagram showing the breakdown of GM2 ganglioside with the help of the following: 1. Hexosaminidase A: Tay-Sachs disease 2. Alpha-galactosidase A: Fabry disease 3. Glucocerebrosidase: Gaucher disease 4. Arylsulfatase A: Metachromatic leukodystrophy 5. Galactocerebrosidase: Krabbe disease 6. Sphingomyelinase: Niemann-Pick disease # Surfactant - These are amphiphilic compounds that reduce the surface tension of fluid. - Surfactant is a surface active agent in water which means that it greatly reduces the surface tension of water. - Is a complex mixture of lipids, proteins and ions secreted by type II alveolar epithelial cells, which constitute about 10% of surface area of alveoli. - The type II alveolar epithelial cells, are granular, containing lipid inclusions that are secreted in the surfactant into the alveoli. The page contains a diagram showing the components of Surfactant, and how they are secreted from the Alveoli. # Surface Tension - H2O molecules at the surface of alveoli are attracted to each other by attractive forces that resist distension called surface tension. - Surface tension tends to oppose alveoli expansion. - Pulmonary surfactant reduces the surface tension of the fluid lining the alveoli. - Collapsing Pressure is caused by surface tension and is indirectly related to the size of alveoli (law of Laplace). # Pulmonary Surfactant - Source or secretion of pulmonary surfactant - Pulmonary surfactant is secreted by two types of cells: 1. Type II alveolar epithelial cells in the lungs, which are called surfactant secreting alveolar cells or pneumocytes. - Characteristic feature of these cells is the presence of microvilli on their alveolar surface. 2. Clara cells, which are situated in the bronchiole. - These cells are also called bronchiolar exocrine cells. # Surfactant Composition - The page contains a diagram showing the components of Surfactant: - 90% Lipids : - 50% Phospholipids: 68.0%PC, 10.0% PG, 5.0% PE, 40% Sph - 10% Neutral Lipids - 10% Proteins: - Hydrophilic Proteins: SP-A, SP-D (50-48%) - Hydrophobic SP-B, SP-C (1%) # Pulmonary Surfactant Composition - **3. Proteins**: Proteins of the surfactant are called specific surfactant proteins. - There are four main surfactant proteins, called SPA, SPB, SPC and SPD. - SPA and SPD are hydrophilic, while SPB and SPC are hydrophobic. - SP-A, SP-D is a glycoprotein. Both SP-A and SP-D are members of the collectin family are involved in innate immunity in the conducting airway as well as in the alveoli. - SP-A is a large glycoprotein and has a collagen-like domain within its structure. It has multiple functions, including regulation of the feedback uptake of surfactant by the type II alveolar epithelial cells that secrete it. - **Protein: (SP-B and SP-C)** - Are smaller proteins, which facilitate formation of monomolecular film of phospholipid. - A mutation of gene for SP-C is associated with familial interstitial lung disease. - Surfactant becomes inactive in the absence of proteins. -**4. Ions**: Ions present in the surfactant are mostly calcium ions # Biosynthesis of Surfactant - Type II epithelial cells synthesize and assemble the lipid and protein components into complexes that are stored as tightly packed membranes in lamellar bodies until secreted into the alveolar airspace. - **Lamellar Body Maturation**: The alveolar epithelial cell surface is covered by a thin aqueous layer (hypophase) in which newly secreted, tightly packed surfactant membranes reorganize to form a loose network of interconnected membranes that contacts the air-liquid interface. The page contains a diagram showing the biosynthesis of Surfactant. - The diagram shows the steps involved in the biosynthesis of surfactant, including: - Secretion of lamellar body particles - Unraveling of lamellar bodies - Adsorption of surfactant intermediates - Formation of a surface phase # Functions of Surfactant - **Surface tension is a retracting force that pulls alveolar wall towards the center and also pulls fluid from capillaries, which leads to pulmonary edema.** - **Surfactant, by reducing surface tension, reduces the inward force drawing fluid out of capillaries, therefore pulmonary edema is prevented.** - **Surfactant causes stability of alveoli, i.e. it maintains almost uniform size of alveoli.** - If alveolus becomes larger in size → surfactant molecules are scattered on larger surface → lesser reduction in surface tension → increase the tendency of alveolus to collapse → prevents change in size of alveolus and alveolar sac. # Alveolar Stability - **Two factors oppose tendency of alveoli to collapse thereby reducing the work of breathing:** - surfactant - Alveolar interdependence The page contains a diagram showing the effect of Alveolar interdependence. # Alveolar Surface Tension - Is displayed by thin liquid film that lines each alveolus. - At an AIR-WATER INTERFACE, the water molecules at the surface are more strongly attracted to other surrounding water molecules, than to the air above the surface. - Attraction of water molecules produces a force known as SURFACE TENSION at the surface of the liquid. - **SURFACE TENSION HAS TWO EFFECTS:** - It opposes expansion of alveoli [therefore trying to collapse of the alveoli]. - Increased surface tension - decreased compliance [stretchability]. - It reduces the size of alveolus (squeezing air inside). # Alveolar Interdependence - Alveoli are surrounded by other alveoli and interconnected by connective tissue. - If alveolus starts to collapse, surrounding alveoli are stretched and these alveoli by recoiling they apply expanding forces on the collapsing alveolus, thereby help to keep it open, this is called Alveolar Interdependence. The page contains a diagram showing the effect of Alveolar interdependence. # Law of Laplace - If air passages leading to alveoli are blocked, and two air spaces are connected to each other, the amount of pressure generated in each is given by the following formulae: > Pressure = 2 * surface tension / radius The page contains a diagram showing how the Law of Laplace is used in Alveolar interdependence. # Summary of forces acting on the Lung to keep the alveoli open and forces promoting alveolar collapse - **TABLE 13-2 Opposing Forces Acting on the Lung** | Forces Keeping the Alveoli Open | Forces Promoting Alveolar Collapse | | :---------------------------------------------------------------------- | :-------------------------------------------------------------------- | | Transmural pressure gradient | Elasticity of stretched pulmonary connective tissue fibers | | Pulmonary Surfactant (which opposes alveolar surface tension) | Alveolar surface tension | | Alveolar Interdependence | | # Respiratory Distress Syndrome of New Born - Lungs normally synthesize enough pulmonary surfactant by 35th week of pregnancy (normal pregnancy is 40 week). - If infant is born prematurely, (for eg. 30th week of pregnancy) not enough pulmonary surfactant may be produced to reduce the alveolar surface tension. - Therefore, symptoms of respiratory distress occur in new born. # Respiratory Distress syndrome of New Born - New born respiratory muscles are weak, therefore, new born respiratory distress syndrome may lead to death if breathing becomes so difficult to support gas exchange in alveoli. - **TREATMENT** - Condition is treated by surfactant replacement until surfactant-secreting cells mature. - Drugs can hasten the maturing process of Type II alveolar cells, which secretes surfactant. # Questions - How would you classify phospholipids? - What is the most common type of phospholipid present in the cell membrane? - Discuss the steps of synthesis of glycerophospholipids. - What are the main functions of Phospholipids? - Name the lysosomal storage disorders and their enzyme deficiency? What are Niemann - pick diseases? - Name the types of cells which secreted by pulmonary surfactant? - What are the composition of pulmonary surfactant? - What are the main function of surfactant? - Which forces acting on the lung to keep the alveoli open? - Which forces acting on the lung to promote alveolar collapse? # Fill in the Blanks 1. Classification of phospholipids are classified into 2 groups according to the type of the **fatty alcohol** present into the types that are the simplest type of phospholipids. 2. **Dipalmitoyl Lecithin** maintain **surface tension** which adherence of inner surface of lungs. 3. **Liver** is the site of synthesis of glycerophospholipids. 4. **Phospholipase C** act on linkage between the glycerol and phosphate giving free glycerol and phosphate - base - phosphoryl base. 5. **Phospholipase D** act on linkage between phosphate and base giving free phosphate and free base. 6. When **Phospholipase A2** act on membrane phospholipids, it releases arachidonic acid from C2 of glycerol. 7. Phospholipids are **amphipathic** molecules. They aggregate to hide their **hydrophobic tail** inside and expose **hydrophilic head** to the exterior. 8. **Sphingomyelin** is the type of phospholipids present in high amount in brain and nerve tissues. 9. **Sphingomyelinase** enzyme in lysosomes hydrolyses sphingomyelins to ceramide and phosphorylcholine. 10. Niemann-Pick disease results from genetic absence of **sphingomyelinase** enzyme. 11. Water molecules at the surface of alveoli are attracted to each other by attractive forces that resist distension called **surface tension**. 12. Surface tension tends to **oppose alveoli expansion**. 13. **Pulmonary surfactant** reduces the surface tension of the fluid lining the alveoli. 14. Collapsing pressure is caused by **surface tension** and is indirectly related to the **radius of alveoli** (law of Laplace). # Biosynthesis of Surfactant - The page contains a diagram showing the biosynthesis of Surfactant. The diagram shows the biosynthesis of surfactant in the following: 1. Alveolar type II cell 2. Alveolar type I cell 3. Lamellar Body 4. Surfactant layer 5. Air space 6. Alveolar fluid 7. Alveolar macrophage 8. Alveolus # Fill in the Blanks 1. Classification of phospholipids are classified into 2 groups according to the type of the **fatty alcohol** present into the types that are the simplest type of phospholipids. 2. *Dipalmitoyl Lecithin* maintain *(surface tension)* which adherence of inner surface of lungs. 3. *Liver* is the site of synthesis of glycerophospholipids. 4. *Phospholipase C* act on linkage between the glycerol and phosphate giving free glycerol and phosphate - base - phosphoryl base. 5. *Phospholipase D* act on linkage between phosphate and base giving free phosphate and free base. 6. When *Phospholipase A2* act on membrane phospholipids, it releases arachidonic acid from C2 of glycerol. 7. Phospholipids are *amphipathic* molecules. They aggregate to hide their *hydrophobic tail* inside and expose *hydrophilic head* to the exterior. 8. *Sphingomyelin* is the type of phospholipids present in high amount in brain and nerve tissues. 9. *Sphingomyelinase* enzyme in lysosomes hydrolyses sphingomyelins to ceramide and phosphorylcholine. 10. Niemann-Pick disease results from genetic absence of *sphingomyelinase* enzyme. 11. Water molecules at the surface of alveoli are attracted to each other by attractive forces that resist distension called *surface tension*. 12. Surface tension tends to *oppose alveoli expansion*. 13. *Pulmonary surfactant* reduces the surface tension of the fluid lining the alveoli. 14. Collapsing pressure is caused by *surface tension* and is indirectly related to the *radius of alveoli* (law of Laplace).