Lecture Notes on the Lymphatic System PDF

**Lecture 1** Learning Objectives Lecture Focus: Lymphatic System At the end of this lecture you should be able to: 22-2 Identify the major components of the lymphatic system Describe the function of these components Provide examples of interaction between the lymph system and other systems...

**Lecture 1** Learning Objectives Lecture Focus: Lymphatic System At the end of this lecture you should be able to: 22-2 Identify the major components of the lymphatic system Describe the function of these components Provide examples of interaction between the lymph system and other systems Reading: Fundamentals of Anatomy & Physiology, Global Edition, 11th Edition pg 834-843.   Introduction Lymphatic system - Pathogens ate microscopic organisms that cause disease - Viruses - Bacteria - Fungi - Parasites - Each attacking in a specfifc way - Antigens - Target that idenify any pathogen or foreign compound - The lymphatic systems protects us agaisnt disease - The lyphatic system cells (lympocytes) respond to - Environemntal ptahigens - Toxins - Abnormal body cells - Eg. Cells under stress or cancer Immune system - Provides the body with the ability to resist infection and disease - All body cells and tissues rae involved in the process of immuunity, not just the lympathic system   Lympathic sytems Function - Immunity - To produce, mainatin and distribute kymphocytes - Draingage network - Mainatin fluid balance in tissues - Absorbs fat and other subtances form. The digestive system Organisation - Lymoh - Fluid similar to plasma - Not actively pumped around the bdoy - Flow of lypm - Forced rhrp8gh vesels by body moevnet including contarction of smooth muscle in the walls of large veslsel, contraction of skeletal muscles during movement an dpressyre changes in the thorax due to breathing - Relatiobship bteween the lympathic an dcradiovasculart systems 1. Blood capillaries (blood) 2. Interstitial spaces (fluid) 3. Lumpathic cappilaries (lymph) 4. Lympathitc vessel (lymph) 5. Lympathic ducts (lymph) 6. Subclavian (blood) - Lymphatic vessel (lympathics) - Carry lymph from peripheral tissues to the venous sytems - Lymphatic capillaries are described are terminal lymphatics and are the entry way for interstitial fluid to enter the system - Endothelial cells loosely bound together with overlap (like tiles on roof) which acts as a one way valve for the entry ofn interstitial fluid into the system - Allows fluids, solutes, viruses and bacteria to enter the lymph system and prevent reurn to intercellular/interstitial space - Superfifcial and deep lymptahics - Superficial 1. Skin 2. Mucous membrances 3. Serous membrane - Deep lymathic 1. Larger vessel that accompany deep arteries and vein - Lymphoid tissues and pymphoid organs - Produce and store most of the lymphocytes - Lymphocytes - Cells that participate in the immune response - Lympathic drainage - Lymph from these strcutures enter the roght lymphatic duct, wbove the right subcalvian vein - rigfht upper limb - Right side of head and neck - Lymph from rest of the body enters Thoracic duct - Thoracic duct empties into left subcalvian vein   Clinical note: lymphedema - Blockage of lymph draingage - Intersitital fluid increase and causes server swelling - Fluid become essentially stagnant - Accumulation of txins and pathogens   Integration with other physiologyical suystems - Lumptahuc and digestive suystems - Lacteals are special lympathic cappularies in the small intestine\'transport lipids from digestive tract Key concept The cells, tissues and organs of the lymphatic system have a pivotal role in the body defences against a variety of different pathogens or disease-causing organisms.   Can you: - Identify the major components of the lymphatic system? - Describe the function of these components?   **Lecture 2** Lecture Focus: Lymphatic System At the end of this lecture you should be able to: 22-2 Discuss the importance of lymphocytes Describe the distribution of lymphocytes within the body Reading: Fundamentals of Anatomy & Physiology, Global Edition, 11th Edition pg 834-843.   Lymphocytes - Make up 20-30% of ciruclating leukocytes (cells of the immune system, helps woth fighteing infection and diease) - Produced in - Lypmphoid tissues - Lymphoid organs - Red bone marrow - Travel to the site of injury or infection as part of an immune repsonse - Types - T cells - produced in the thymus - Cytotoxic T (Tc) cells 1. Attacks cells infected by viruses 2. Specific cell-mediated immunity - Memory T cells 1. Fomred un repsone to foreign substances 2. Remain in bofy to give immunity - Helper T (T~H~) cells 1. Stumulate function fo T cells and B cells - Suppressor T (T~S~) cells 1. Inhbit function of T cells and B cells - B cells - made in bone marrow - Make up 10-15% cirucating lympocytes - Differnetiate (change) into plasma cells - Plasma cells produce and secrete antibodies (immunoglobin proteins) - The bidning of a specific antibody to its specific target antigen initiates specific antibody-mediated immunity - NK cells - natural killer cells - Resposinbile for immunological surveillance - Attack foreign cells, virus-infeted cells and cancer cells - Non-sepcifci immunity - Lymphopoiesis - How lymphocytes are prodoced - Involved bone marrow, thyus and peripheral lymphoid tissue - Lympoid stem cells - Group 1 - stem cells in bone marrow, can be triggered to change into B cells or NK cells, using a group of molecules called cytokine (interleukin - 7) - Group 2 - differntiated into T cells by thymic hromone - All transported to peripheral tissue to complete respective function   Lymphoid tissues and organs - Lymphoid tissue - Connective tissue dominated by lymphocytes - Lymphoid nodule - Small localised collection fo lymhpoid tissuye - Raspiratoet tract (tonsils) - Located along the digestive, urnary and reproductive tracts - Open to environemnt, wheer pathogens can enter our physiology and help to fihot of these atogens - Lympohodi organs - Seperated from surrounding tissues by a fibrous connective tissue capsule - Lymph nodes - Filters- flows in via afferent vessel, flows out via efferent vessel - Presenc of B cells and T cells to help fight infection - Lymph are taken to look for cancer cells (centenal node), as cancer cells can travel through lymph nodes and vessels - Thymus - Thymosin is a protein produced un the thymus that promotes the production of lymphocyres - Rpoucdes gromones important in the developemnt and maintenance of normal immune system function - Thymus reduces in size as we age which contributes to a decreased iin immune function - Spleen - The spleen has 3 functions 1. Removal of abnormal blood cells and other blood components by phagocytes 2. Storage of iron recycled rom RBC 3. Initionation of immuune response by B cells and T cells in repsonse to antigens in circulating blood   Key conecpts - Lymphocytes are the primary cells of the lymphatic system and are central to the immune response against pathogenic threats to the body. - The three classes of lymphocytes are T-cells, B cells and Natural Killer (NK) cells - The lymphatic system produces, maintains and distributes lymphocytes, helps maintain blood volume and composition of interstitial fluid.   Can you: - Identify the three different types of lymphocytes and discuss their role in immunity? - Describe where the different lymphocytes are found within the body? - Why do lymph nodes enlarge during some infections? - If the thymus failed to produce thymic hormones which population of lymphocytes would be affected? - Explain why people who have their spleen removed are more susceptible to infections compared to people who have a spleen   **Lecture 3** Lecture Focus: Innate Immunity = Non-Specific Immunity At the end of this lecture you should be able to: 22-3 Describe what innate immunity / non-specific immunity is. State and describe the physical barriers that contribute to innate immunity / non-specific immunity. List and describe the internal defence mechanisms that contribute to innate immunity / non-specific immunity. Reading: Fundamentals of Anatomy & Physiology, Global Edition, 11th Edition pg 843-851.   Innate Immunity - Non-sepcfifc immunity - Mechanism always work in the same wat agaisnt any type of pathogen - Non-sepcfifc defense - 7 categories of innate defense - Physical barriers/ epitheal liniing - 1st line of defence - Epidermal layer of skin - Hair - Epitheal layers of internal passageways - Scretion that flush away materails 1. Sweat glands, mucus and urine - Secretion that kill or inhiibit microorganisms 1. Enzymes, antibodies and tsomach acid - Internal defence - 2nd line of defence - Phagocytes - First line of celllulatr defnce; enguld or detsru pathogen - Two classes of phagocytes 1. Microphages - Neutrophls and eosinophils - Leave the bloodstream - Enetr peripheral tissues to fight infection 2. Macrohpahes - Large pahgoctic cells derived from monocytes - Distributed throughout the body - Make up monocyte-macrohpahe system - The main phagocyitc cell - Phagocytosis - Activated macrohpahes - Repsonde to pathogens in sereval ways - Enguld pathogen and destroy it with lysossomal enzymes - Bind to pathogem so other cells can destroy it - Detsrot pathoigen by releasung toxic chemcials into intersitital fluid - Two types - Fixed macrophages - Stau in specfifc tissue or organ - Eg. Dermis and boen marroe - Free macrophages - Also called wandering macrophages - Travel throughout body - Immunological surveillance - Carried out by NK cells - Recognise and destroy abnormal cells - Activated NK cells 1. Identify and attch to abnormal cell (nonselective), e.g. cancer cell, cells infected with a virus or stressed (dying) cell 2. Golgi apparatus in NK cell forms perforin vascicles 3. Vesiciclaes release protein called perforins (exocytosis) 4. Perforins lyse abnormal plasma membarnce 5. Perforins protein is screted by golgi apartus and embeds itself into the membrane of the pathogen, by forming a pore, this results in the pathiegn being compromised as its contents are release, leading the death of the pathogen - Interferons - Proteins called cytokines are released byactivated lymphocytes and macrophages 1. Cytokines are chemcial messangers released by tissue cells that act as hormones to affect the whole bofy - The infection of a cell by a virus stimulates the experesiion fo interferons proteins - Interferons proteins are exocytosed and them bond to receptors on an uninfected cell trigerring the production of antiviral proteins - The antiviral protein block the replication of the vrius which causes it to die - Complement - Plasma contain approximately 11 complement (C) proteins - Induced lysis of forwign cells - Enhgances both non-specfifc and specific defense mechanisms - Complements antibody action - Three pathways activate the complement system 1. Classical pathway - Antibodies attachs onto cell wall of pathgen, the attachment of 1 coplement prpotien (C3) act as an eznyme, catalysing a series of reactions, resulting in the formation of C3 top C3a to C3b. - C3b binds to the plasma membrance, creating a membrane attack complex (indriect pore), signalling other complement protein (C5-C9) to embed into the cell wall 2. Lectin pathway 3. Alternate pathway 4. Min role is to convert the iactive complement protein C3 to active form of C3b - Five complement proteins join to form Membrane Attack Complex (MAC), destruction of the tragert plasma membarnces 1. Increased phagocytoisi by opsonisation - C3b may also increase pahgocytosis. The pathogen is coated by complement protein, signalling for macrophages to engulf pathogen 2. Inflammation - Complemnet proteins can trigger the release of histamine by mast cells and basophils (chemical change in intersitital fluid), increaseing inflmamtion and resulsting in the attraction of macropahges to engluf the pathogen within the area - Inflammatory response - A localised repsonse to injury or infection - Triggered by any stimulus that kills cells to injuries rtissue - Four key signs 1. Increased tissue fluid - Swelling - Pain 2. Icreased blood flow - Redness - heat - Fever - An increase in body tempareture above 37º - Caused y the release of pyrogens which are molecules associated with circulatijg opathigens, toxins or antibody complexes - Signals the hypothalamus to rasie the bdoy temperature which disrupts the lifecycle of the pathogen   Key concepts - Innate immunity is also described as non-specific immunity. - There are seven major categories of innate defences: 1\. Physical barriers 2\. Phagocytes 3\. Immunological surveillance 4\. Interferons 5\. Complement 6\. Inflammatory response 7\. Fever - Each defence mechanism does not distinguish one type of threat from another i.e. the response is the same, regardless of the type of invading agent. Can you Describe what innate immunity is? - State and describe the physical barriers that contribute to innate immunity? - List and describe the internal defence mechanisms that contribute to innate immunity - Describe in detail how NK cells detect and destroy cancer cells. - A rise in the level of interferon in the body suggests what type of infection? - How do pyrogens affect the body?   **Lecture 4** Lecture Focus: Adaptive / Specific Immunity -- cell mediated immunity & antibody mediated immunity   At the end of this lecture you should be able to: 22-4 Describe what adaptive / specific immunity is. Explain the role of the major histocompatibility protein complexes. Understand the difference(s) between cell and antibody mediated immunity. Describe the mechanism for cell mediated immunity. Describe the mechanism for antibody mediated immunity.   Reading: Fundamentals of Anatomy & Physiology, Global Edition, 11th Edition pg 851-867.   Adaptive/specific immunity - Repsinds to specfifc antigems - With coordinated action fo T cells (cell mediated cytotoxic T cells) and B cells (antibody mediated) - 3rd line of defence - Cytotxic T cells - Provide cell-mediated immunity - Defends agasnit abnormal cells and pathigens inside cells - B cells - Provide antibody-mediated immunity - Defend agaisnt antigens and pthaogens in body fluids   Four proerties of immunity - Specificity - Each T or B cell reposends only to a specfifc antigen and ognores all others - Versatility - The body produces many types of kymphocytes - Each fight a different type of antigen - Active lymphocytes clone itself to fight specfifc antigen - Memory - Some active lymphocytes (memory cells) - Stay in ciruclation - Provide immunity against new exposure - Tolerance - Immune syste ignores \'normal\' antigens (self-antigens)   Antigen presentation - T cells only recognise natigens that are bound to glycoproteins iin plasma membranes - Major histocompatibility complex (MHC) proetins - Differ maong indvidiauls - Two classes of MHC proteins - Class 1 1. Found in mebrance of all nucleated cells 2. Pick yp small peptides in cell and carry tehm to the surface - T cells ignore normal epptides - Abnromal peptides or viral proteins acxtivate T cells to destroy cell - Class 2 1. Found in membrance of antigen-rpesenting cells (APCs) 2. Found in lymphocytes 3. Antigenic fragemnts - From antigenic processing of ptahogens - Bind to class 2 protein - Inserted in plasma mambrane to stimulate T cells 4. Antigen-presenting cells - Repsonsible for activated T cells against frogein cells and proteins - Phagocyitic cells - Monocyte-macrophage; liver and CNS macrophage - T~H~ cells are activated upon conmtact with eth APC - Non-phagocytic cells - Langerhans cells in skin - Dendritic cells in lymph nodes and spleen   Cluster of Differnetaition (CD) Markers - CD markers - In t cell membrane - Moleuclar mechanism of antigen recogintion - More than 70 types - Designated by an identify number - Two important CD markers - CD8 1. Found of cytotoxic T cells and supressor T cells 2. Reposnd to antigens on class 1 MHC proteins - CD4 1. Found on helper T cells 2. Reposnd to antigens on Class 2 MHC proteins     Cell mediated Immunity (cytotoxic T cells T~c~) - Seek out and immedialtely destroy target cells - Active helper T cells (T~H~ cells) - Secret cytokines - Stimulate B cells ro produce antibodies (IL-4,5,6) - Augemnst activty of cytotoxic T cells (IL-2) - Some actr as chemotaxins-lure cells to inavde area (chemokines) - Keeps cell within the area (macrophage migration inhibition factor)   Anitbodfy mediated immunity (B cells and Plamsa cells) - B cells - Repsonible for nitobdy0mediuated immunity - Pathogen outside the cell - Differntiate into plasma cells - Producing specfifc antibodies to attach antigens - Illion of populatiom, each woth different antibody molecules - Three steps - Sensitiation - Activation by an activated T helper cell - Division and diferenation - Blood cancer - overproduction of antibodies - Deposited on organs, building up and causng destruction of organs   Antibudt produtcion - 5 classes of antibodies - IgG (immunologlobin) - Laregtes subclass - Several subtyes - Resposbile for majority of defence - Second type of secretion - IgM - First type secredt follwong priary expsire to antigen - IgA - Attack pathogen before they enter body tissues - Increased when tonsil removed - IgE - Accelerates inflammatiuuon on exposure to antigen - Allergies, etc. - IgD - Binds antigen int the extracellulat fluid to B cells - Memory cells - Repsone to antigen exposure - First exposure 1. Produces intial primary repsonse - Second exposurw 1. Triggers secondary repsonse 2. More extensive and prolonged 3. Memory cells already primed - Primary and secondary repsonses occur in both cell mediated and antibody mediated immunity   Key concepts Specific defences - Cell-mediated immunity involves close physical contact between activated cytotoxic T cells, and foreign, abnormal or infected cells - Antibody mediated immunity involves the production of specific antibodies by plasma cells derived from activate B cells MHC Proteins & Antigen Presentation - Class I MHC proteins are always present in membranes of nucleated cells - Antigen presentation by Class I MHC proteins is triggered by viral or bacterial infection of a body cell - Infection results in abnormal peptides within the cytoplasm - Abnormal peptides are incorporated into the Class I MHC proteins as they are synthesised at the ER - Exported to the Golgi and then transported in vesicles to the PM - The abnormal peptides are displayed by Class I MHC proteins on the PM - Class II MHC proteins are only present in membranes of antigen presenting cells and lymphocytes - Class II MHC proteins appear in the plasma membrane only when the cell is processing antigens For a phagocytic cell: - Extracellular pathogen is engulfed - Lysosomal action produces antigenic fragments - Endoplasmic reticulum produces Class II MHC proteins - Antigenic fragments become bound to Class II MHC proteins in vesicles which are then transported to, and displayed on, the plasma membrane Can you - Describe what adaptive immunity is. - Explain the role of the major histocompatibility protein complexes I and II in immunity. - Describe the mechanism (s) for cell mediated immunity. - Describe the mechanism for antibody mediated immunity. - Explain the difference(s) between cell and antibody mediated immunity. - Explain the difference between primary and secondary responses in adaptive immunity. - Describe the difference between the humoral immune response and the cell-mediated immune response, being sure to name any cell types involved. - Describe the activation of B cells when exposed to a pathogen. - Human Immunodeficiency Virus (HIV) infection can lead to the destruction of helper T cells. How would this affect a patient's response to infection by a pathogenic bacteria? - How does increased stress decrease the effectiveness of the immune response?    Lecture 1 Lecture Focus: General overview of metabolism At the end of this lecture, you should be able to: Understand what metabolism is and know the definitions. Describe the role of oxidation and reduction reactions in metabolism. Describe the two mechanisms for ATP generation   Reading: Fundamentals of Anatomy & Physiology, Global Edition, Chapter 25 - relevant sections.   Definition - Metabolism - The chemical reactions that occur within our body and is an energy-balancing act between catabolism and anabolism - Catabolism - Chemical reaction that breaks down complex molecules into smaller units and release energy - Anabolism - Chemical reaction that combine simple molecules to form the body\'s complex structural and functional components - Adenosine triphosphate (ATP) - couples, energy-releasing catabolic reaction to energy-requiring actions   Energy Transfer - Redox reactions - Catabolic reactions transfer energy into the high energy bonds of ATP. Oxidation and reduction (redox) are two important reactions that are involved in this process - Oxidation - The removal of electrons from a molecule resulting in a decrease in potential energy of the molecule - Loss of hydrogen atoms - Reduction - The addition of electrons to a molecule increasing the potential energy of the mole - Gain of hydrogen atoms - Two coenzymes that are involved in oxidation-reduction are nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD) (Coenzyme is a small organic non-proteins that carry chemical groups between enzymes) - NAD^+^ \ NADH + H^+^ - FAD \ FADH~2~ - Oxidised \ reduced - Mechanism of ATP generation - Some of the energy released during oxidation reactions is captured in a cell when ATP is formed - Adenosine - P - P + energy (ADP) \-\--\> adenosine - P - P - P (ATP) - The addition of a phosphate group to a molecule is called phosphorylation and increases the potential energy of the molecule - Substrate level phosphorylation - Transferring a high energy phosphate group from a substrate directly to ADP. - This process occurs in the cytosol - Oxidative phosphorylation - Removes the electrons form organic compounds and passes them through a series of electron acceptors (electron transport chain) to molecules of oxygen. - This process occurs in the inner mitochondrial membrane of cells.   Nutrient use in cellular metabolsim - - Glucose metabolism - Glucose + oxygen \-\--\> carbon dioxide + water + ATP + heat - C~6~H~12~O~6~ + 6O~2~ \-\--\> 6CO~2~ + 6H~2~O + ATP + heat - Oxidised \-\--\> reduced - The oxidation of glucose to produce ATP is also called **cellular respiration** and the **total yield** of energy is **36 molecules of ATP** -    Key concepts - Metabolism refers to all the chemical reactions in the body. - Oxidation-reduction reactions are important for transferring energy into high-energy bonds of ATP - ATP is the energy currency of a cell - Cells make ATP by two different mechanisms of phosphorylation   1. Can you: a. Describe the role of redox reactions in metabolism b. Describe the two different mechanisms of phosphorylation that make ATP.   Lecture 2 Lecture Focus: General overview of carbohydrate metabolism & glycolysis At the end of this lecture, you should be able to: Explain the role of glycolysis in carbohydrate metabolism Describe the basic steps of glycolysis. Briefly explain the fate of pyruvate in the presence and absence of oxygen   Reading: Fundamentals of Anatomy & Physiology, Global Edition, Chapter 25 - relevant sections.   Glucose metabolism - The oxidation of glucose to produce ATP is also called **cellular respiration** and the **total yield** of energy is **36 molecules of ATP** - Four steps of reactions 1. Glycolysis - Takes place in the cytosol of the cell - Once glucose has entered the cell, one glucose molecule is oxidized into 2 pyruvic acid/pyruvate molecules (carbon molecules) - Can occur in the absence or presence of oxygen but the fate of pyruvate is different - Consume 2 molecules of ATP, 4 moles of ATP ate produced; with a net gain of 2 ATP molecules - 2 molecules of NADH produced - Phosphofructokinase the enzyme that catalyses fructose 6-phosphatre to fructose 1,6-biphosphate is the key regulator of glycolysis 2. Formation of acetyl coenzymes A 3. Krebs/critic acid cycle reactions 4. Electron transport chain reaction and chemiosmosis  - Pyruvate - The fate of pyruvate depends on the availability of oxygen - Oxygen present - Aerobic respiration - Transported into mitcohrondira matrix - Conversion to acetyl coenzyme A - Entry into the Krebs cycle - Oxygen absence - Anaerobic reparation - Skeletal muscle fibres during strenuous exercise риечв арАчар-ваэу 1ПOЧИМ УОО нџриочэоиш ц H(IVN   Key concepts - In glycolysis each molecule of glucose makes 2 molecules of pyruvate, 2 molecules each of ATP (net), and 2 molecules of NADH - In the presence of oxygen, pyruvate molecules are transported into the mitochondria matrix where they are converted to acetyl CoA which will then enter the Krebs/TCA cycle. 1. Can you: a. Explain the role of glycolysis in metabolism b. Describe the basic steps of glycolysis and outline the main molecules produced.   Lecture 3 Lecture Focus: Conversion of pyruvate to Acetyl-CoA and the Krebs Cycle At the end of this lecture you should be able to: Explain why pyruvate is converted to Acetyl-CoA in the presence of Oxygen Explain the role of the Citric Acid Cycle. Explain the fate of electrons produced by the Citric Acid Cycle.   Reading: Fundamentals of Anatomy & Physiology, Global Edition, Chapter 25 - relevant sections.   Acetyl-coenzyme A and Krebs cycle - Conversion of pyruvate to acetyl-CoA - Pyruvic acid enters the mitochondrion and is converted to acetyl coenzyme A (acetyl CoA, is a sulphur compound derived from vitamin A) - acetyl CoA enters the Kreb cycle -  - Krebs/crtic acid cycle - Starting with acetyl CoA , the krebs cycle is a series of aproxximately 8 enzyme-catalysed reactions that take place in the mitochondrial matrix - Formation of the high energy electron carriers NADH and FADH~2~ and CO~2~ - Very little ATP is produced n this cycle -   Key concepts - In the presence of oxygen, pyruvate molecules are transported into mitochondria and converted to Acetyl CoA. - Acetyl CoA enters the citric acid cycle, producing the high-energy electron carriers NADH and FADH2, and CO2.   1. Can you: a. Explain when and why pyruvate is converted into Acetyl CoA. b. Explain the role of the Krebs Cycle.   Lecture 4 Lecture Focus: Electron Transport Chain and Chemiosmosis which together are called Oxidative Phosphorylation At the end of this lecture, you should be able to: Describe the basic steps in the electron transport chain. Explain the role and mechanism of chemiosmosis.   Reading: Fundamentals of Anatomy & Physiology, Global Edition, Chapter 25 - relevant sections.   Electron transport change (ETC) and chemiosmosis - Carbons in glucose - Gylcolysis - produced 2 x 3-carbon molecules call pyruvate (6C) - 2 x Pyruvate (2 x 3C) \--\> 2 x Acetyl CoA (2 x 2C) + 2 x CO~2~ - Citric acid cycle - produce 2 X CO~2~ per Acetyl CoA that enters the cycle - Acetyl CoA (2 x 2C) \--\> 2 x (2 x CO~2~) - Produced some water in glycolysis - Haven\'t used O~2~ - Made some ATP - Net production of 2 in glycolysis - 1 ATP per turn in Krebs cycle - Reduced NAD^+^ \-\--\> NADH + FAD \--\> FADH~2~ - ETC \-\--\> ATP    A blue curved line on a black background Description automatically generated Key concepts - The NADH and FADH2 molecules formed during aerobic respiration are high-energy electron carriers. - The NADH molecules carry these to the inner mitochondrial membrane where they transfer their electrons to a series of membrane-associated proteins - As the electrons move through the integral membrane proteins protons (H+) are pumped into the mitochondrial space creating a proton gradient - The protons (H+) diffuse through ATP synthase driving the formation of ATP from ADP and Phosphate = Chemiosmosis - Together the electron transport chain and chemiosmosis are called oxidative phosphorylation   1. Can you: a. Briefly describe how the electron transport chain is involved in producing ATP. b. Can you explain the role and mechanism of chemiosmosis?     Lecture 5 Lecture Focus: Electron Transport Chain and Oxidative Phosphorylation At the end of this lecture, you should be able to: Describe anaerobic respiration including how and why it is different from aerobic respiration Reading: Fundamentals of Anatomy & Physiology, Global Edition, Chapter 25 - relevant sections.   Anaerobic respiration - Allows for the oxidation of NADH and FADH~2~ in the absence of oxygen - Produces less energy than during aerobic respiration - Oxygen is not the terminal electron acceptor - Processes require another electron acceptor to replace oxygen - CO~2~ (e.g. Archae) - Sulphates (e.g. Prokaryotes) - Fermentation of organic molecules (e.g. Eukaryotes)   Fermentation of Organic Molecules - Anaerobic respiration -  - Anaerobic respiration is often used interchangeably with fermentation - Lactic acid fermentation - Fermentation allows the cells to oxidise NADH back to NAD+ in the absence of oxygen - NAD+ can be reused during glycolysis to generate ATP - Lactic АСЕ Fermentation \'n мизс\'е Сеиз 2 МЭР 2 АТР сн, 2 Lactate 2 Pynwate - Alcohol fermentation - Fermentation allows the cells to oxidise NADH back to NAD^+^ in the absence of oxygen - NAD^+^ can be reused during glycolysis to generate ATP -    Key concepts - In the absence of oxygen, a small amount of energy can be produced by anaerobic respiration - The conversion of pyruvate to either ethanol or lactate/lactic acid produces NAD+ which can enter glycolysis   1. Can you: a. Describe how anaerobic respiration contributes to the production of ATP.     Lecture 1 Learning objectives - Name the fundamental structures of the nephron and renal blood supply - Describe the 3 forces the govern glomerular filtration - Describe the factors that control glomerular filtration rate - Understand the principles of reabsorption and secretion - Describe the processes of sodium and water reabsorption along the different segments of the nephron - Understand the roles of the renin-angiotensin system in regulating glomerular filtration and aldosterone actions - Detail the actions of ADH and aldosterone in in controlling water and sodium reabsorption respectively to control ECF concentration and volume - Understand the principles of chemical buffer system to quickly and temporarily control pH - Explain the role of respiration in controlling pH balance - Describe the actions of the kidney in maintaining bicarbonate buffer system while excreting excess hydrogen ions during an acidosis   Structure and General Function - Organs - Kidneys - Paired organs that produce urine - Urinary tract - Eliminates urine - Ureters - Paired tubes - Urinary bladder - Muscular sac - Urethra - Exit tube - Function - **Urination or micturition** - Process of eliminating urine (metabolites and foreign chemicals) - Contraction of muscular urinary bladder forces urine through urethra and out of body - Kidney Urine production Ureter Urine transportation Bladder Urine storage Urination Urethra Elimination of urine from the body - **Filters blood** - Kidneys filter plasma removing - Toxins - Metabolic waste - Excess ions from circulating - Returns filtered nutrients and important ions back to blood - **Water and ion balance** - Regulation of blood pressure - Sodium balance - Renin-angiotensin system - **Regulation of RBC production** - Erythropoietin (EPO) - Regulation of vitamin D activity - Calcitriol prevent low calcium levels in bone - Calcitonin releases calcium from bone to raise blood calcium, calcitriol inhibits this - process    Nephrons - Functional and structural unit of the kidney - Approximately 1 million per kidney - Perform the processes to filter blood plasma and form urine - Consist of - Renal corpuscle - RENAL CORPUSCLE Glomerular capsule Capsular Glomerular Capsular Visceral space capillary epithelium epithelium (podocyte) Proximal convoluted tubule Efferent arteriole Distal convoluted tubule Macula densa Juxtaglomerular cells Juxtaglomerular complex Afferent arteriole - Site of blood filtration - Passive - Blood pressure - Forces water and small solutes across membrane into capsular space - Solutes enter capsular space - Metabolic wastes and excess ions - Glucose, free fatty acids, amino acids and vitamins - Large solutes, such as plasma proteins and blood cells are excluded -  - Glomerulus - Knot of capillaries - Glomerular capsule - Is connected to the initial segment of renal tubule - Forms outer wall of renal corpuscle - Encapsulates glomerular capillaries - Renal tubule - Three main parts - Proximal convoluted tubule (PCT) - Site of tubular reabsorptions - First segment of renal tubule - Reabsorption of water, ions and all organic nutrients - Keep the \'good stuff\' before filtrate leaves kidneys - Nephron loop (loop of Henle) - Descending limb - Fluid flows down toward renal pelvis - Ascending limb - Fluid flows up toward renal cortex - Each limb has specific functions defined by - Thick segments - Thick descending limb - Similar to function of proximal convoluted tubule - Pumps sodium and chloride ions out of tubular fluid - Thick ascending limbs - Creates high solute concentration in peritubular fluid - thin segments - Thin descending limb - Freely permeable to water, not to solutes - Water movement helps concentrate tubular fluid - Distal convoluted tubule (DCT) - Drains into collecting duct \> renal pelvic \> ureter \> bladder \> urethra \> void out of body - The third segment of the renal tubule - Active secretion of ions, acids, drugs and toxins - Selective reabsorption of sodium and calcium ions from tubular fluid - Selective reabsorption of water; concentrates tubular fluid - Bowman\'s capsule Arteriole from renal Arteriole Glomerulus \'O from glomerulus Branch of renal vein O Loop of Henle with capillary network O Proximal tubule O Distal tubule another nephron Collecting duct   Juxtaglomerular complex - Formed by - Macula densa - Collective of specialised DCT cells - Juxtaglomerular cells - Sense change in filtrate concentration and flow rate in the DCT - Secretes renin - Secrets erythropoietin   Collecting Ducts - Variable reabsorption of water - Concentrates the tubular fluid - Variable reabsorption or secretion - Sodium, potassium, hydrogen and bicarbonate ions reabsorption from tubular fluid - Delivery of urine   Renal Physiology - Basic kidney function - Concentrates filtrate by altering tubular secretion and tubular reabsorption of water and ions - Absorbs and retains valuable materials for use by other tissues - Sugars and amino acids - Basic process of urine formation - Filtration - Reabsorption - Secretion   Renal Tubule - Functions 1. Reabsorb useful organic nutrients that enter filtrate, e.g. all glucose and amino acids 2. Reabsorb more than 90% of water in filtrate 3. Secrete waste products e.g. fine tuning to rid body of any unwanted ions in blood back into tubules for final excretion in urine - While travelling along tubule, the tubular fluid (protein-free filtrate) gradually changes in composition to become urine 1. Due to valuable substance e.g. glucose being reabsorbed in various segment of the renal tubule into the peritubular capillaries that closely surround the tubule and then these substances are returned to the systemic blood supply 2. Due to other waste substances e.g. excess hydrogen ions being secreted out of the peritubular capillaries that surround the tubule back into the tubule, destined to be excreted as urine 3.    Urine Formation - Filtrate is modified as it passes through the tubule to become urine 1. Glomerular filtration - Makes a protein-free filtrate that contains water, ions, nutrients and waste products 2. Tubular reabsorption - Selective movement of valuable wanted substances from filtrate, back in to blood via peritubular capillaries - Glucose, amino acids, 99% of water, salt (NaCl) 3. Tubular secretion - Selective movement of some unwanted substrates from blood (peritubular capillaries) back into filtrate - Afferent arteriole Cortical radiate artery Three major renal processes: Urine O Glomerular filtration Tubular reabsorption Tubular secretion Glomerular capillaries Efferent arteriole Glomerular capsule Renal tubule and collecting duct containing filtrate Peritubular capillary To cortical radiate vein - Simplified version of a nephron to show how urine is formed. Amount excreted in urine= amount filtered (Step 1) + amount secreted (Step 3 ) - amount reabsorbed (Step 2) -    - (e.g. drugs) (e.g. sodium) (e.g. glucose)   -    Clinical Notes - Chronic kidney disease (CKD) - 1.7 million Australians, or 1 in 10 over 18 years of age have some sort of CKD - But only 1 in 10 of those are aware they have CKD - 1 in 3 are at risk of developing CKD - Risk factors - Diabetes - High blood pressure - Obesity - Smoking - 100 E 80 c O 90 70 60 50 40 30 20 10 Often No Symptoms STAGE 1 Below normal to mild loss of kidney function High B/R Protein in Urine STAGE 2 Mild to moderate loss of kidney function Anemia, Early Bone Disease STAGE 3 Moderate to severe loss of kidney function Stages of CKD Fatigue, Swelling, Nausea, Vomiting, etc. STAGE 4 Severe loss of kidney function STAGE 5 Kidney failure ---Dialysis   - Dialysis occurs at stage 5 of CKD   Lecture 2 Glomerular filtration - Involves passage across a filtration membrane - Membrane endothelial pores - Dense layer (basal lamina) - Filtration slits - Rate of glomerular filtration -  - Filtration generates about 180 litres of filtrate per day - 99% is reabsorbed in renal tubules - The glomerular filtration rate (GFR) is the amount of filtrate kidneys produce each minute - Average 125mL/min - Glomerular filtration rate depends on filtration pressure - Any factor that alters filtration pressure alter GFR - The three forces that determine filtration pressure - Net hydrostatic pressure (NHP) - Glomerular hydrostatic pressure (GHP) - Capsular hydrostatic pressure (CsHP) - 55 mmHg - 15 mmHg - 40 mmHg - GHP - Is blood pressure in glomerular capillaries - Tends to push water and solute molecules - Out of plasma - Into filtrate - Is significantly higher than capillary pressures in systemic circuit - Due to arrangement of vessels at glomerulus - CsHP - Opposes glomerular hydrostatic pressure - Pushes water and solutes - Out of filtrate - Into plasma - Results from resistance to flow along nephron and conduction system - Averages about 15 mmHg   - Net filtration pressure - NHP - Blood - colloid osmotic pressure (BCOP) - 40 mmHg - 30 mmHg - 10mmHg - Governed by the balance between - Hydrostatic pressure (fluid pressure) - Colloid osmotic pressure ( of materials in solution) on either side of capillary wide - BCOP - is the osmotic pressure resulting form the presence of suspended proteins in capillaries - Draws water out of filtrate back into plasma - Opposes filtration - Averages 30 mmHg   - A diagram of a gastrointestinal system Description automatically generated - Control of glomerular filtration - Three controllers of GFR - Autoregulation/intrinsic ( at the local level) - Autonomic regulation/extrinsic (by sympathetic division of ANS) - Hormonal regulation/extrinsic (initiated by kidneys) - Autoregulation of the GFR - Maintain GFR despite change in local blood pressure and blood flow - By changing diameters of afferent arterioles, efferent arterioles and glomerular capillaries - Myogenic mechanism - Stretch receptors - An increase in renal blood flow or pressure (e.g. running) - Stretch wall of afferent arterioles - Causes smooth muscles cells to contracts - Constricts afferent arterioles - Decreases glomerular blood flow -  - A decrease in blood flow \> decreased glomerular pressure (e.g. lying down) - Dilation of afferent arteriole - Dilation of glomerular capillaries - Constriction of efferent arterioles \>\> increases glomerular blood flow - Diagram of a blood pressure diagram Description automatically generated - Tubuloglomerular feedback - Paracrine signalling -  - Immediate local regulation - Acting locally at kidneys and involves the nephron, also known as intrinsic - Maintains normal homeostatic GFR despite changes in local blood hydrostatic pressure and renal blood flow - Operate to maintain GFR over systemic/mean arterial BP fluctuation ranging from 80-160mmHg; outside this range extrinsic mechanisms (acting from a distance) are activated: 1. Autonomic regulation (by sympathetic nervous system) 2. Hormonal regulation (initiated by kidney) - Extrinsic regulation - The GFR is also affected by extrinsic controls, by the endocrine (hormonal) and neural signals (sympathetic NS) from outside the kidney - These extrinsic systems respond mainly to stressful condition, and their primary purpose is to maintain BP - Autonomic regulation by sympathetic NS - Increases sympathetic activity - Vasoconstriction of afferent arterioles (e.g. hypovolemic shock; diarrhoea) - Diagram of a blood pressure diagram Description automatically generated   renin-angiotensin-system - Three interrelates stimuli cause the release of renin from the juztaglomerular complex (JGC) -  1. Decreased blood volume, decline in afferent arteriole blood pressure (detected by intra-renal baroreceptors) 2. Stimulation of granular cells by renal sympathetic nerves 3. Decreased osmotic concentration of the tubular fluid detected by the macular densa A diagram of a human body Description automatically generated   - What does renin do - Angiotensiongen \--\> renin \--\> angiotensin I (10AA) \-\--\> Angiotensin Converting Enzyme (ACE) \-\--\> Angiotensin II (8AA) - What does angiotensin (AT II) activation do - 6\. major functions - Stimulates increased glomerular filtratuon rate 1. Increases symapthetic motor tone by: - Constriction of venous reservoirs - Increased cardiac output - Stimulates peripheral vasocontriction 2. Constricts efferent arterioles of nephron - Elevates glomerular pressures and filtration rates 3. Stimulates reabsoprtion of sodium ions and water at PCT 4. Stimulates secretion of aldosterone (from adrenal cortex) - Incr5eases sodium reabsorption - In DCT - In the cortical portion of collecting ducts 5. Stimulates thrist 6. Trigger\'s release of anti-diuretic hormone (ADH) - From hypothalamus - Stimulates reabsorption of water in distal portion of DCT and collecting system -    - A diagram of a medical system Description automatically generated with medium confidence   Natriuretic peptides (ANP and BNP) - Released by the heart in response to a very large increase in blood volume or pressure - Stretching receptors in heart walls will trigger release - Atrial natriuretic peptide (ANP) is release by atria - Brain natriuretic peptide (BNP) id releases by ventricles - ANP and BNP trigger dilation of afferent arterioles and constriction of efferent arterioles - Elevates glomerular pressures and increases GFR - Increases urine production -  **Lecture 1 - control of reabsorption and secretion of solutes** Control of Reabsorption and secretion of solutes - What is the osmolarity of the extracellular fluid (ECF) - Approximately 300 mOsm/L - The concentration of a solution is the total number of solute particles/litre - ECF = all the fluid in blood vessels and fluid in tissue - Regulation of volume and concentration of ECF   Normal plasma concentration ------------- ----------------------------- sodium 135 - 145 mmol/L chloride 95 - 110 mmol/L bicarbonate 22 - 32 mmol/L potassium 3.4 - 4.5 mmol/L glucose 3 - 5.4 mmol/L calcium 2.1 - 2.6 mmol/L phosphate 0.8 - 1.5 mmol/L   Sodium and Water Reabsorption - Proximal convoluted tubules - Sodium ion reabsorption via 1. Epithelial Na channel (ENaC) - apical membrane 2. Cotransport with glucose (SGLT) - apical membrane 3. Exchange pump - Na+-K+ - basolateral membrane - Water reabsorption via 1. Osmosis (i.e. Follows the sodium) - As sodium moves, so does water, through gaps between the cell, at PCT wall - Proximal convoluted tubules (PCT) - Main site of reabsorption of nutrients and solutes (sodium) 1. Pass wall of convoluted tubule into interstitial fluid that surround tubule, then into peritubular capillaries into renal vein, into blood stream - Reabsorb 1. 65% Na+ 2. 65% H2O - Diagram of a nephron tube Description automatically generated with medium confidence - Sodium reabsorption in the proximal tubule active transport 1. Sodium passively enters/diffuse cell through cell membrane through epithelia sodium channel (EnaC) (high concentration \> low concertation), going down electrochemical gradient 2. Sodium ions actively out of the basolateral side of the cell by the ATP exchange pump (Na+-K+-ATPase pump), potassium ion moves into cell, can get back into interstitial fluid via leak channel (low concentration \> high concertation) 1. Yellow = inside proximal convoluted tubule, blue = inside cells inside proximal convoluted tubule, purple = interstitial fluid -  - Sodium-linked reabsorption indirect (secondary) active transport 1. Sodium ions moving down electrochemical gradient use the SGLT protein to pull glucose into the cell against its concentration gradient 2. Glucose diffuses out of basolateral side of cell using the GLUT protein. 100% of the glucose is reabsorbs into blood stream, no glucose in urine 3. Sodium ions is pumped out by Na+-K+-ATPase - - Nephron Loop - Sodium ion reabsorption via 1. Cotransport Na+-K+/2Cl-, only in the thick ascending limb - apical membrane 2. Exchange pump - Na+-K+ - basolateral membrane - Water reabsorption via 1. Osmosis (i.e. follows the concentration gradient, only in the thin descending limb - Reabsorb 1. 25% Na+, ascending loop 2. 15% H2O, descending loop 3.  - Thick ascending limb 1. 1200 mOsm entering ascending loop of Henle 2. Salts are reabsorbed on apical, Na+, K+ and 2 Cl-, basolateral side ATP exchange pump occurs 3. Water cannot follow solute 4. 100 mOsm leaving the loop, hypoosmotic (lots of water, not a lot of solutes) 1. Yellow = filtrate, blue = cell of ascending loop of Henle, purple = interstitial fluid 2. The thick ascending limb - Has high effective pumping mechanism - Na+ and Cl- are pumped out of the tubular fluid before it reaches Distal Convoluted Tubule - Solute concentration in tubular fluid declines - Impermeable to water 3. - Thin descending limb 1. 300 mOsm to 1200 mOsm 2. Is permeable to water, but impermeable to solutes 3. As tubular fluid flows along the thin descending limb - Osmosis moves water into peritubular fluid, leaving solutes behind - Osmotic concentration of tubular fluid increases - Distal Convoluted Tubules and Collecting Ducts - Small amount of filtrate, around 100mOsm - Sodium ion reabsorption via 1. Na channel - luminal membrane 2. Exchange pump - Na+-K+ - basolateral membrane - Water reabsorption via 1. Water channels/aquaporins, stimulated by antidiuretic hormone (ADH) - Reabsorb 1. 9% Na+, reabsorbed at DCT 2. 19% H2O, reabsorbed at collecting duct 3. The main sites where hormonal control of reabsorption occurs 4.  - Distal Convoluted Tubules and Collecting Ducts 1. 1. Aldosterone combines with a cytoplasmic receptor, moves from blood through interstitial fluid to cell 2. Hormone receptor complex initiates transcription in the nucleus 3. Translation and protein synthesis makes new proteins channels and pumps 4. Aldosterone-induced proteins modulate existing channels on lumen side of DCT and pumps on basolateral side, ATP exchange pump 5. Result is increased Na+ reabsorption into cell and K+ (and Na+ secretion) into blood 1. Yellow= lumen of DCT, blue=cells/wall of DCT , purple= interstitial fluid, red= blood 2. Aldosterone regulates sodium in DCT, released from adrenal cortex - Reabsorption of Water 1. Water reabsorption in medulla region via water channel/aquaporins 2. Shared nephron, feed by many other nearby nephrons 3.  4. Yellow = collecting duct, adjacent yellow section = DCT, red = peritubular capillaries, purple = interstitial fluid 5. With ADH - Water moves freely out of collecting duct through aquaporin formed by Adh into blood capillaries by osmosis/osmotic gradient - 100mOsm \--\> 1200 mOsm 6. Without ADH - Water moves down the collecting duct, but there is no aquaporins formed by ADH and despite the concentration gradient trying to pulling water into capillaries, it is impermeable. No water is reabsorbed - Large quantity of water, diluted to 100mOsm 7. ADH levels fluctuate due to water concentration needs   Renal Threshold - Renal threshold is the concentration of a substance dissolved in the blood above which the kidneys begin to excrete it into the urine - Example glucose: the PCT can only reabsorb a limited amount of glucose, about 180mg/dL - When it exceeds this amount, then glucose remains in filtrate and is ultimately excreted in urine = glycosuria - E.g. in poorly managed type 1 diabetes BGL can reach 500mg/dL - Diabetes causes glycosuria because there either isn\'t enough insulin or your body cant use what\'s available - Without insulin, blood glucose levels become too high and your kidneys cant reabsorb all the filtered glucose at the PCT. The renal threshold for glucose has been reached. You body gets ride of the excess glucose that cannot be reabsorbed at eth PCT through your urine - The threshold beyond which glucose cannot be absorbed is called the glucose renal threshold - The threshold rate of reabsorption is called it \"tubular maximum\" or Tm or Tmax -   Poorly Managed Diabetes - Having high blood glucose levels can interfere with the function of the glomerulus. This filtering function of the kidneys doesn\'t work properly, and proteins start to leak form the blood into the urine = proteinuria - High blood glucose levels can also cause scarring of the glomerulus (glomerulosclerosis). As the scarring gets worse, the kidneys stop being able to filter waste products from the blood - When enough glomeruli have been damaged, kidney failure results (CKD) - People who have diabetic nephropathy also often have high blood pressure. High blood pressure can further contribute to kidney damage   Countercurrent Multiplication - Countercurrent - Refers to exchange between tubular fluid moving in opposite directions (vasa recta) 1. Fluid in descending limb flows towards renal pelvis 2. Fluid in ascending limb flows towards renal cortex - Multiplication - Refers to effect of exchange 1. Ascending limb solute exchange effect the descending limb water exchange 2. Positive feedback loop - Yellow= descending and ascending limb, red = blood capillaries, purple = interstitial fluid - Blue circles = movement of water, orange circle = movement of sodium -    - - More solutes is continually added by the PCT - The higher the osmolarity is the ECF, the more water leaves the descending limb by osmosis - The more water that leaves the descending limb, the saltier the fluid is that remain in the tubule - The saltier the fluid in the ascending limb, the more salt the tubule pumps into the ECF - The more salt that is pumped out of the ascending limb, the saltier the ECF is in the renal medulla - Benefits of countercurrent multiplication - Effectively reabsorbs solutes and water 1. Before tubular fluid reaches DCT and collecting system - Establishes concentration gradient 1. That permits passive reabsorption oF water form tubular fluid in collecting duct - Regulated by circulating levels of antidiuretic hormone (ADH)   Key Concepts - Name the fundamental structures of the nephron and renal blood supply - Describe the 3 forces that govern glomerular filtration - Describe the factors that control glomerular filtration rate - Understand the principles of reabsorption and secretion - Describe the processes of sodium and water reabsorption along the different segments of the nephron - Understand the roles of the renin-angiotensin system in regulating glomerular filtration and aldosterone actions - Detail the actions of ADH and aldosterone in controlling water and sodium reabsorption respectively, to control ECF concentration and volume - Understand the principles of chemical buffer system to quickly and temporarily control pH - Explain the role of respiration in controlling pH balance - Describe the actions of the kidney in maintaining bicarbonate buffer system while excreting excess hydrogen ions during an acidosis   **Lecture 2 -Fluid Balance** - Regulation of Volume and Concentration of Extracellular Fluid - What is more important to the body: controlling the EC volume or concentration -  - A black background with a black square Description automatically generated with medium confidence - Two different hormones controlling 1. Water reabsorption - Anti-diuretic hormone (ADH) - Controls fluid concentration - Important in preventing changes in cell volume - Released in response to an increase in plasma osmolarity/ECF concentration - Stimulates incorporation of water channels/aquaporins, in DCT and mainly collecting ducts - Allows for water to be reabsorbed along the collecting ducts concentration gradient - Fastest way to restore balance to ECF concentration/osmolarity 2. Sodium reabsorption - Aldosterone - Control fluid volume - in mainly DCT and collecting ducts - Important in regulation of BP - A decreased in plasma volume triggers aldosterone release 3. Inter-related process controlling blood volume and concentration   - Anti-diuretic Hormone - Where does ADH come from 1. ADH is made and packaged in cell body of a neuron 2. Vesicles are transported down the cell 3. Vesicles containing ADH are stored in posterior pituitary 4. ADH is released into blood, can be released quickly be stimuli, especially due to ECF concentration 1.  - What cause ADH release 1. If we get an increase in ECF concentration, that increases osmolarity fluid in hypothalamus, triggering osmo-receptors 2. AP is generated in hypothalamus and moves down neuron to posterior pituitary gland 3. Results in ADH release form vesicles into blood stream 4. - ADH promotes water reabsorption in the DCT and Collecting Duct 1. Aquaporin, cells become more permeable to watre 2.  1. ADH from blood stream bonds to membrane receptor on basolateral side of collecting duct wall 2. Receptor activates cAMP second messenger system, causes exocytosis of vesicles inside cell that contain aquaporins, causing them to move to apical surface 3. Cell insert Aquaporins-2 water pores into apical membrane 4. Water is absorbed by osmosis form filtrate into the blood 1. Red = blood capillary, purple = interstitial fluid, blue= wall of collecting duct, yellow = filtrate of collecting duct 2.   - Aldosterone - Regulation of ECF Volume 1. renin-angiotensin-system - Extrinsic regulation of Glomerular Filtration Rate, when blood pressure an volume falls - Renin is produced by granular cells associated with the afferent arterial on the nephron, when released it catalyses the reaction below to form angiotensin II, causes aldosterone release -  - Aldosterone is produced in adrenal glands, more specially adrenal cortex (on top of kidneys) - - How does aldosterone work 1. Takes hour/days to occur, for aldosterone to form pump/channel takes between 12-24 hours 1. Aldosterone combines with a cytoplasmic receptor 2. Hormone-receptor complex initiate transcription in the nucleus 3. Translation and protein synthesis make new NA+ channels and ATP exchange pumps 4. Aldosterone-induced protein modulate existing channels on basolateral side and pumps on apical side 5. Result is increase Na+ reabsorption and K+ secretion, water follows 1. Red = blood capillary, purple = interstitial fluid, blue= wall of DCT, yellow = filtrate of DCT 2.  3. Regulation of ECF volume - Aldosterone stimulate synthesis and incorporation of Na+-K+ pumps/ATP exchange pump - In DCT and cortical region of collecting duct - Increases sodium reabsorption - Increase sodium retention, resulting in greater water retention. 1. ECF concentration/osmolarity is rapidly adjusted by ADH 2. ECF volume is slowly adjusted by aldosterone   - Natriuretic Peptides - A third emergency controller of ECF volume - Released by the heart in response to very large increase in blood volume or pressure - Stretching receptor in heart wall trigger release: 1. Atrial natriuretic peptide (ANP) is released by atria 2. Brain natriuretic peptide (BNP) is released by ventricles - Recall glomerular filtration 1. Natriuretic peptides - ANP and BNP trigger dilation of afferent (to) arterioles and constriction of efferent (away) arterioles - Elevates glomerular pressure \> increasing GFR \> increasing urine output \> decreasing fluid in blood \> decreasing blood volume \> decreased blood pressure - Block the reabsorption actions of ADH and aldosterone -    - Summary - Regulation of fluid homeostasis 1. Water reabsorption: anti-diuretic hormone (ADH) - Controls fluid concentration - Important in preventing changes in cell volume - Triggered by increases in ECF/plasma osmolarity, increased NaCl 2. Sodium reabsorption: aldosterone - Controls fluid volume - Important in regulation of blood pressure - Triggered by increases in blood ECF/plasma volume - Effects of ADH on the DCT and Collecting Duct 1.   - Water pills/Diuretics - Substance that slow renal reabsorption of water and causes diuresis (increased urine flow water - Diuretics are common treatment for high blood pressure (hypertension), oedema and heart failure - Examples 1. Prescription medication can act on the PCT, loop of Henle or DCT e.g. a loop diuretic is Furosemide (Lasix) 2. Caffeine which inhibits Na+ reabsorption 3. Alcohol which inhibits secretion of ADH   Key Concepts Can you: - Name the fundamental structures of the nephron and renal blood supply - Describe the 3 forces that govern glomerular filtration - Describe the factors that control glomerular filtration rate - Understand the principles of reabsorption and secretion - Describe the processes of sodium and water reabsorption along the different segments of the nephron - Understand the roles of the renin-angiotensin system in regulating glomerular filtration and aldosterone actions - Detail the actions of ADH and Aldosterone in controlling water and sodium reabsorption respectively, to control ECF concentration and ECF volume. - Understand the principles of chemical buffer system to quickly and temporarily control pH - Explain the role of respiration in controlling pH balance - Describe the actions of the kidney in maintaining bicarbonate buffer system while excreting excess hydrogen ions during an acidosis   **Lecture 3 - Acid Base Balance** - Acid-Base Balance - pH ECF is narrowly controlled, 7.35-7.45 range 1. Acidosis: pH \< 7.35, the lower the pH then the higher concentration of H+ ions 2. Alkalosis : pH \> 7.45, the higher the pH then the lower the concentration of H+ ions - Bothe conditions are life threatening and need to be corrected immediately - pH is maintained by the gain or loss of hydrogen (H+) ions - Homeostasis - The maintenance of physiological pH of body fluid is important because: 1. Protein structure and function are pH sensitive 2. Nerve and muscle excitability are pH sensitive 3. pH affect membrane structure 4. pH determines enzyme activity - Average person - Gains 40 mmol H+ per day - Excretes 40 mmol H+ per day - Fluctuate due to 1. Diet - e.g. Meat eater, increased H+ - pH balance - There are 2 steps in handling H+ that are added to the ECF to minimise the impact on pH by 1. Chemical buffers - In blood plasma, act as a sponge to remove or add H+ 2. Respiration - Chemical buffer systems include: 1. Proteins, e.g. albumin 2. Carbonic acid-bicarbonate 3. Haemoglobin 4. Phosphate - important in urine buffering 5. Ammonia - important in urine buffering - Bind to free H+ in blood - Act quickly to buffer pH changes - Short term measure - Do have limits to their buffering capacity   Carbonic Acid-Bicarbonate Buffer System - Works in blood - Yellow = blood/ECF - Always H+, carbonic acid (H2CO3) and bicarbonate ion (HCO3-) in blood/ECF - Increase in H+ - HCO3- binds to H+ to form H2CO3 - H2CO3 immediately breaks into water and CO2 - Moves to lungs and exhale CO2 - Bicarbonate reserve -    Respiration - Respiration compensation for H+ imbalance - What is normal arterial PCO2 (partial pressure) 1. 40mmHg - How you maintain PCO2 at this level 1. Through respiration controlled by the central chemoreceptors 2. Increase in CO2, alerts central chemoreceptors, tell lungs to breath off CO2 - Respiration compensation for an acidosis - Increase in H+ Step 1. increase in H+ starts chemical buffering, excess H+ ions bind to HCO3- in blood stream Step 2. pushes reaction to left, creating more H2O and CO2, decreasing H+ and HCO3- Step 3. more CO2 stimulate central chemoreceptor to increase RR/exhalation, decreasing CO2, returning PCO2 to normal, pushes reaction to the left even more Step 4. H+ closer to normal - pH closer to normal than a \'standard\' chemical buffer system - But HCO3- lower than normal - Eventually HCO3- must be replaced - Reabsorb all remaining HCO3- in our kidneys - Generate new HCO3- in our kidneys - - All HCO3- is freely filtrated at glomerus, end up at PCT -    - A diagram of a chemical reaction Description automatically generated - All HCO3- is freely filtrated at glomerulus, end up at PCT - H+ in blood is actively secreted to PCT - H+ combines with HCO3- to form H2CO3 - H2CO3 quickly dissociates to H2O and CO2 - CO2 diffuses across PCT walls/cells - Combines with water to reform H2CO3 with the help from enzyme carbonic anhydrase - H2CO3 quickly dissociates to H2O and CO2 - HCO3- back in cell and diffuse back into blood, H+ move back into filtrate Renal - Renal compensation for acidosis - Plasma pH is low (H+ is high) - Kidney secretes a lot of H+ - All HCO3- reabsorbed - Excess H+ is excreted, adding HCO3- back to plasma -    - - H+ move into cell/PCT wall - Secret at apical side of PCT into filtrate, excretion in urine - As you secret the H+, you replace HCO3- that it had combined with in the blood - Renal compensation for alkalosis - Plasma pH is high (H+ is low) - Kidney secretes less H+ - Some filtered HCO3- is not reabsorbed - Plasma HCO3- is reduced, reaction moves towards the H+ + HCO3- side, generating H+ -  1. Reduce H+ secreted, no H+ to bind to HCO3- 2. HCO3- excreted in urine   Acid-base disorders - pH of EFC is usually within a tight range of 7.35 to 7.45 - Respiratory acid-base disorders - Imbalance between CO2 generation in peripheral tissues and CO2 exertion at lungs - Causes abnormal CO2 levels in ECF 1. Respiratory acidosis (e.g. emphysema 2. Respiratory alkalosis (e.g. sustained hyperventilation) - Metabolic acid-base disorders - Production of organic or fixed acids - Condition affecting H+ or HCO3- concentrations in ECF 1. Metabolic acidosis (e.g. ketoacidosis frmo uncontrolled diabetes) 2. Metabolic alkalosis (e.g. vomiting) -   Key concepts Can you: - Name the fundamental structures of the nephron and renal blood supply - Describe the 3 forces that govern glomerular filtration - Describe the factors that control glomerular filtration rate - Understand the principles of reabsorption and secretion - Describe the processes of sodium and water reabsorption along the different segments of the nephron - Understand the roles of the renin-angiotensin system in regulating glomerular filtration and aldosterone actions - Detail the actions of ADH and aldosterone in controlling water and sodium reabsorption respectively, to control ECF concentration and volume - Understand the principles of the chemical buffer system to quickly and temporarily control pH - Explain the role of respiration in controlling pH balance - Describe the actions of the kidney in maintaining the bicarbonate buffer system, while excreting excess hydrogen ions during an acidosis   Lecture 1 Objectives - Describe the components of the male reproductive systems and their functions. - Describe all aspects of the male reproductive cycle. - Spermatogenesis - Understanding the hormonal regulation of male reproductive function.   Introduction to Reproduction - Purpose - To ensure the survival of the human species - Humans reproduce sexually: - Combination of haploid gametes (half the normal content/chromosomes \[23\] sex cell, as known as goands) to form diploid (contain 46 chromosomes) offspring - Combining genetic material from both parents - Distinct between male and female - Includes: - Gonads - that produce the gametes - Ducts that receive an transport gametes - Accessory glands and organs that secrete fluid involved - Perineal structures - external genitalia - Males \--\> testes produce spermatozoa (sperm) -  - Females \--\> ovaries that produce oocyte (become ovum) - Uterus Ovary Uterine tu   -    Meiosis - Mitosis - Process of standard cell division in crating two identical daughter cells, with each cell containing an exact replica of 23 chromosome pairs/46 chromosomes - Genetic material is duplicated and spilt evenly - Production of haploid cell from diploid cells - Undergo round of specialised cell division to create haploid -   - Two stages - Meiosis 1 - Division of gametes into haploid cells - Genetic material is duplicated, chromosome form a product called tetrad (all 4 copies of chromosome pair joint together), divide into 2 daughter cells - Meiosis 2 - Cell division of meiosis 2 occurs producing 4 haploid gamete containing 23 chromosomes - Haploid human cells (sperm and ova) contain 23 chromosomes - Total = 23 - Diploid human cells contain 23 pairs of chromosomes - Total = 46 - Chromosome number in cells - In males - Produce 4 immature gametes - Goes through maturation to produce spermatozoa - In females - Produces 1 large ova and 3 polar bodies   - Mitosis Meiosis ova sperm diploid diploid 23+23 (46) diploid 23+23 (46) diploid haploid ---\...\...\...\....\> 23 23 23 polar bodies 23 23 23 23 haploid 23 - Haploid gametes combine to form new humans -    Key concepts - Male gonads = testes = sperm. - Female gonads = ovaries = egg (ova). - Meiosis is the production of haploid (sex) cells. - Haploid cells = 23 chromosomes. - Sperm and eggs join (fertilization) = 46 Chromosomes.   The Male Reproduction System - Purpose - To produce haploid spermatozoa - Deliver spermatozoa into the uterus and fallopian tubes - Sex cell/gametes - Sperm, produced from testes - Sperm delivered to external body - Epididymis - The ductus deferens - Ejaculatory duct - Urethra - Organs/glands - Testes - Endocrine function - Produce hormone/antigens - Produce spermatozoa - Epididymis - Maturation of spermatozoa (18hrs - 10 days) - Stores spermatozoa - Ductus deferens (VAS Deferens/spermatic cord) - Stores spermatozoa - Conduit for spermatozoa delivery - Moves into seminal gland/ejaculatory duct - Ejaculatory duct - Mixes of fluid to produce semen - Empties into urethra - Urethra - Passageway from urine from bladder - Spermatozoa/semen from ejaculatory duct - Membranous urethra Spongy urethra Ductus deferens Epididymis Testis - Accessory glands - Seminal gland/vesicle - Secrets largest quantity fluid for semen production - Duct drains into the ductus deferens - Prostate gland - Produces prostatic fluid - Mix with seminal fluid in the urethra - Smal muscular organ - Bulbourethral gland - Mucous secreting glands located at base of penis - External genitalia - Penis - release of urine and semen - Erect \--\> blood flow to penis - Scrotum - Sac containing testes (two sections) - Made of muscle and connective tissue - Allows temperature regulation below normal body temperatures for normal development of spermatozoa - Two chambers - Houses testes - Lobules - Containing coiled seminiferous tubules, where sperm production takes place - Sperm empties into mediastinum into tubules of rete testis - Through efferent ductulus, into epididymis -  - Histology - Spermatic Cord Ductus deferens Efferent ductules Rete testis Seminiferous tubules Testis Mediastinum of testis Scrotum Epididymis Head Body Tail Interstitial cells of Leydig surround the tubules Efferent ductules Rete testi o Testis Seminiferous tubules   Key concepts - Male Reproductive Anatomy: - Testes = spermatozoa (sperm) production. - Made of lobules (coiled seminiferous tubules) that produce sperm. - Mediastinum of testis, empty into epipdidymis. - Interstitial cells (Leydig) produce hormones. - Epididymis = spermatozoa maturation. - Ductus Deferens = spermatozoa storage. - Urethra = ejection of sperm/semen. - Glands (seminal, prostate, bulbourethral) = semen production. - External genitalia = scrotum (temperature control for sperm production) & penis. - Testes Histology - Lobules: - Seminiferous tubules (tightly coiled). - Sperm production takes place here. - Empty into mediastinum - Interconnected passageways called rete testis. - Empty into the efferent ductules that connect to the epididymis. - Interstitial cells (Leydig cells) - Present in space around seminiferous tubules. - Produce male sex hormones (Androgens). - Spermatogenesis occurs in the seminiferous tubules with support from the nurse cells.   Spermatogenesis, spermiogenesis and semen production - Spermatogenesis - Production of spermatozoa begins in outermost later of seminiferous tubule wall - Proceeds towards lumen \--\> each production step sperm cells get closer towards the lumen -  - Spermatozoa - Begins as stem cell (spermatogonium) - Divide by mitosis to produce daughter cells. - One stays as a stem cell and the other differentiates into primary spermatocyte - Supported by interstitial endocrine cells and nurse cells - Spermatocytes undergo meiosis to form spermatocyte - Primary spermatocytes divide into secondary spermatocytes - Secondary spermatocytes divide and differentiate into spermatids (immature gamete) - LUMEN Nurse cells cytoplasm Blood testis barrier Nurse cell nuclei Interstitial cells of Leydig Spermatids Secondary spermatocyte Primary Spermatocyte Spermatogonium  - Spermiogenesis - Maturation of spermatid into sperm - Acrosome - Helps get through the layers protecting the ovum - Flagellum - Moves in a corkscrew motion - Nucleus Sperm Acrosomal vesicle Tail (flagellum) --- approx. 55 gm 55 Nucleus Acrosome   Movement of Sperm - Epididymis - Spermatozoa travel into epididymis after release into seminiferous tubules - 3 main functions - Maturation and storage of spermatozoa - Monitors and adjust fluid composition - Acts as a recycling centre - Ductus deferens - Spermatozoa from epididymis to ductus deferens - Storage of inactive spermatozoa - Accessory glands aid with creation of semen when spermatozoa are moved into ejaculation duct (this empties into urethra) - Urethra - Used for urine coming from the bladder as well as semen from reproductive system   Accessory Glands - Seminal glands - 60% of the volume of semen - Alkaline - neutralise prostate and vaginal acids - Contains - Prostaglandins - Smooth muscle contractions to move semen - Fructose - Energy for sperm - Fibrinogen - Help form semen clot - Prostate gland - 20-30% of the volume of semen - Muscular gland - Secretes acidic, prostatic fluid, containing seminal plasmin - Contributes to sperm motility and viability - Seminal plasma - Antibiotic protein, kills bacteria - Bulbourethral gland - Secretes thick, alkaline mucous - Helps neutralise urinary acids and lubricates the penis -    Semen - contents - Thick whitish fluid contain: - Sperm - Seminal fluid (from all of the accessory glands) - Enzymes (protease - dissolve mucous in vagina, seminal plasmin, fibrinogen, fibrinolysin - breaks down clot) - 2-5mL/ejaculation - 20-100 million sperm/mL of semen - Factors influence sperm formation - Varicoceles - Increased testicular temperature - Smoking - Stress - Alcohol Some conflicting evidence regarding safe limits) - Increased BMI and poor diet - Infrequent ejaculation - Aging - Infection of male reproductive organs - Cancer - Pollution, toxins and radiation - High intake of caffeine - Recreational drugs and medication - Increased BMI & Poor Diet Alco hop Smoking Increased Testicular Temperatu re Va ricoceles Some conflicting evidence regarding safe limits Infrequent Ejaculation Aging Sperm DNA SPERM DNA DAMAGE Infection Of Male Reproductive Organs Cancer Pollution , High Intake Of Caffeine Recreational Drugs & Medications   Key concepts - Spermatogenesis (in testes): - Spermatozoa (sperm) production and maturation. - Begins in outer most layer of seminiferous tubules each step moves towards lumen. - Mitosis -- of the stem cell (spermatogonium). - Meiosis -- creation of spermatids (haploid cells). - Spermiogenesis -- maturation from spermatid to sperm (with acrosome and flagella. - Movement of sperm: - Seminiferous tubules → Epididymis → Ductus Deferens → Ejaculatory duct → Urethra → External Body. - Semen production: - Seminal, prostate and bulbourethral glands form semen with sperm from ejaculatory duct.   Key Cell and Endocrine Functions - Nurse Cells and interstitial Cells of Leydig -  - Nurse cells - Maintenance of blood-testis barrier - Outer compartment spermatogonia - Inner luminal compartment - meiosis and spermiogenesis - Support mitosis and meiosis - FSH and testosterone - Promotes division of spermatogonia and spermatocyte - Support spermiogenesis - Surround/enfold spermatid - Provides nutrient and stimulate development - Secretion of inhibin - Negative feedback control \--\> depress FSH - Secretes androgen-biding protein - binds androgen to testosterone - Elevate concentration of hormone in the tubules - Secretes mullerian-inhibiting factor - Important for descent of testes during development - o Maintenance of blood-testis barrier: Outer compartment --- Spermatogonia Inner luminal compartment --- Meiosis & Spermiogenesis Supports mitosis & meiosis: FSH & Testosterone Promotes division of spermatogonia & spermatocytes Supports spermiogenesis: Surround/enfolds spermatids Provides nutrients & stimulates development Secretion of Inhibin: Negative feedback control depresses FSH Secretes Androgen-Binding Protein: Binds androgens --- Testosterone Elevates concentration of hormones in the tubules Secretes Mullerian-lnhibiting Factor: Important for descent of testes during development - Interstitial Cells of Leydig and Testosterone - Are in between seminiferous tubules - Secretes androgens - Most important in males - testosterone - Function of testosterone - Synthesised from cholesterol in Leydig cells - Released in response to LH from pituitary - Controls development, growth and maintenance of male sex organs - Development and maintenance of male secondary sex characteristics - Stimulates bone and muscle growth - Sexual behaviour (libido) - Final maturation of sperm - Stimulate descent of testes   Regulation of male reproduction - GnRH/ gonadotropin releasing hormone - Hypothalamus secretes GnRH, acts upon anterior pituitary gland releasing LH and FSH - Secretion of FSH - FSH targets nurse cells of the seminiferous tubules - stimulation of nurse cell: - facilitates of spermatogenesis and spermiogenesis - release of androgen-binding protein - Bind to androgen in seminiferous tubules - Increase local concentration of androgens - Stimulates physical maturation of spermatids - secrete inhibin in response to factors released by developing sperm (negative feedback) - Depressed the pituitary production of FSH and GnRH - Faster rate of sperm more inhibin secreted - By regulating FSH and GnRH secretion nurse cell provide feedback control of spermatogenesis - Secretion of LH - Target interstitial endocrine cell of testes - Induces the secretion of testosterone and other androgens - Nurse cell stimulation - Peripheral effects of testosterone - Maintains libido (sexual drive) and related behaviours - Stimulates bone and muscle growth - Establishes and maintains male secondary sex characteristic - Maintain accessory gland and organs of the male reproductive system - Inhibin release of GnRH - High testosterone level inhibit release of GnRH by hypothalamus - Decreases LH secretion, lowering testosterone   - ![Male reproductive function is regulated by the complex interaction of hormones from the hypothalamus, anterior lobe of the pituitary gland, and the testes. Negative feedback systems keep testosterone levels within a relatively narrow range until late in life. HYPOTHALAMUS Release of Gonadotropin. Releasing Hormone (GnRH) The the hormone GnRH at a rate that remains relatively steady. As a result, blood levels Of FSH, LH, and testosterone remain Within a relatively narrow through out a man\'s life. Whm stimulated by GnRH, the anterior ot the g\*tuttary gland releases luteinizlng hormone (LH) and follicle-stimulating hormone (FSH). Negative feedback High testosterorp levels inhibit the release of GnRH by the hypothalamus, causing a decrease in LH Which lowers to normal Inhibin &presses the pituitary production ot FSH, and perhaps the hypothalamic secretion ot gonadotropin-releaslng hormone (GnRH). The taster the ot production, more inhibin is secreted. By regulating FSH and GnRH secretion, nurse cells provide control ot Secretion of Follicle. Stimulating Hormone (FSH) FSH targets primarily the nurse cells ot the wminlterous tubules. ANTERIOR LOBE OF THE PITUITARY Secretion of Luteinizing Hormone (LH) LH targets the interstitial endærlne cells ot the testes. GLAND TESTES 2 z Inhibin Nurse Cell Stimulation Under FSH sumulatlon, and With testosterone from the Interstitial endocrine cells, nurse (l) secrete Inhibln In response to factors by developing sperm, (2) secrete androgen blndlng protein (ABP), and (3) and Interstitial Endocrüte Cell Stimulation LH In duces the ot testosterorp and other by the Interstldal cells ot me t.te. KEY Andro\*n-blndlng protein (ABP) binck androgens within the tubules, which increases the concentrauon ot andro\*ns and stimulatæ the physical of Nurse cell environment facilitates both and Peripheral Effects of Testosterone Maintains liNdo (sexual drive) and related tEhaviors Stimulates bone and muscle grow