Week 13: Blood and Immunity Notes PDF

**Week 13: Blood and Immunity** Class 11/18/24 - Slide 1 - Neutrophils are main phagocytes, basophils in allergic reactions, eosinophils - Difference between neutrophils and macrophages (larger, differences in roles) - Know each cell type and their physiolog...

**Week 13: Blood and Immunity** Class 11/18/24 - Slide 1 - Neutrophils are main phagocytes, basophils in allergic reactions, eosinophils - Difference between neutrophils and macrophages (larger, differences in roles) - Know each cell type and their physiological function - Slide 2 - If innate immune response second line of defense is not working, it will stimulate the adaptive immune response - Slide 3 - Microbe with antigens are called pathogen associated molecular patterns (PAMP) and the cell (macrophage) has a pattern recognition receptor (PRR), when they meet = phagocytosis and antimicrobial things inside cell break down microbe - There is also a MHC-II on cell surface and microbe remnant is brought to it so that it can get cycled into lymph nodes and then show the T-helper cell what the microbe looks like so it can make cells that can kill it. - Dendritic cells are the phagocytic cell here, so dendritic are the bridge between innate and adaptive immunity - The 3 APCs are dendritic (primary), also macrophages/B lymphocytes only have MHC-II - Every other nucleated cell has MHC-I - Know what the complement system does - Know the common pathway, extrinsic/intrinsic too (but mostly common) 11/20/2024 - Neutrophil first on scene of infection, then monocytes (macrophages), (resident macrophages are first on scene to invading bacteria/pathogen) - Mast cells release final mediator once antibody docks there Lectures - 13.1: Blood Cell Types - Composition of whole blood - Blood cell types - Blood cells come from the bone marrow - Three main types of WBC - Granulocytes (neutrophils, basophils, eosinophils) - Monocytes - Lymphocytes (B/T) - NK - White Blood Cells - 13.2: Red Blood Cells - Erythrocytes (RBCs) - No organelles, destroyed by macrophages in liver/spleen after 120d - Erythrocyte functions - Hold onto hemoglobin and the enzyme carbonic anhydrase - Shape and size of RBCs - Biconcave disk that can alter shape to squeeze through capillary (old RBCs rupture when squeezing through spleen red pulp) - No spleen = more old RBCs in circulation - RBCs - At 100% saturation men hold 20mlO2, women 19ml - Relative rates of RBC production in the Bone Marrow - Tibia and femur fall off first, then ribs, then sternum, then vertebrae - A multipotent stem cell gives rise to all classes of blood cells - All blood cells come from a multipotent stem cell - All blood cells develop in bone marrow except for T lymphocyte and macrophages - Regulation of hemopoiesis -- role of CSFs - CSF: glycoproteins in blood acting as hormones or directly on bone marrow - Erythropoietin is a CSF - EPO Regulates RBC Production - Kidneys produce EPO, losing them makes you anemic - Extramedullary hemopoiesis: liver and kidney - Low o2 can also promote angiogenesis - High O2 = low IF, low O2 -- high IF, high IF promotes angiogenesis (growth of new vascular tissues) - 13.3: Pathological Considerations - Nutritional requirements for erythropoiesis - Vitamin B12/Folic Acid -- essential for RBCs maturing, DNA synthesis - If they can't proliferate they are bigger and have a shorter lifespan - Pernicious anemia - IF released by parietal cells of the gastric glands, binds B12 to rescue it from digestion, B12 lack causes macrocytic normochromic anemia (big cell, normal coloring) - Macrocytic anemia - The iron cycle - Most of iron is in RBCs/muscle cells or in macrophages, iron is mostly recycled in RBC - Bilirubin causes jaundice - Microcytic-hypochromic anemia - Small RBC with less Hb, related to bad iron metabolism/globin synthesis - Iron deficiency anemia: shows when Hgb falls to 7-8gm/dl, caused by nutrition, blood loss, metabolic/functional problems - Normocytic-normochromic anemias - Everything is normal except low amount of rbcs - Caused by wacky bone marrow, blood loss, immune destroys rbcs, chronic inflammation - Effects of anemia on the circulatory system - Raises cardiac output and leads to risk of HF (makes heart work harder to get avoid hypoxia of itself and other tissues) - Increased CO balances with low O2 but low viscosity and compensatory mechanisms causes turbulent blood flow and hypoxia happens with exercise, can lead to HF - Myeloproliferative RBC disorders - Polycythemia: more rbcs than normal - Relative polycythemia: dehydration causes more rbcs/hgb concentration - Absolute polycythemia: Primary absolute means there is a bone marrow stem cell Jak2 mutation (PV), secondary means more EPO due to chronic hypoxia or tumors - Polycythemia vera: blood cells proliferate quickly and manifests in higher blood viscosity and hypercoagulopathy - Effect of polycythemia on the circulatory system - The increase in viscosity lowers venous return but the increase in bood cells/volume increases VR, balancing each other to a certain point until hypertension will develop - Usually not as pronounced as anemia symptoms - 13.4: hemostasis - Hemostasis - The prevention/arrest of blood loss, called thrombosis if blood is clotting with vessel still intact - Includes vascular constriction, primary hemostasis (platelet plug), secondary (blood coagulation), fibrous organization of the clot (clot resorption) - Vascular constriction - Myogenic spasm, local autacoid factors (things released), nerve reflex, platelets release thromboxane A2 (TXA2) (a potent vasoconstrictor) in small vessels mostly - Formation of the platelet plug - Platelets made in bone marrow by megakaryocytes and half-life is 8-12 days - Platelets - Can contract, make things from their ER/golgi apparatus, make ATP, glycoproteins top them from sticking to healthy blood vessel wall, phospholipids in membrane activate clotting - Formation of the Platelet Plug - Von Willebrand factor: has to do with platelets sticking onto damaged vascular wall - Change shape once adhered into more SA spiky sea urchins: makes them coagulate better (fibrinogen/Ca affinity) - Granule release: ADP released by platelet granules, makes more granules release, TXA2 releases (vasoconstrictor) - Recruitment and aggregation: platelets change shape to let fibrinogen bind and thrombin helps cement it - Secondary Hemostasis (Blood Clot Formation) - Starts in 15-20s, clot formed in 2-6min, clot tightens in 20-60min, heals in 1-2 weeks - Tissue factor: initiates coagulation at injury, thrombin: turns fibrinogen into fibrin - The coagulation cascade - Blood Clotting Mechanism -- The Common Pathway - Extrinsic and intrinsic pathway meet at the common pathway to activate prothrombin into thrombin - Prothrombin and Thrombin - Prothrombin activator: rate-limiting factor of blood coagulation, liver creates with vitamin K - Coumadin: inhibits prothrombin activation through vitamin K - Formation of prothrombin activator - Intrinsic pathway: factor XII hits -ve surface (platelets -- or sub endothelium/collagen) - Extrinsic pathway: tissue factor released by damaged cells (much faster than int) - Synergy between intrinsic and extrinsic pathways - Tissue injury activates both int/ext, ext is more explosive than int - Fibrinogen - Large, made in liver, if leaks out of capillary will cause clotting in ISF - Conversion of fibrinogen to fibrin - Thrombin makes fibrinogen into fibrin and activates fibrin stabilizing factor (XIII, 13) that cements the fibrin/platelet plug - The role of thrombin - Thrombin causes inflammation, anti-coagulation effects? (helps balance its own effects on the body) - Factors that limit coagulation and initiate clot retraction - More fibrin added and platelets contract to retract clot, blood flow washes out activated coagulation factors, then fibrinolytic cascade takes over (is activated by the coagulation cascade) - The fibrinolytic system - Plasminogen: injured tissues release tPA making plasminogen plasmin - Plasmin: digest fibrin and more, cleans up clot after healing - Blood vessel damage, clot formation, and clot dissolution - The role of the endothelium - Getting anti/pro coagulant signals always - Antithrombotic properties of the endothelium - Inhibit platelets (vWF/collagen shielding, NO/degrade ADP, thrombin altering), anticoagulants (TF shield, thrombomodulin competes, heparin/antithrombin III, and fibrinolytic (ECs make tPA) - Intravascular anticoagulants -- heparin - Heparin: amps anti-thrombin III, removes thrombin, made by mast cells/basophils - 13.5: Conditions of Excessive Bleeding - Condition of excessive bleeding - Liver disease, vitamin K lack, hemophilia, thrombocytopenia (platelet lack) - Vitamin K deficiency - Made by bacteria in intestine, bile lack can lead to K lack - Hemophilia - Hemophilia A: lack of factor VIII, most common - B: lack of factor IX - Intrinsic pathway impaired in males - Thrombocytopenia - Can be caused by hypersplenism, autoimmune disease, hypothermia, DIC, HIT - Tendency to bleed from small vessels - Petechiae: small hemorrhages into skin bc of platelet lack - Purpura: just slightly larger - Thromboembolic conditions - Thrombus: abnormal clot, embolus: its floating - Caused by rough vessels or slow flow - Pulmonary embolism - Deep leg vein thrombus breaks off into embolus, occluding pulmonary arteries - Disseminated intravascular coagulation - DIC: wide-spread coagulation in small vessels, causes deficiency of clotting factors made from liver and leads to excessive bleeding elsewhere - Blood coagulation tests - Small cut should stop bleeding in 1-6 minutes - Prothrombin time - Add Ca/TF to blood and measure the time to clot to assess int/ext pathways(usually 12s) - International normalized ration - INR: standardized measurements of pro-thrombin time (1.0 -- 2.0), the higher the value the more bleeding risk - 13.6: White Blood Cells - Three Main Types of WBCs - WBCs - Granulocytes: neutrophils (phagocytes), eosinophils (parasites/antigen-antibody complexes, allergies), basophils (like mast cells, inflame) - Genesis of WBCs - Granulocytes, monocytes develop in bone marrow reserve, megakaryocytes in marrow make platelets (hang out in marrow until needed) - Lymphocytes develop in lymphoid peripherals - Life Span of WBCs - Granulocytes: 4-8hr(blood), 4-5d(tissue) - Monocytes/macrophages: longer circulating and tissue residing even longer - Lymphocytes: longest - Platelets replaced every ten days - Basophils and mast cells - Release heparin, histamine, bradykinin, serotonin, leukotrienes, lysosomal enzymes when IgE binds to them. - Role of IgE in histamine release - Basophils and mast cells - Release chemotaxic factors, cytokines, histamine, and some others too - Leukopenia - Leukopenia: low WBCs (marrow failure), allowing infection - Leukemia - Abnormal WBCs produced, can be any kind of WBC and conditions vary by person - Clinical effects of leukemia - Abnormal WBCs replace bone marrow with the abnormal cells, causing whole mess of problems - 13.7: Resistance of The Body to Infection - The innate and adaptive immune systems - Pathogens activate both innate and adaptive immune responses - Principle components of the immune system - Innate immunity - Epithelial surfaces serve as a barrier to infection - Defensins: disrupt pathogen membranes, released by epithelial cells - Microbiome and mucus - Recognizing pathogens - PAMPs: patterned molecules on pathogens - PRRs: receptor proteins that identify PAMPs - Toll-like receptors, C-type Lectin, NLRs, MBL - Activated PRRs Trigger an Inflammatory Response - Cytokines and prostaglandins and leukotrienes cause inflammation - Leukocyte activation - Phagocytosis - Neutrophils and macrophages, opsonization - Phagocytes - Monocytes become macrophages (long living), usually first to respond to infection - Neutrophils are short-living but can be sent to sites of infection fast - Phagocytosis - Digestion of ingested particles - Phagosomes fuse with lysosomes and other granules to make phagolysosomes - Phagolysosomes: have proteolytic enzymes and sometimes lipases to kill things - Bactericidal agents - Reactive oxygen species: generated by enzymes in phagosome or in peroxisome (some bacteria are resistant to them) - Phagocytosis - Macrophages are more effective than neutrophils - NETs: neutrophils eject chromatin to make a web when a pathogen is too big to be ingested - Complement system - A collection of soluble proteins and their membrane receptors, work in both innate/adaptive response, cause inflammation, when activated start an enzymatic cascade, critical step is proteolysis of C3 - Activation and functions of the complement system - Three main functions of the complement system - C5a/C3a release histamine to cause inflammation, C3b acts as an opsonin, MAC destroys membrane - Virus-infected cells - No PAMPs so can only catch by detecting viral genome - Antiviral cytokines: Interferon-alpha/beta (both type I), released when virus in cell detected - They stop protein synthesis and even do apoptosis - Type I interferon... - The canonical type I - Natural Killer Cells - MHC-1 shows viral fragments on cell, NK cells come and kill it (some viruses evolved to not show MHC-1 protein so NK cells will kill a cell if it has lower than normal MHC-1 expression) - How a NK cell recognizes its target - Actually makes virus cell kill itself - Dendritic cells - Link innate to adaptive response, express many PRRs (kill pathogen, put protein on MHC, present MHC to T cells of adaptive immune system in lymph nodes) - Dendritic cells as... - 13.8: Adaptive Immunity - Adaptive immunity - Includes lymphocytes and antibodies, very powerful, either humoral (B cell) or cell-mediated (T cell) - Antigens - Antigen = antibody generator - Epitopes: structure identified by adaptive immunity - APCs bring antigens to lympgocytes: B cells make antibodies and T-cells do something else - Lymphocytes - Form in bone marrow or thymus (T cells, thymus) - The adaptive immune system works by clonal selection - Lymphocytes randomly generated and each is specific to an antigen, once one comes in contact with its antigen it causes clonal expansion of itself and causes effector cells to form - Immunological memory - Formation of memory cells makes second response quicker and stronger - Mechanisms of immunological self-tolerance - Lymphocytes go through screening and if they respond to a self-antigen it is destroyed, in the central lymphoid organ it can still be edited but in the peripheral it must be destroyed - Failure to tolerance -- autoimmune disorders - Rheumatic fever, post-streptococcal glomerulonephritis, myasthenia gravis, systemic lupus erythematosus - B cells and antibodies - B cells release antibodies that can disable viruses and recruit innate system - B cells also make immunoglobins (serve as antigen receptors or as antibodies) - New B cell insert Igs into itself to make a BCR, when BCR meets its antigen it is partially activated by when T-helper fully activates it it becomes an effector (plasma) cell and makes hella antibodies - Antibodies - Igm, IgG, IgA, IgD, IgE, mechanisms of action - Antibody activated phagocytosis - Role of IgE in histamine release - Antibody IgE and antigen cause histamine release from mast cells - Complement system for antibody action - Can be set off by antibody binding - Bunch of proteins made by liver circulate the blood/ECF, activate C3, causes amplifying cascade, attract phagocytes - T cells - Only activated by APC and act in a short range - Dendritic cells are pro APCs, macrophages and B lymphs or nonpros - MHC proteins - MHC-1: present to cytotoxic T cells, MHC-II: present to helper T cells - Only APCs have MHC-II - The processing.. - TCRs need co-receptors - TCRs need CD8 (cytotoxic) or CD4 (helper) to properly bind to MHC protein - Killing by cytotoxic T cells - Helper T activate cytotoxic T and then cytotoxic T kills directly (not hurting nearby cells) - Helper T cells - Most T cells are helpers, produce lymphokines and cytokines - Effector helper T cells help activate other - Basically, just rally the troops by releasing cytokines (AIDS gets rid of these) - T helper activate B cells - T helper cell activity - Naïve T helper cells can differentiate - Both T and B cells require multiple signals for activation - 13.9: Inflammation - Inflammatory response - Infection or damage causes tissue to inflame to get host defense there - Inflammation - Chronic can be bad - Supposed to acutely heal and prevent more damage - Walling-off sites of inflammation - Fibrinogen clots seal off area, staphylococci cause intense inflammation and get walled off, streptococci cause less intense inflammation and can spread easier - Sequence of events in an inflammatory reaction - Recognition, recruitment, removal, regulation, resolution - Recognition of microbes and damaged cells - DAMPs: can sense damages to cells and cause inflammatory response - Reaction of blood vessels in acute inflammation - More blood flow to the area and more permeability - Transcytosis: increased transport of fluids and proteins - Leukocyte recruitment to sites of inflammation - Leukocytes overkill can cause prolonged inflammation - Macrophages make growth factors to help repair - Leukocyte adhesion to endothelium - Margination: leukocyte attaches to endothelium, selectins (mediate roll), during roll encounters chemokines that cause expression of integrins (mediate adhesion) - Leukocyte transmigration and chemotaxis - Transmigration: leukocytes exit blood and enter tissue, mediated by PECAM-1, use collagenases to enter ISF, chemotaxis is cells releasing chemicals that attract the WBCs - - Secondary macrophage invasion - Macrophages take over and due a lot of the work, resident macrophages first, then neutrophils and then second macrophage wave - Bone marrow responses - Growth factors produced bc of infection/inflammation drive proliferation - Phagocytosis - Macrophages - Dominant cell in chronic inflammation - Monocyte-macrophage cell system - MPS: phagocytic system seen in skin, lymph nodes, alveola, Kupffer cells, spleen/bone marrow (mostly macrophages) - 2 major pathways for macrophage activation - Classical (M1): microbrial products and IFN-y cause NO and ROS to help phagocytosis - Alternative M2: cytokines cause growth factor for tissue repair - Macrophage-lymphocyte interactions - Positive feedback - Formation of pus - Basically just graveyard of dead cells - Inflammatory mediators - Cytokines: proteins released by many cells that cause inflammation (peptide derived) - Prostaglandins: lipids released by mast cells and others and cause pain and fever - Leukotrienes: leukocyte recruitment and smooth muscle reactions - Major roles of cytokines in acute inflammation - Help WBCs squeeze through vessels, activate immune cells, bone marrow production, when chronically elevated though they are not good for body - Prostaglandins and leukotrienes - TXA2 - Steroids block these pathways at the very start so are powerful pain blockers - Termination of the acute inflammatory response - Clean up is pretty fast, TGF-B and IL-10 turn off inflammation process and their release is started by the inflammatory response itself **Week 14: Renal Physiology** Class 11/25/2024 - Afferent arterioles, capillaries, efferent arterioles (unique artery to capillary to artery again) - NKCC2 : reabsorbs Na,K,Cl, increases osmolarity of ISF, water follows out of nephron, blocking that receptor makes more water stay in - Low NaCl in nephron means it can handle more filtration - 14.1: Introduction to renal physiology - Multiple functions of the kidneys - Excrete waste, regulate water/ions/acids/RBC, gluconeogenesis - Physiological anatomy of the kidneys - Huge blood supply to organ size ratio, have cortex and medulla - Structure of the nephron - Juxtamedullary nephrons: nephrons with glomeruli near medulla, have vasa recta - Cortical nephrons: glomeruli in outer cortex - The collecting duct has 2 cell types - Principle cells: reabsorb NaCl and secrete K - Intercalated cells: regulate acid-base balance - Nonmotile primary cilium: every nephron (except intercalated) has these that serve as mechanosensors for the kidney - Urine formation - Glomerular filtration, reabsorption, secretion - Renal handling of 4 hypothetical substances - 14.2: Ultrastructure of the glomerulus - Glomerular capillary membrane - Filtration barrier: endothelium (perm to water, not cells), basement membrane (-ve and blocks plasma proteins), podocytes (size-selective filter) - The glomerulus - Glomerular capillaries - The mesangium - Mesangial cells (can contract, structural support to glomerular capillaries) - Extraglomerular mesangial cells: outside glomerulus - Mesangial cells involved in the immune complex-mediated glomerular disease - Podocyte injury - Damage to podocytes allow proteins to go through filtration barrier - Importance of electrical charge for filtration - Negatively charged molecules are filtered less easily than positively charged - Proteoglycans in endothelium cause -ve charge - Clinical significance of proteinuria - Finding protein in urine can suggest renal disease, especially people with hypertension, diabetes, pregnant - 14.3: Renal clearance - Renal clearance - Based on law of conservation - input = output - only focuses on how much of a substance is excreted into urine, so excretion rate of x is prop. To plasma conc of x - removal rate of substance X is the clearance (Cx): volume of plasma cleared of a substance over unit time - example - excretion rate = concentration \* urine rate, then divide that by the arterial plasma concentration and you get the amount cleared over unit time - used to measure GRF and RPF - clearance of various substances - renal clearance: 0-600 ml/min - glucose and albumin = 0 - Inulin: freely filtered so the concentration of inulin = GFR - Clearance ratio - Clearance ratio: clearance of x compared with inulin clearance - Lower than 1 = not filtered, or is filtered and reabsorbed (albumin, Na, urea, glucose, aminos) - Higher than 1 = filtered and secreted (acids, bases, K) - 14.4: Glomerular filtration - Glomerular filtration - GFR depends on blood flow, filtration fraction = GFR / RPF (0.2 usually) - Glomerular filtration -- main points - Glomerular filtrate is just plasma without proteins and other cells - Measurement of GFR - Glomerular marker: freely filtered, not reabsorbed/secreted, does not alter GFR, best is inulin - Renal clearance of creatinine estimates GFR - Creatinine: secreted by renal tubules slightly, but can also be used to estimate GFR - Determinants of GFR - Filtration coefficient (Kf): glomerular wall water permeability/SA, higher than in any other capillaries, lowers with disease - Net filtration pressure: hydrostatic and colloid osmotic P sum - Increased Bowmans capsule hydrostatic pre - Increased glomerular capillary colloid osmotic P lowers GFR - Net filtration P decreases aong glomerulus due to increase in colloid osmotic P in capillary - Losing fluid, causes more relative protein concentration - Increases in capillary hydrostatic P raises GFR - Main way GFR is regulated - Efferent arteriolar constriction has a biphasic effect on GFR - Causes build up in the glomerulus that increases P but also a higher colloid osmotic that kinda balances it out, small change increases GFR and big changes lower it - 14.5: Renal Blood Flow and Autoregulation - Determinants of RBF - Change in P: P diff between renal artery/vein (higher = more RBF) - Resistance - Autoregulation of RBF and GFR - Mechanisms of autoregulation - Myogenic (P) or tubuloglomerular (NaCl) - Renal autoregulation - All raise and lower together, but GFR and RBF levek back out from autoregulation - Myogenic autoregulation - More P, stretches vessel, Ca enters cell, vasoconstricts and lowers RBF/GFR - Tubuloglomerular feedback -- macula densa - Renal artery BP rises, RBF/GFR rise, more water and NaCl delivered to macula densa, macula densa secretes ATP/adenosine that tells juxtaglomerular cells to constricts afferent arterioles - Macula densa feedback - Macula densa can also release NO when GFR is low to raise it back up ang II and renin also help bring it back up by constricting efferent arteriole - Ang II impacts efferent more than afferent arteriole - Main considerations - Renal can function separate from high BP, lower than 90mmHg doesn't work, hormones can also impact - 14.6: Neurohormonal regulation of RBF and GFR - Neurohormonal regulation of RBF and GFR - Happens when ECF volume changes - Sympathetic nerve activity - Afferent (more) and efferent arterioles have alpha-1 receptors that make them constrict from SNS (catecholamines) (lower GFR/RBF) - Angiotensin II - Afferent and efferent (more), low levels of it just impact efferent (raise GFR, low RBF) and high levels impact both (lower GFR/RBF) - Atrial natriuretic peptide (ANP) - Dilates afferent, constricts efferent, released when ECFV raises, increases RBF/GFR - Prostaglandins - PGE2/PGI2 dilate afferent/efferent, happen with SNS activation to oppose constriction - Nitric Oxide - Opposes constriction of AngII and catecholamines, increases GFR/RBF - Endothelin - Constricts, released when AngII, bradykinin, Epi detected, lowers RBF/GFR - Other factors that influence GFR - Read the slide - 14.7: Reabsorption and Secretion - Urine formation - Most water/solutes that are filtered are reabsorbed - Measurement of reabsorption and secretion - Filtration: stuff filtered into bowmans space is the filtered load and fluid inside nephron is tubular fluid - Reabsorption: taken from tubular fluid into the peritubular capillary - Secretion: peritubular capillary into tubular fluid - Excretion: ultimate amount that is pee - Tubular reabsorption and secretion - Examples - Tubular reabsorption employs passive and active mechanisms - Substance goes across tubular epithelium into renal interstitial fluid into peritubular capillary - Primary active transport through the tubular lumen - Bunch of ATPase, Na has brush border and carrier proteins for additional support - Net reabsorption of Na involves 3 steps - Na diffuses across luminal membrane bc of gradient made by Na/K ATPase, across basolateral membrane by Na/K ATPase, ultrafiltration (passive) drives it into peritubular capillary - Secondary active reabsorption through the tubular membrane - Glucose and amino acids very efficiently use this method, some things are secreted with this method too - Transport maximum - Transport maximum: limit with reabsorption due to carriers so once threshold in a nephron is passed that substance will start getting excreted - Glucose transport maximum - Filtered load: freely filters, straight forward - Reabsoprtion: 200mg/dL is the threshold (begins getting excreted) and at 350 you are at transport maximum - Once Tmax is reached, excretion matches filtration - Gradient-time transport - Things that passively transport bc of gradient,perm,time in contact with membrane - In proximal tubule Na shows gradient-time transport but in distal it shows Tmax transport (Na Tmax can increase from aldosterone) - Reabsorption of water and solutes is coupled to Na reabsorption - Self-explanatory really - Movement of Na attracts other -ve ions - Mechanisms of coupling water, chloride, and urea reabsorption with sodium reabsorption - 14.8: Absorption and secretion along different parts of the Nephron - Proximal tubular reabsorption - Most Na/water reabsorbed by proximal tubule (Na/K ATPase creates low na concentration in tubule cell), proximal tubule epithelial cells are very good at active/passive transport (high mitochondria, brush border, high channels) - Cellular mechanisms of Na reabsorption in the proximal tubule - Concentration changes in the proximal tubule - First half (Na absorbed by cotransport with glucose), second half (with Cl) - Amount changes, but Concentration stays same throughout bc water reabsorption keeps up - Sodium is isosmotic (concentration stays same in relation to water) - Solute and water transport in the loop of henle - Thin descending/ascending: no brush border, few mitochondria, water only absorbed through descending limb - Thick: high metabolic activity, absorbs 25% of Na,Cl, K - Mechanisms of Na,Cl,K transport in thick ascending loop of Henle - Na transport mediated by NKCC2 transporter (loop diuretics alter this activity) - K into lumen creates +ve charge, makes Mg/Ca move through paracellular space - Thick segment of ascending loop is impermeable to water (hypo-osmotic) - Early distal tubule - Like thick ascending loop (diluting segment), macula densa here, reabsorb Na,Cl,K,Mg - Thiazide diuretics inhibit the NaCl cotransporter here - Early and late distal tubule and cortical collecting tubule - Early: just the ions - Late/cortical: can bring in water depending on ADH - Neither permeable to urea - Principle cells reabsorb Na and Secrete K - K secretion: K enters cells due to Na/K ATPase, then diffuses down gradient into lumen - Principle cells: what potassium-sparing diuretics act on by either stopping aldosterone or the ATPase itself - Intercalated cells secrete or reabsorb H,HCO3, K - Acid-base regulation, make up almost half of collecting tubules/ducts - Type A: secrete H, absorb HCO3, prevent acidosis - Type B: opposite, alkalosis - Summary of functional characteristics of the late distal tubule/cortical collecting tubule - Impermeable to urea, absorb Na (hormone control), Type A/B cells, water permeability controlled by ADH - Transport characteristics of the medullary collecting duct - Water perm (ADH), permeable to urea, can secrete H against a large conc gradient - Na handling in the nephron - 14.9: Regulation of Tubular Reabsorption - Regulation of tubular reabsorption - Outline - G-T balance - Reabsorption rises as filtered load rises independent of hormones - GFR rises, protein concentration rises in peritubular capillaries, draws fluid into peritubular caps, - Filterd loaf rises, more glucose and AA in filtrate which is coupled with Na transport - Always absorbing 67% in proximal tubules - Importance of autoregulation and GT balance - Peritubular capillary and renal interstitial fluid physical forces - Determinants of capillary hydrostatic pressure - Proximal tubular and peritubular reabsorption - Normal conditions: soltes/water reabsorbed from tubular lumen to peri caps well (low hydrostatic P in tubular lumen, high osmotic P) - Decreased Peritubular capillary reabsorption - Higher peri caps hydrostatic P, decreased colloid osmotic P - Reduced peri caps reabsorption backups ISF space and then tubular lumen, causing less reabsorption in proximal tubule - Aldosterone increases Na reabsorption and K secretion - Increase aldosterone: AngII, high K, ACTH - Decrease: ANP, high Na - Late,distal,cortical,medullary collecting tubules - AngII raises Na/water reabsorption - Aldosterone rise, Na absorbed more, efferent arterioles constrict (lowers hydrostatic, raises colloid osmotic by reducing renal blood flow) - Effect og angII on peritubular capillary dynamics - Above illustrated - AngII constriction causes Na/water retention - ADH - Makes distal/collecting tubules reabsorb more water to control ECF osmolarity - ANP - excretes Na and water - 14.10: Water Balance - Water transport along the nephron - - Water Balance -- Concentration and dilution of urine - Normal: 290 - Osmoregulation: renal system and water balance controls body osmolarity - Control happens at late distal tubule/collecting duct - Responses to water deprivation and drinking - Corticopapillary osmotic gradient - Osmolarity gradient between ISF of kidney cortex the papilla ISF (usually 1200:300, respectively) - Countercurrent multiplication - Concentration gets bigger the deeper in henle loop you go because of way that na is pulled and that water is also pulled - Urea recycling - ADH transports urea too which contributes to corticopapillary osmotic gradient - Countercurrent exchange in the vasa recta preserves the corticopapillary osmotic gradient - - Mechanism of excretion of dilute urine **Week 15: Gastrointestinal Physiology** - 15.1: Introduction to GI Physiology - Segments of the GI Tract - Layers of the GI Tract - Neural Control of the GI Tract - Extrinsic: ANS -- PSNS (ACh) / SNS (NE) - Intrinsic: Enteric nervous system -- Myenteric/Submucosal plexus - Extrinsic nervous system - PSNS -- vagal nerves synapse close to intestine plexus - SNS -- synapse on prevertebral ganglia - Enteric nervous system -- myenteric plexus - Goes from esophagus to anus between longitudinal and circular smooth muscle layers - Plexus controls GI motility, inhibited by relaxation of sphincter - Submucosal plexus - Mucosal layer from the esophagus all the way to the anus - Functions to secrete, absorb, contract muscularis mucosa locally - The splanchnic circulation - Blood from the gut goes tto liver through portal vein and into the heart through the hepatic veins (mononuclear phagocyte system kills bacteria) - Control of GI Blood Flow - Blood flow prop to local activity (meal) - Vasodilator hormones or kinies and low oxygen set off - PSNS increases blood flow by first increasing gut activity, SNS decreases activity - Countercurrent blood flow in the villi - Artery flows one way, veins flow the opposite way is countercurrent blood flow - Most of blood in o2 of villi is shunted away from tip of villi, sometimes this can cause ischemia in the tips of the villi - 15.2: Gastrointestinal Hormones - GI Regulatory Substances - Endocrines (peptides), neurocrines (peptides, AcH, NE), paracrines (peptides, histamine) - Criteria to qualify as a GI hormone - Secreted in response to stimulus, carried in bloodstream, no neural activity, own chemical - GI Hormones - Gastrin and CCK: - Secretin - Gastrin - Release: G cells in antrum and duodenum, released to digest protein, calcium, coffee, or wine, inhibited by somatostatin and acidification of antrum - G17: large amount released from antrum - G34: small amount from duodenum - Two main actions of gastrin - Promote H secretion by gastric parietal cells - Trophic activity: grows mucosa of stomach, duodenum, colon - Gastrinoma: Zollinger-Ellison Syndrome - Gastrin secreting tumor: Non-beta cell or duodenum G-cell secretes lots of gastrin into blood - Hypergastrinemia causes hypersecretion of acid: more parietal cells causes more H secretion - Gastrinoma -- Summary - Causes ulcers and destroys bile and fat will not be able to be digested - GI Hormones -- Cholecystokinin (CCK) - Promotes fat digestion/absorption, relased from duodenum/jejunum I-cells after sensing fats - Actions: empty gallbladder, secrete pancreatic enzyme/HCO3 (potentiates secretin), stop gastric emptying, can grow exocrine pancreas and gallbladder mucosa - CCK -- Physiological Effects - Pancreatic enzymes and bile into small intestine - Secretin - Released by duodenal mucosa S-cells bc of fatty acids or acidic pH - Effects: stops gastric secretion, pancreatic enzyme/bile/HCO3 release, stops forward chyme movement, grows exocrine pancreas - Glucose -- Dependent Insulinotropic peptide (GIP) - Similar to secretin/glucagon, released by duodenum and proximal jejunum K-cells after sensing any nutrient/ oral glucose - Causes insulin release and stops gastric acid secretion - Candidate hormones (don't qualify as GI hormones) - Motilin: upper duodenum secretes in fasted states, starts interdigestive myoelectric complexes - Pancreatic polypeptide: stops pancreatic enzyme/HCO3 release - Enteroglucagon: low blood glucose causes release from intestinal cells, makes liver make glucose - GLP-1: small-intestine L-cells, incretin, made from proglucagon - Paracrines - Somatostatin: D-cells of GI mucose bc of low pH, inhibits other hormones, made by hypothalamus/pancreas too - Histamine: endocrine cells of GI mucosa, causes H secretion. By gastric parietal cells - Neurocrines - 15.3: Propulsion and mixing of food - GI Smooth muscle - Functions as a syncytium, gap junctions allow for ion movement and signal propagation, contract as one unit - Circular and longitudinal muscle - Circular or longitudinal contractions that are either phasic or tonic - Membrane potentials in GI Smooth Muscle - Slow Waves: happen at fixed frequency at a variable amplitude, not a true AP, diff parts of - Spike Potentials: true action potentials caused when slow waves reach threshold, voltage dependent ca channels, frequency affected by nerve input (variable) - Remember Ach and PSNS causes more contractions here and NE and SNS does opp - Relationship between the electrical and mechanical activity - Electrical slightly precedes mechanical - Chewing and swallowing - Breaks cells apart, more SA of food, get saliva on it to digest starches and lubricate it - Swallowing - Oral phase (voluntary), pharyngeal phase (involuntary), esophageal phase (involuntary) - Esophageal phase - UES opens/closes, primary peristaltic contraction (continuation of pharyngeal peristalsis and executed by swallowing center), LES opens and stomach relaxes, secondary peristaltic wave if first did not work (stretch receptors cause, intrinsic, can happen with vagotomy) - Disorders of swallowing (Dysphagia) - Stroke (UES and pharyngeal contractions lose coordination), muscular diseases, anesthesia (aspiration of stomach contents) - Gastric motility - Orad area: relaxes to receive food (receptive relaxation) - Caudad area: mixes food with gastric juice (propulsion/retropulsion) and propels chyme into duodenum (antral pump) - Motility of the orad region - Contractile activity: small contractions as meal empties, lose with vagotomy - Receptive relaxation: Vasovagal reflex, vagotomy inhibits reflex - Gastric distensibility: CCK increases, lowering gastric emptying - Factors that increase gastric emptying - Higher tone of orad, peristaltic contractions, lower pylorus tone, no segmental contractions in intestine - Decrease gastric emptying - Opposite of increasing factors caused by receptors in intestinal mucosa - Gastric emptying -- role of intestinal receptors - Intestinal mucosa receptors stimulated by osmolarity, acid, fat, or protein trigger enterogastric reflexes (fat/proteins causes CCK release to lower gastric emptying and H ions also lowers through intrinsic neural reflex) - Small intestinal motility - Mixes chyme with enzymes/etc, circulates to expose to mucosa, propulsion - Slow waves in small intestine are more frequent than stomach, either segmentation contraction (mix) or peristaltic (propel) - Large intestine motility - Mixes feces through segmentation/haustral contractions and propels it in mass movements - Mass movements - Function to move feces long distances in colon (bowel movements), 1-3x a day - Water absorption makes feces hard to move in late parts of colon - Defecation - Rectosphincteric reflex: rectum fills, internal anal sphincter relaxes involuntarily, external opens voluntary - Gastrocolic reflex: distension of stomach by eating increases colon motility (mass movements) - 15.4: Secretory functions of the GI Tract - Salivary secretions - Acinar cells: produce primary secretion similar to plasma - Ductal cells: modify primary secretion - High flow rate: isotonic, low: hypotonic - Regulation of saliva secretion - PSNS control, stim increases production - Gastric secretion - Gastric juice: HCl, pepsinogen, intrinsic factor, mucus (HCl activates pepsinogen into pepsin) - Oxyntic glands contain parietal cells (HCl and IF) and chief cells (pepsinogen) - Pyloric glands in antrum of stomach have G cells (gastrin), Mucus neck cells (mucus, HCO3, pepsinogen) - Mechanism of HCL secretion by Gastric Parietal cells - H/K pump sends the H ions out - Agents that stimulate and inhibit H secretion by gastric parietal cells - - Phases of gastric secretion - Cephalic: vagus (seeing, smelling food) - Gastric: local nerves, vagal nerves, gastrin-histamine stimulation - Intestinal: nerves and hormones (only 10% of HCl secretion but depends on protein content of food) - Peptic ulcer disease - Digestion of mucosa and muscle layers that serve as a protective barrier to the gastric acid - Duodenal ulcer - Pancreatic secretion - Acid from stomach causes release of secretin and cholecystokinin that make pancreas release enzymes and HCO3 into duodenum, vagal also helps - S cells make secretin that causes HCO3 release (CCK helps) - I cells make CCK that makes enzymes get released - Bile secretion - Gallstones - Bile is off (too much acid, water, or cholesterol in it) that makes it harden into stones Class - Pancreatic tumor leads to higher levels of somatostatin - Pepsinogen is released from the stomach