Gastrointestinal Physiology Study Notes PDF

Gastrointestinal Physiology (GI) Lecture 1 recording 1: General Introduction  Functions of the Gastrointestinal Tract (GIT):  Transfer digested organic nutrients, minerals and water, from the external environment into the internal environment: involves digestion...

Gastrointestinal Physiology (GI) Lecture 1 recording 1: General Introduction  Functions of the Gastrointestinal Tract (GIT):  Transfer digested organic nutrients, minerals and water, from the external environment into the internal environment: involves digestion and absorption o Digestion  Form absorbable molecules from food through GIT motility, pH changes, and biologic detergents and enzymes (enzymes are predominantly produced by the pancreas) o Absorption  Movement of digestive food from the intestine into the blood or the lymphatic system  Functions of the Gastrointestinal Tract (GIT):  Functions of the GIT: o Excretion  Non-absorbable components of food, bacteria, intestinal cells, and hydrophobic molecules (drugs), cholesterol and steroids are excreted o Host defense  Lumen of the GIT is considered to be outside the body  It is continuous with the exterior of the body  The GIT forms a barrier with the outside environment and contains a highly developed immune system  The GIT can inactivate t harmful bacteria or other microorganisms  Components of the GIT:  Components of the GIT: o Mouth, pharynx, esophagus, the stomach, the small intestine (duodenum, jejunum, ileum), large intestine  3 accessory organs: o Pancreas, liver, gallbladder Lecture 1 recording 2: Layers of the GIT  Structure of the GIT:  GIT is a long muscular tube stretching from the mouth to the anus o Composition is similar form mid-esophagus to anus  The top third of the human esophagus is made of skeletal muscle, while the rest of the GIT is composed of smooth muscle  Tube of the intestine o Lumen  Inside of the tube  Contains many folds and processes to increase the surface area  Circular fold is where the entire inner surface folds in on itself  Contains villi (singular villus)   Villus projects into the lumen of the tube, and below the surface still is a crypt or an invagination  Structure of the GIT:  Layers of the GIT o Mucosa  The mucosa contains three different subsections:  Epithelium → a very thin layer of cells  Lamina propria  Muscularis mucosa → a very thin, smooth muscle layer o Submucosa o Muscularis externa (outer muscular layer) o Serosal layer (connective tissue layer)  Layers of the Mucosa:  3 layers of the mucosa: o Epithelium, lamina propria, muscularis mucosa  Epithelium:  A layer of cells that lines all body cavities and surfaces  Epithelial cells are polarized cells: they have a basolateral surface and an apical surface  Apical surface → inserts the inside of the tube or the lumen of the tube  Basolateral surface → closest to the blood surface, facing away from the tube; basal surface and the lateral surface  The polarized epithelial layer has different transport proteins at the apical surface compared to the basolateral surface  Transport proteins are confined to the different cell surfaces due to presence of tight junctions  Layers of the Mucosa:  Epithelial layer: o Single layer of cells o Function:  Selective uptake of nutrients, electrolytes and water  Prevent the passage of harmful substances o Surface area is amplified by the presence of villi and crypts  Villus contains a single layer of epithelial cells containing microvilli  Crypt is a region which invaginates into the lamina propria o Stem cells within the crypts divide and produce daughter cells which differentiate into a variety of cells  Stem cells divide and migrate up the villus. At the top of the villus, they reach the end of their life and slough off  In the small intestine the epithelial cell layer is replaced every 5 days   As these cells are dividing rapidly, they are affected by anticancer drugs and are killed by the drugs before they can be replaced  Selective Transport of Nutrients Across the Epithelium: o Epithelial layer is selective, allowing specific nutrients across the intestinal epithelium and into the body  2 pathways that chemicals or molecules can use to get across an epithelial layer:  Paracellular pathway → chemicals move between cells across the cell junctions; limited by tight junctions between cells, so only water and small ions can actually diffuse through the tight junctions; not many substances can get through this way in a healthy intestine  Transcellular pathways → cross the cell and therefore require transport proteins  More Layers of the Mucosa: o Lamina propria  Includes everything above the muscle layer  Connective tissue, blood vessels, nerve fibers and lymphatic vessels, immune and inflammatory cells for immune protection  Lacteal or lymphatic vessel o Muscularis mucosa  Thin layer of smooth muscle  Not involved in contraction of the GIT and may function in moving the villi Lecture 1 recording 3: More Layers of the GIT  Structure of the GIT: (Shows the different layers of the GIT)  Submucosa:  Beneath the mucosa layer  Submucosa: contains blood vessels, lymphatic vessels, submucosal nerve plexus (network of nerves), connective tissue o Submucosal nerve plexus relays information to and away from the mucosa  Muscularis Externa:  Muscularis externa: circular muscle, myenteric nerve plexus, longitudinal muscle o Circular muscle: fibers are orientated in a circular pattern and contract and relax to close and open the tube o Myenteric nerve plexus: myo = “of muscle”  Regulate the muscle function of the GIT o Longitudinal muscle: lengthens and shortens to control the length of the tube (does not change the diameter)   Serosa:  Serosa layer: a connective tissue layer that encases the intestine and forms connections with the intestine and the abdominal wall Lecture 1 recording 4: Blood Supply to the GIT  Blood Supply to the GIT:  GIT blood supply carries away many nutrients as well as other components absorbed from the diet o Blood supply transports water-soluble nutrients and other molecules o Lacteals (lymphatic system; lamina propria in the mucosa layer) are important for fat absorption  Food → digested in the stomach → absorption and secretion in the small intestine → processing in the colon → elimination of feces containing ingested material that cannot be digested and absorbed o Blood is highly oxygenated entering the GIT but loses oxygen as it perfuses the intestine  Blood does not flow directly from GIT back to the heart- blood is taken to the liver before returning to the heart. o Blood that perfuses the intestine goes to the liver via the portal vein  Portal Circulation:  Portal circulation → circulation that carries the blood from the intestinal tract to the liver o Blood in the portal circulation is nutrient rich o Important for:  Liver removes harmful substances (liver acts as a filter and has many enzymes)  Processing of nutrients  Portal Circulation:  Other organs in the body are perfused by arterial blood (fully oxygenated) o Liver is an exception:  When you have not been eating, ~ 30% of the blood in the liver is from an arterial source (ie. fully oxygenated)  After eating, this is reduced to 10%  Hepatic artery → contains fully oxygenated blood that perfuses the liver  Hepatic portal vein → carries blood to the liver that has already perfused the stomach, pancreas, SI and LI o These two blood supplies mix, so that the liver is perfused with nutrient-rich blood coming from the GIT organs with a poor oxygen content  “In Series” versus “In Parallel” Circulation:  Most organs are perfused in parallel within the systemic circulation, but the liver is perfused in series as the liver is perfused predominantly by blood that has already perfused another organ; blood flows from the digestive organs to the liver Lecture 1 recording 5: Regulation of GI Processes  Regulation of GI Processes:  GI processes include secretion and motility, or the movement of the GI tract o These processes are governed by the volume and composition of what is inside the intestinal tract  Reflexes regulating GI processes are initiated by: 1. Distension of the GIT wall by the volume of luminal contents 2. Osmolarity of the contents pH of the contents 3. The concentrations of the specific digestion contents, such as monosaccharides, fatty acids, peptides and amino acids  The digestion contents initiate different regulatory pathways  These reflexes are propagated by various receptors:  Distension of the wall, osmolarity, pH of the contents and the concentration of specific digestion contents initiate reflexes by acting through various receptors located in the wall of the tract  Mechanoreceptors → activated by mechanical stimuli (pressure and stretch)  Osmoreceptors → activated by a change in osmolarity  Chemoreceptors → activated by specific chemicals  Intrinsic Neural Regulation of GI Processes:  To control motility and secretion  Intrinsic neural regulation: o Intrinsic → contained wholly within the organ o Occurs through nerve plexi located in the GIT wall itself  Nerve plexi = branching networks of intersecting nerves o Enteric nervous system → intrinsic nerve regulation  Controls the activity of the secretomotor neurons which play a role in secretion and motility  Contained completely within the walls of the GIT  Large number of neurons: “Brain of the gut”  Can function independently of the CNS  Critical for involuntary functions  The enteric nervous system allows us to digest our food without having to think about it  There are two main nerve networks: myenteric plexus and the submucosal plexus  Intrinsic Neural Regulation of GI Processes:  Myenteric plexus: o Found between the two muscle layers, the circular muscle and the longitudinal muscle, of the muscularis externa o Responsible for influencing and regulating the smooth muscle  Submucosal plexus: o Found in the submucosa o Predominantly influences secretion   Nerves extend from the submucosal plexus to the mucosa to control secretion  The neural activity in one plexus influences the activity in the other o Communication between the two layers occurs so that motility and secretion of digestive enzymes work together  Extrinsic Neuronal Regulation of GI Processes:  Extrinsic → outside of the GIT wall o Extrinsic regulation occurs through the autonomic nervous system (ANS) (parasympathetic and sympathetic divisions) o Nerve fibers from the parasympathetic and sympathetic pathways enter the intestinal tract and synapse with neurons in both plexuses o Through the autonomic nervous system, the CNS can influence motility and secretion  Smell of food sends signals through your brain to the GIT through the ANS  Different emotional states in the brain (CNS) will influence appetite  Autonomic Pathways and Digestion:  Parasympathetic → “Rest and digest” response o Stimulates the flow of a large volume of watery saliva o Stimulates peristalsis (muscle contraction) o Stimulates secretion o Stimulates bile release from the liver  Sympathetic → “Fright, flight, fight” response o Stimulates the small volume of a thick saliva o Inhibits peristalsis o Inhibits secretion  Long and Short Neural Reflex Pathways:  Long reflex = extrinsic pathway  Short reflex = intrinsic pathway o The pathways coordinate to modify the motility and secretion of the GIT  (From the figure): o Eating a meal activates receptors in GIT wall (mechanoreceptors, osmoreceptors, chemoreceptors) → stimulus from the receptors feeds into the nerve plexus and stimulates the smooth muscle to contract or a gland to secrete → causes a response in the GIT (ie. contraction of the muscle which breaks down the food) o Smell of food when hungry/emotional state → stimulates the CNS → efferent autonomic neurons fire and interact with the same nerve plexus → stimulates the smooth muscle to contract or a gland to secrete → causes a response in the GIT (ie. contraction of the muscle which breaks down the food)  Stimulation of CNS causes the same response but response is due to a CNS stimulation o Responses in the GIT can occur without any input from the CNS   Receptors are activated in response to different stimuli causing release of chemical messengers Lecture 2 recording 6: Chemical Messenger Regulation  2 slides: Chemical Messenger Regulation: and Chemical Messenger Control of GI Activity:  4 categories of chemical messenger regulation: o Endocrine regulation → a hormone secreting gland cell releases a hormone across its basolateral surface into the blood; the hormone enters the blood and travels to its target cells in one or more distant places in the body o Neurocrine regulation → a nerve cell produces an electrical signal resulting in the release of a neurotransmitter which travels across a synapse and acts on a post-synaptic target cell (either a neuron or an effector cell) o Paracrine regulation → a local cell releases a paracrine substance which diffuses through the interstitial fluid to act on target cells in close proximity to the site of release of the paracrine substance; this would occur across the apical surface of the cell into the lumen of the gland o Autocrine regulation → a local cell releases a substance which acts on the cell that released it  Hormonal Control of GI Activity:  Endocrine cells: o Produce hormones o Found in the epithelium of the stomach and the small intestine o Enteroendocrine cells release hormones which control GI functions  Hormones released across the opposite surface of the cell into blood vessels in the lamina propria  Hormonal Control of GI Activity:  GI hormones: (These 3 we will look at in more detail) o Secretin, cholecystokinin (CCK), gastrin  All peptide hormones  Each hormone participates in a feedback control system  Most of these hormones affect more than one type of target cell  CCK As an Example:  CCK: o Release stimulated by the presence of fatty acids and amino acids in the SI o Released into blood o Stimulates the pancreas to increase digestive enzyme secretion and causes contraction of the gallbladder  Contraction of the gallbladder releases bile acids for fat breakdown  Absorption of fats and amino acids stops the release of CCK  This is a negative feedback control system  Major Hormones of the GIT: (We will look at these hormones in more detail later) Lecture 2 recording 7: Intestinal Motility  Intestinal Motility:  Intestinal motility: stimulated by contraction and relaxation of the two muscle layers in the outer portion of the GIT; causes contents to move along tract o Peristalsis - the main driving force for food moving through the intestinal tract; propulsion  Circular muscle contracts on the oral side of a bolus of food (Longitudinal layer relaxes)  Circular muscle contracted moves toward the anus, propelling the contents of the lumen in that direction, as the ring moves, the circular muscle on the other side of the distended area relaxes (Longitudinal muscle contracts), facilitating smooth passage of the bolus  Intestinal Motility:  Segmentation - important for the mixing of food o Involves contraction and relaxation of intestinal segments with very little net movement of the food towards the large intestine o Mostly occurs in the small intestine o Functions:  Allows the mixing of the contents of the GIT with digestive enzymes  Slows the transit time to allow for the absorption of nutrients and water  Basic Electrical Rhythm:  Pacemaker cells: o Cells in the GIT that are distributed throughout the smooth muscle cells o Constantly under spontaneous depolarization-repolarization cycles called slow waves  Slow waves give the GIT the basic electrical rhythm  Under all circumstances the pacemaker cells undergo spontaneous depolarization-repolarization cycles and every time this happens, if there is a stimulus, there is the potential for action potential generation and muscle contraction  Slow waves are propagated through the circular and longitudinal muscle layers through gap junctions  In the absence of any neural or hormonal input, the spontaneous slow waves do not result in any contraction; only when there is a stimulation, such as an excitatory hormone or neurotransmitter, further depolarization occurs and the membrane potential is increased enough that threshold is reached and an action potential is generated resulting in muscle contraction  Basic Electrical Rhythm:  Slow waves: o At rest, period fluctuations drift up and down due to regular variations in ion flux across the membrane  o With an excitatory input, the slow waves are depolarized above threshold, and an action potential occurs leading to smooth muscle contraction  The number of action potentials fired is proportional to the force of the contraction o The frequency of the contraction is dictated by the basic electrical rhythm and the force of contraction is mediated by neuronal and hormonal input o The force of contraction is mediated by neuronal and hormonal input Lecture 2 recording 8: Gastrointestinal Control  Phases of Gastrointestinal Control (The next 2 slides are combined together):  Neural and hormonal control of the gastrointestinal system is divisible into 3 phases: o It is classified based on where the stimuli initiates the reflex, or where the stimulus is perceived  Each of these phases of control is named for the site at which the various stimuli initiate the reflex and not for the sites of effector activity  Cephalic phase: head  This phase is initiated through stimulation of receptors in the head by the sight, smell, taste and chewing of food and the emotional state  These reflexes are predominantly regulated by parasympathetic fibers that activate neurons in the GIT nerve plexuses  Gastric phase: stomach  Receptors in the stomach are stimulated by distension, or stretching of the stomach, acidity, amino acids and peptides  The responses to these stimuli are mediated by both short and long neural reflexes Gastrin (hormone) represents the short reflex Acetylcholine represents the long neural reflex  Intestinal phase: intestine  Receptors in the intestine are stimulated by distension, acidity, osmolarity and digestive products  The intestinal phase is mediated by short and long neural reflexes and by the hormones secretin, CCK and GIP, which are all secreted by endocrine cells in the small intestine  Control of Food Intake:  Hypothalamus: o Important for maintaining homeostasis, command centre for neural and endocrine control coordination and for control of behavior o Contains a feeding centre in the lateral region  Activation of this region increases hunger  Animals with lesions in this region become anorectic and lose weight o Contains a satiety center in the ventromedial region  Activation of this region makes you feel full  Animals with lesions in this area overeat and become obese   Factors that Influence Food Intake:  Orexigenic factors: o Increase intake  Neuropeptide Y → neuropeptide in the hypothalamus that stimulates hunger or appetite  Ghrelin → synthesized and released from the endocrine cells in the stomach during fasting; when you start to starve. ghrelin is released into the blood and travels to the hypothalamus stimulating the release of neuropeptide Y in the hypothalamus feeding centre to try and increase food intake  Anorexigenic factors: o Decrease intake or cause a loss of appetite o Leptin → produced by adipose or fat tissue o Insulin → produced by the pancreas; stimulates a reduction in food intake o Peptide YY → released from the intestine to reduce food intake o Melanocortin → released directly from the hypothalamus acts to reduce intake of food  Factors Affecting Food Intake: Leptin:  Take in more energy/eat more than burned during exercise → deposit fat in tissues → increased secretion of leptin from the adipose tissue → plasma leptin concentrations increase → leptin travels to the hypothalamus through the blood altering the activity of the integrating center in the hypothalamus → leptin inhibits neuropeptide Y release (neuropeptide stimulates eating) → results in a decrease in appetite and reduced energy intake and an increase in the metabolic rate  Factors Affecting Food Intake:  Lack of leptin results in no appetite regulation, overeating and obesity Lecture 2 recording 9: Regulation of Water Intake  Regulation of Water Intake (The next two slides are combined together):  Hypothalamus: o Contains a thirst centre o Stimulated by: 1. Increased plasma osmolarity (most important factor)  Increased plasma osmolarity stimulates osmoreceptors (sensory receptors in the thirst centre of the hypothalamus)  Increased osmolarity of the blood stimulates thirst and the release of a hormone called vasopressin or anti-diuretic hormone resulting in conservation of water at the kidney 2. Decreased plasma volume  Pathophysiological conditions (large blood loss or diarrhea and vomiting) which cause dehydration and reduce plasma volume  A significant decrease in blood volume will reduce blood pressure and stimulate arterial baroreceptors which will act to  alter sympathetic and parasympathetic outflow to increase arterial pressure towards normal levels  Intrarenal baroreceptors within the kidneys Juxtaglomerular cells located in the walls of the afferent arterioles act as pressure receptors When blood pressure in the kidneys decreases, baroreceptors in the kidney afferent arteries are stimulated and activate the renin-angiotensin system Activation of the renin-angiotensin system produces angiotensin II, which has a direct effect on the hypothalamus to increase thirst; studied in experimental animals, but its occurrence in humans has not been proven 3. A dry mouth and throat stimulates thirst 4. Prevention of over-hydration  Occurs so that a person stops drinking well before water is absorbed by the GIT and has had a chance to affect baroreceptors and osmoreceptors in the body  Mediated by stimulus from the mouth, throat and the GIT  Water Intake Summary:  (Summary of this section) Lecture 2 recording 10: Salivary Glands  Salivary Glands:  3 main pairs of large glands: parotid, submandibular, sublingual  Composition of Saliva:  Saliva: o Hypotonic, slightly alkaline o Made of:  Water  Electrolytes - potassium and bicarbonate (gives alkaline nature); poor in sodium and chloride  Digestive enzymes - amylase (breaks down starches into disaccharides and trisaccharides); lipase (breaks down fat into fatty acids)  Glycoproteins, such as mucin (when combined with water mucin is called mucus)  Antimicrobial factors  Lysozyme - breaks down the bacterial cell wall  Lactoferrin - chelates iron which prevents the multiplication of bacteria as iron is required for bacterial growth  Functions of Saliva:  Moistens and lubricates the food to make it easier to swallow  Initiates digestion with digestive enzymes (amylase and lipase)  Dissolves a small amount of food to allow it to diffuse to the taste buds   Prevents microbial colonization due to the presence of antibacterial factors  Aids in speech  Buffers - contains bicarbonate which helps to neutralize acid from food or acid reflux Lecture 2 recording 11: Formation of Saliva and Regulation of Salivary Gland Function  Anatomy of the Salivary Glands:  Structure of a salivary gland or a salivary duct: o Salivary glands are made up of many microscopic ducts that branch out from grossly visible ducts o Composed of 3 different cell types: acinar cells, ductal cells, myoepithelial cells (Myo = “of muscle”)  Acinar cells → secrete the initial saliva  Ductal cells → create the alkaline and hypotonic nature of saliva  Myoepithelial cells → have characteristics of both smooth muscle (can contract) and epithelial cells o Saliva moves from the acinus to the striated duct; myoepithelial cells contract to constrict the acinus end of the duct and move the components of the saliva towards the striated duct  Formation of Saliva:  Tight junctions: o Acinar cells have tight junctions between them which are leaky and allow the passage of water and small ions through them o Ductal cells have tight junctions which do not allow the passage of water through  Saliva is hypotonic and alkaline: o All of the components of saliva are pumped into, or passed into, the lumen of the acinus o The primary secretion from the acinar cells is not yet alkaline or hypotonic; it is isotonic (has a similar osmolarity to the blood)  The primary secretion will contain sodium, potassium, chloride, bicarbonate and water  Enzymes, as well as mucous, are produced within the acinar cells and added to the saliva through exocytosis  Acinar cells have very leaky tight junctions; electrolytes in the primary secretion (bicarbonate, chloride and potassium) are actively secreted into the saliva and sodium and water can follow between the cells into the saliva through the leaky tight junctions  Movement of substances between cells = paracellular transport  Primary secretion is isotonic because there is no limitation to the passage of sodium and water through the leaky tight junctions  Myoepithelial cells contract to push the saliva into the region where there are ductal cells   Ductal cells modify the saliva to form the hypotonic and alkaline saliva Sodium and chloride are actively taken up into the cells from the saliva and there is a net gain of potassium and bicarbonate; saliva is hypotonic due to loss of sodium and chloride  Bicarbonate makes the saliva basic or alkaline  Formation of Saliva: A Summary: (This is a summary of the previous slides)  Acinar cells → secrete the initial saliva o Water, electrolytes, and proteins (Enzymes and mucous)  Proteins are released by exocytosis  Cl-, HCO3- and K+ are actively secreted  Na+ and H2O follow paracellularly via (Leaky) tight junctions  Initial secretion is isotonic (Ionic composition comparable to plasma) due to leakiness of acinar cell layer  Myoepithelial cells contract and expel formed saliva from acinus into the duct  Ductal cells → modify the initial saliva to a hypotonic, alkaline state o Net loss of Na+ and Cl- (Active reabsorption) o Addition of K+ and HCO3- (Active secretion); to a lesser extent o Duct cells are tightly joined and impermeable to H2O  Regulation of Salivary Gland Function:  Regulation of saliva production: o No hormonal regulation o Regulated by parasympathetic and sympathetic pathways  Both stimulate salivary secretion  Parasympathetic stimulation:  Dominant regulatory pathway  Increases blood flow to the salivary glands resulting in increased secretion of saliva; blood flow provides the metabolic and fluid requirements to sustain high rates of secretion Important for protein secretion from acinar cells, Stimulates myoepithelial cells to contract to increase flow of saliva  Regulation of Salivary Gland Function:  Parasympathetic pathways: o Stimulated by the smell and taste of food, by pressure receptors in the mouth and during situations of nausea o Can be inhibited and reduce salivary production by tiredness or fatigue, during sleep, fear, dehydration o Some drugs have a dry mouth side effect ( psychiatric drugs have anticholinergic effects and reduce parasympathetic stimulation of the salivary glands)   Sympathetic pathways: o Stimulatory but is minor o Increases saliva flow o Increase protein secretion from the acinar cells and stimulate the myoepithelial cells to contract to increase flow Lecture 3 recording 12: Role of Saliva in Digestion  Role of Saliva in Digestion:  Amylase: o Found in saliva o An enzyme that can breakdown starches o Also called ptyalin o Inhibited by the acidic pH in the stomach once swallowed o Greater than 95% of carbohydrates consumed are digested in the small intestine by pancreatic amylase  Role of saliva in digestion is very small  Plant starch is made up of glucose polymers including amylose and amylopectin  Polymer → a large molecule made up of many repeated subunits o Amylose → a straight chain of glucose molecules with alpha-1,4 linkages o Amylopectin → chain of glucose molecules with alpha-1, 4 linkages as well as alpha-1,6 linkages o Amylase → can only cleave the internal alpha-1, 4 linkages o Amylose → breakdown leads to the formation of maltose (disaccharide) and maltotriose (trisaccharide) o Amylopectin → breakdown leads to the formation of maltose, maltotriose and alpha-limit dextrin  Amylase can only cleave the alpha-1,4 linkages; it cannot cleave the alpha-1,6 six linkages so it generates these branched glucose molecules in alpha-limit dextrin  Role of Saliva in Digestion:  Lingual lipase: o Found in saliva o Stable in acid - can remain active in the stomach  Amylase and lingual lipase: o May be more important during pathological conditions where there is reduced pancreatic activity  Pancreatic secretions include digestive enzymes o Important for neonates as they tend to have immature digestive systems  Salivary Pathophysiology (Xerostomia “dry mouth”):  Conditions where salivary secretion is impaired: o Congenital o Sjögrens syndrome - autoimmune disease; the immune system destroys the salivary glands  o Side effects of drugs - antidepressants, psychotropic, antihypertensives, anti- cancer drugs o Radiation treatment  Xerostomia = dry mouth  Salivary Pathophysiology (Xerostomia “dry mouth”):  Consequences impairment to salivary secretion: o Dry mouth o Decreased oral pH  Tooth decay  Esophageal erosions as there is no saliva to neutralize the stomach acid that is coming up into the esophagus o Difficulty in lubricating and swallowing food  Treatment: o Frequent sips of water and fluoride treatment to combat the microbial populations which flourish in the absence of saliva Lecture 3 recording 13: Swallowing and the Esophagus  Swallowing:  Swallowing: o A series of reflexes o Initiated by pressure receptors in the wall of the pharynx  Pharynx → the passage at the back of your throat that is common to air and food  Receptors are stimulated by food or liquid entering the pharynx and send signals to the swallowing centre in the brainstem which signals muscles in the pharynx, the esophagus and the respiratory muscles  Swallowing: (You do not need to memorize the function of the pharynx, larynx, glottis, epiglottis…they are given to help understand the process of swallowing)  Pharynx → the passage at the back of your throat that is common to air and food  Larynx → air passage between the pharynx and the trachea; voice box as it contains the vocal cords  Glottis → area in the larynx around the vocal cords, where the air passes through the vocal cords  Epiglottis → flap of cartilage that closes off the trachea when swallowing so food cannot enter the lungs  Chew food → tongue pushes it to the back of throat→ soft palette elevates to stop food from entering nose → impulses from the swallowing centre inhibit respiration, raise the larynx and close the glottis → epiglottis covers the trachea to prevent fluid or liquid from entering the trachea → food descends into the esophagus  Esophagus:  Esophagus:  o A tube containing skeletal muscle in the top 1/3 and smooth muscle in the lower 2/3 o No absorption in the esophagus o Mucus is secreted to lubricate and aid in the passage of the food. o Stratified squamous epithelium  Layers of flattened cells, or stratified cells  Stratified = in layers (compare to squamous = flattened  Protect the underlying regions of the esophagus from food  Esophagus:  Upper esophageal sphincter just below the pharynx o Ring of skeletal muscle  Lower esophageal sphincter located where the esophagus joins the stomach o Ring of smooth muscle  Both of sphincters are closed except when swallowing, vomiting or burping  Esophageal Phase of Swallowing:  Upper esophageal sphincter relaxes to allow the food to pass through → sphincter closes and glottis opens to breathe again → peristaltic waves move the food bolus down the esophagus towards the stomach (~ 5 - 9 seconds) → lower sphincter at the stomach opens and allows food to pass through → sphincter closes  Main force for this swallowing phase is peristalsis o Gravity not necessary for this phase of swallowing  Heart Burn:  Lower esophageal sphincter prevents gastric contents from reaching the esophagus o Aided by the equal pressure of the lower esophagus and the stomach (no pressure gradient forcing the gastric contents out)  When small amounts of acid get into the esophagus: o Stimulation of peristalsis to push the acid back into the stomach o Increased salivary secretion o Aids with neutralization of the acid with saliva and clearance of the acid out of the esophagus  Heartburn: o Lower esophageal sphincter does not close properly o A big meal o During pregnancy Lecture 3 recording 14: The Stomach  The Stomach:  Muscular organ  A sac located between the esophagus and the small intestine  Functions: o Storage of food o Mechanical breakdown of food (breaking food into smaller pieces) o Chemical breakdown of food  Secretes pepsinogen   Cleaved to form an enzyme called pepsin Pepsin is important for initiating protein digestion  Secretes hydrochloric acid (HCl)  Dissolves food and partially digests macromolecules in food o These different steps reduce the food to fragments of proteins and polysaccharides, droplets of fat, salt and water, which is referred to as chime  HCl also results in the “partial” sterilization of food  More Stomach Functions:  Functions: o Controls the rate at which food enters the small intestine o Secretes intrinsic factor  A glycoprotein important for the absorption of Vitamin B12 in the ileum  Vitamin B12 is required for normal red blood cell formation  Fail to absorb Vitamin B12 can result in pernicious anemia and red blood cell deficiency  Very little absorption occurs across the stomach - the stomach is not an absorption phase o Alcohol can be absorbed across the stomach and a small amount of water  Stomach Components:  Anatomy of the stomach: o Fundus and body:  Upper part of stomach  Both have thin layer of smooth muscle  Mucus, pepsinogen and hydrochloric acid are secreted o Antrum:  Lower region of the stomach  Thicker smooth muscle layer  Important for physically breaking down, mixing and grinding food  Mucus, pepsinogen and gastrin are secreted  Pyloric sphincter → controls emptying of the stomach  Secretions of the Stomach:  Exocrine → a chemical messenger secreted into ducts and then onto an epithelial surface without passing into the blood o Endocrine requires passage into the blood o Major exocrine secretions of the stomach include mucus, hydrochloric acid and pepsinogen:  Mucus → protects the stomach epithelium from acid and digestive enzymes, predominantly pepsin  Helps to avoid self-digestion  HCl → important for the hydrolysis (breakdown) of proteins into their component amino acids, dissolving food, digesting macromolecules and sterilization of food  Pepsinogen → precursor to the enzyme pepsin which is important for the digestion of proteins   Secretions of the Stomach:  Minor secretions of the stomach: o Intrinsic factor for Vitamin B12 absorption o Gastrin (endocrine)  A hormone important for stimulating HCl production and increasing stomach motility o Histamine (paracrine)  Stimulates HCl production o Somatostatin (Paracrine)  Inhibits HCl production Lecture 3 recording 15: Cell Types of the Stomach  Generalized Gastric Gland:  Generalized gastric gland → it is called generalized because some of these cell types are not found in all regions of the stomach  Mucous cell o At luminal end of gland o Produce mucus to protect the stomach lining from cell digestion  Parietal cell o Secretes intrinsic factor and hydrochloric acid (HCl) o Found mostly in the body and the fundus of the stomach (not found in the antrum)  (Remainder of cells (chief cell, enteroendocrine cell, ECL cell, D cell) will look at more detail in next slides)  Cell Types and their Functions:  Chief cell o Found in gastric glands in all regions of the stomach o Secretes pepsinogen  Pepsinogen is an inactive precursor to pepsin  Zymogen is a precursor for a protein that is not active and some type of chemical reaction needs to occur to make it active  Pepsinogen is cleaved by stomach acid to pepsin  Pepsin accelerates protein digestion  Enteroendocrine cell o Found in gastric glands in the antrum o Also known as G cells o Secretes gastrin (hormone)  Stimulates HCl production by the parietal cell  Stimulates GI motility  Cell Types and their Functions:  Enterochromaffin-like cell (ECL cell) o Found in gastric glands in all regions of the stomach (More in antrum) o Secretes histamine  Histamine stimulates HCl production   D-cell o Found in gastric glands in all regions, but more are found in the antrum o Secretes somatostatin  Regulator that negatively regulates HCl production  Parietal Cell:  Found in gastric glands in the fundus and body regions of the stomach  Also called oxyntic cell  Secretes HCl and intrinsic factor  Modified surface with canaliculi o Canaliculi increase the surface area of the cells to maximize the secretion of the acid and intrinsic factor into the lumen of the stomach o An inactive parietal cell has much less defined, or smaller, canaliculi o As the parietal cell is activated, the canaliculi become more defined  Movement of membrane to the canaliculi, distending them and greatly enlarging them, and insertion of proton pumps  Many mitochondria to produce ATP required for active acid secretion Lecture 3 recording 16: Acidification of the Stomach Lumen and Pepsinogen Release  Acidification of the Stomach Lumen:  Transporters and channels acidify the stomach lumen while maintaining a neutral pH in the cell  Acidification of the Stomach Lumen:  Parietal cell o Apical surface faces the stomach lumen o Na+/K+ ATPase  Pumps 3 Na+ out of the cell and pumps 2 K+ into the cell for every molecule of ATP hydrolyzed  Establishes electrochemical gradients with a high concentration of K+ inside the cell and a low concentration of Na+ inside the cell o H+/K+ ATPase:  Apical/luminal membrane of the parietal cell  Pumps out a proton (acid) from the parietal cell into the stomach lumen  Primary active transport pathway (ATP is hydrolyzed)  As acid is leaving the parietal cell, the cell will become more basic  Mechanisms prevent the cytosolic pH of the parietal cell from becoming too basic o Carbonic anhydrase:  Parietal cell gets rid of base by removing bicarbonate (HCO3 = bicarbonate, a base)  Catalyzes the formation of H2CO3 (carbonic acid) from H2O and CO2 (CO2 is produced during metabolism)  H2CO3 dissociates into H+ (For secretion into lumen) and HCO3- o Cl-/HCO3- exchanger:   HCO3- is pumped out in exchange for a chloride ion (Cl-) (secondary active transport) o K+ channels:  As protons are pumped out through the apical primary active transporter, K+ levels increase in the cytosol; K+ channels in the apical surface open and allow K+ to leave the cell down its concentration gradient  Diffusion through channels  Loss of positive charge with every K+ ion lost; must lose a negative charge to compensate through the loss of Cl- o Cl+ channels:  Apical membrane  Cl- lost into lumen of stomach as diffuses through Cl- channel  Compensates for loss of positive charge through K+ channels o HCl is secreted into the lumen of the stomach as a proton leaves the cell through the apical H+/K+ ATPase and Cl- through the Cl- channel  Acidification of the Stomach Lumen (2 slides): (Summary of transporters/channels involved in acid secretion from parietal cell)  Regulation of Acid Secretion:  Regulatory components to acid secretion: o Chemical messengers regulate the insertion of the H+/K+ ATPase into the plasma membrane of the parietal cell  4 chemical messengers that regulate insertion:  Gastrin:  Gastric hormone released by G cells  Stimulates insertion of the H+/K+ ATPase into the membrane, stimulating HCl secretion  Acetylcholine:  Neurotransmitter Increased parasympathetic activity causes the release of acetylcholine increases insertion of the H+/K+ ATPases into the cell membrane, stimulating acid production  Histamine: Paracrine released from the ECL-cells  Stimulates insertion of the H+/K+ ATPase into the membrane, stimulating acid secretion  Somatostatin:  Paracrine released from D-cells Inhibits the release of HCl, gastrin and histamine   Histamine potentiates the effects of gastrin and acetylcholine to stimulate acid production  Pepsinogen Secretion and Activation:  Pepsinogen: o Secreted by chief cells as an inactive precursor o Release is stimulated by the enteric nervous system o Parallels the release of HCl o Cleaved and activated to pepsin by acidic pH in the lumen  Release of an inactive precursor is a mechanism to prevent autodigestion  Pepsin is irreversibly inactivated in SI Lecture 4 recording 17: Regulation of Gastric Secretions  The Phases of Gastric Secretion:  Regulation of stomach secretion is divided into 3 phases: cephalic phase, gastric phase and intestinal phase o Cephalic phase → stimulation in the brain  Sight, smell or taste of food provides excitatory stimulation mainly via the vagus nerve to the stomach  Vagal nuclei in the brain cause the parasympathetic nerve to release acetylcholine at the parietal cell; results in the stimulation of acid production o Gastric phase → occurs when food reaches the stomach  Major phase for regulating acid production  Stimulatory phase mediated mainly via the release of gastrin  Food in the stomach causes G cells to release gastrin into the blood  Gastrin interacts with the parietal cell to increase acid production o Intestinal phase → occurs when food that has been partially broken down by the stomach enters the SI (duodenum)  Inhibitory phase  Mainly inhibitory due to the presence of acid, fat, digestion products and hypertonic solutions in the duodenum  Mediated by gastrointestinal hormones including secretin and CCK  Secreted by small intestinal epithelial cells  Enter the blood and have a negative influence on gastrin production  Regulation of Gastric Secretion: Interaction Between Various Factors:  4 chemical messengers that regulate the insertion of the H+/K+ ATPase into the plasma membrane of the parietal cell: gastrin, ACh, histamine somatostatin  Parietal cell produces acid: o ACh, histamine and gastrin directly stimulate acid secretion o Somatostatin negatively regulates acid secretion  Indirect effects on acid secretion from parietal cell: o ACh:   Stimulates ECL cells to release histamine which stimulates the parietal cell  Inhibits somatostatin production from the D cells to stimulate acid secretion  Stimulate G cells to produce gastrin which stimulates acid secretion o Gastrin:  Stimulates ECL cells to release histamine which stimulates the parietal cell  Once acid secretion is occurring at a high rate: o ACh is released from the parasympathetic nerves  As eating and acid production are occurring, the stimulation will be reduced o Acid production itself has a negative effect on gastrin release  H+ released from the parietal cell inhibit gastrin release from G cells o Somatostatin:  Somatostatin inhibition by ACh is reduced as ACh levels decrease  Has a direct negative effect on the parietal cell and inhibits acid secretion from the parietal cell  Can inhibit histamine release from the ECL cells  Can inhibit gastrin release from the G cell  Regulation of Gastric Secretion: Interaction Between Various Factors (2 slides): (Summary of the diagram) Lecture 4 recording 18: Gastric Motility  Gastric Motility:  Important for breaking down food  Huge capacity to stretch o After you consume of a meal, smooth muscle in the stomach relaxes, allowing the stomach to increase without increasing pressure o This relaxation is mediated by the parasympathetic nerves to the enteric nervous system  Arriving food causes peristaltic wave: o Weak contractions in the body of the stomach o Antrum powerfully contracts to allow the mixing of the luminal contents and closes the pyloric sphincter  Pyloric sphincter → sphincter between the antrum and the duodenum  Closure of the sphincter results in a small amount of stomach contents reaching the duodenum, but most is retained and forced backwards towards the body of the stomach to allow more mixing to occur  Gastric Motility:  A peristaltic wave in the body of the stomach and a stronger force of contraction in the antrum will result in the pyloric sphincter closing  o A small amount of chyme will enter the duodenum; the backwards flow of contents towards the body of the stomach allows mixing due to this muscle contraction  Electrical Basis of Stomach Motility:  Stomach has pacemaker cells in the smooth muscle layer: o Spontaneous slow waves of depolarization and repolarization  Spontaneous slow waves are the basic electrical rhythm  In the absence of neural or hormonal input, the basic electrical rhythm does not cause any contractions as depolarizations are too small  The basic electrical rhythm allows the timing of contractions  Excitatory hormones and neurotransmitters will act upon the smooth muscle to further depolarize the membrane, resulting in contraction o Amount of stimulus determines strength of the contraction o The frequency of the contraction is determined by the basic electrical rhythm Lecture 4 recording 19: Gastrointestinal Complications  Vomiting:  Cause of vomiting: o Psychogenic o Gastrointestinal disturbances o Inner ear infections o Chemoreceptors in the brain and the gastrointestinal tract that can detect toxins o Pressure in the CNS  All of the different stimuli feed into the vomiting centre located in the medulla oblongata  Nausea, salivation, breath held in mid-inspiration  Glottis closes off trachea  Lower esophageal sphincter and esophagus relax  Diaphragm and abdominal muscles contract  Reverse peristalsis moves upper intestinal contents into stomach  Stomach contents move up through esophagus and out through mouth (Soft palate is raised)  Vomiting: Beneficial and Negative Consequences:  Benefits: o Remove harmful substances before they are taken into your body o Nausea and feeling bad associated with vomiting are a negative conditioning, so that if you experience these, they may prevent you from consuming the noxious substance again  Negative consequences: o Dehydration o Electrolyte imbalance o Metabolic alkalosis → a condition in which the pH of a tissue is elevated beyond the normal range, due to the loss of acid from your stomach  o Acid erosion of tooth enamel  Ulcers:  Peptic ulcers: o Damage to or erosion of the GIT mucosa o Occurs in regions which are acidic such as the esophagus, the stomach or the duodenum  What causes an ulcer? o Imbalance of aggressive factors (acid and pepsin) and protective factors (mucus and bicarbonate) o Most common cause of ulcers: infection from the bacterium Helicobacter pylori, which results in inflammation of the lining and irritation and eventually chronic inflammation and erosion o Non-bacterial factors: non-steroidal anti-inflammatory drugs which reduce prostaglandin production, smoking, excessive alcohol, gastrinomas  Ulcers:  Treatment for ulcers: o Antibiotics to get rid of the H. pylori infection o H+/K+ pump inhibitors o Histamine receptor antagonists o Prostaglandin-type drugs  Ulcers:  An ulcer can occur in the esophagus, stomach, duodenum  Gastric Bypass Surgery:  Is the stomach essential for life? o No, it is not essential, but problems can occur without it o What problem would occur if you had a very small stomach or a stomach removed?  Stomach is important for producing intrinsic factor  Intrinsic factor is secreted by the stomach lining and aids in vitamin B12 absorption  People that have lost a lot of their stomach must have Vitamin B12 injections so they do not become anemic  Stomach is useful for reducing the amount of bacteria that enter your system- HCl the stomach secretes sterilizes food  Stomach regulates how much food enters the SI Lecture 4 recording 20: The Pancreas  The Pancreas:  An exocrine and endocrine gland  Exocrine pancreas: o Important for digestion o Produces secretions that go into the GIT o Source of the majority of enzymes required for digestion of carbohydrates, proteins, fats and nucleic acids  o Problems with digestion and absorption will not be noticed until the organ function falls below 10% o Secretes bicarbonate into the duodenum for neutralization of stomach acid  Digestive enzymes produced by the pancreas are completely inactive under acidic pH  The stomach acid must be neutralized by bicarbonate for these enzymes to be functional  Endocrine pancreas: o Not involved in digestion but it is important for producing hormones that regulate the entire body (eg. Insulin)  Functional Anatomy of the Pancreas:  Main pancreatic duct drains the exocrine secretions into the SI o Main pancreatic duct joins common bile duct from the liver just before entering duodenum  Sphincter of Oddi (hepatopancreatic sphincter) → sphincter common to the bile duct and to the main pancreatic duct o Regulates the release of both liver and pancreatic contents into the SI  Exocrine pancreas → secrete substances into ducts that drain onto the epithelial surface, or the apical surface, and converge into the pancreatic duct o Secretions ultimately enter the SI  Endocrine pancreas → is a ductless gland o Secretion occurs across the epithelial basolateral surface for diffusion into blood o Endocrine cells surround capillaries o Eg. Insulin  Pancreatic islets (Islets of Langerhans) produce the hormone insulin  Pancreatic Ducts:  Acinar cells: o Pancreatic ducts have acinar cells at the end portion of the duct o Produce and secrete digestive enzymes  Exocytosis of vesicles within the acinar cells  Ductal cells: o Secrete bicarbonate for neutralization of acid o Water is also secreted  Pancreatic Juices:  Pancreatic juices: o Isotonic and alkaline  Alkaline because of bicarbonate (HCO3-) o Electrolytes:  High in HCO3- and low in Cl-  Na+ and K+ concentrations are the same as in plasma (this is why pancreatic juice is isotonic; iso = same)  HCO3- and water are secreted by duct cells  HCO3- neutralizes gastric acid in duodenum o Contain digestive enzymes:   Essential for the digestion of proteins, carbohydrates, fats and nucleic acids  Secreted by acinar cells  Proteolytic enzymes (break down proteins into amino acids) are stored and secreted in inactive forms  Activated in the duodenum Lecture 4 recording 21: Production of HC03- in the Pancreas and Tides  Production of HCO3- by Pancreatic Duct Cells:  How do the ductal cells of the pancreas produce the alkaline, watery solution? o Cl- channel:  Apical (luminal) surface of the ductal epithelium  CFTR  Cl- channel  Cystic fibrosis transmembrane conductance regulator  Allows Cl- to diffuse out of the duct cell into the lumen o Cl- that has diffused out of the channel is then exchanged for HCO3-:  In the pancreas HCO3- (base) leaves the cell  Carbonic anhydrase catalyzes the formation of carbonic acid (H2CO3) from CO2 and water  H2CO3dissociates into HCO3- and H+. and this HCO3- is the base that is moved into the duct lumen o Neutral pH of cytosol is maintained by exchange of H+ (Exported from cell) for Na+ (Imported)  Na+/H+ exchanger  Secondary active transport pathway where Na+ moving down its concentration gradient provides the energy to efflux H+ from the cell  Na+ gradient is provided by the Na+/K+ ATPase o Cl- gradient into the duct lumen draws Na+ and water paracellularly, or between the cells  Ductular Cell Secretion of HCO3-: (Summary of previous slide)  Alkaline and Acid Tide:  After a meal: o Acid is being produced by the parietal cell and enters the lumen of the stomach o Base leaves the cell into the bloodstream as bicarbonate (HCO3-) o Whatever is moving into the blood is referred to as the tide  In the stomach, a large amount of bicarbonate (alkaline) is pumped across the basolateral surface into the blood  Alkaline tide  Alkaline and Acid Tide:   In the pancreas, the duct cells are producing base as bicarbonate, which is moving into the lumen of the pancreatic ducts  Large amounts of acid are being pumped across the basolateral surface into the blood stream o Acid tide  Alkaline and Acid Tide:  In the stomach, acid is produced by the parietal cells and secreted into the stomach lumen, resulting in base moving into the blood  In the pancreas base moves into the lumen while acid moves into the blood  While the process is first initiated in the stomach, the two processes occur simultaneously o Eventually, HCO3- which is released into the blood from the stomach and the acid that is released into the blood from the pancreas meet up in the portal vein o These two separate processes will compensate for each other and maintain the acid-base balance in the blood stream Lecture 5 recording 22: Digestive Function of the Pancreas  Digestive Function of the Pancreas:  Pancreas: o Source of the major enzymes required for digesting carbohydrates, proteins, fats and nucleic acids  Starve without pancreas  Proteases → enzymes that digest proteins into peptides and amino acids  Amylolytic enzymes → digest starches into sugars  Lipases → digest triglycerides into free fatty acids and monoglycerides  Nucleases → digest nucleic acids into free nucleotides  Enzymes are synthesized and packaged into vesicles by pancreatic acinar cells  Enzymes are packaged as proenzymes into zymogen granules that are stored at the apical pole of the acinar cell until appropriate stimuli causes exocytosis  Zymogens = proenzymes or inactive precursor enzymes  Secretion of Digestive Enzymes:  Most pancreatic enzymes secreted as inactive forms o Activated in the duodenum  Enterokinase:  Enzyme  Enterokinase is attached to the apical, or luminal, surface of the epithelial cells in the duodenum  Cleaves a pro-protease called trypsinogen into the protease trypsin Trypsinogen is an inactive precursor molecule  Trypsin activates other enzymes  Prevention of Autodigestion Under Normal Conditions:  Pancreas produces and stores proenzymes: o Proenzymes are not activated until they reach the SI  Pancreas secretes a variety of trypsin inhibitors to prevent any premature activation of trypsin  Trypsin can also degrade itself if it is activated prior to reaching the SI  The Major Proteases Secreted by the Pancreas:  Enzymes which form a mixture of peptides and amino acids: o Endopeptidases:  Trypsinogen → activated by enterokinase in the duodenum to trypsin  Trypsin important as it activates other enzymes  Chymotrypsinogen → activated by trypsin to the active enzyme chymotrypsin  Pro-elastase → activated by trypsin to the active enzyme elastase o Exopeptidase:  Pro-carboxypeptidase A and B → activated by trypsin to the active enzyme carboxypeptidase A and B  Amylolytic and Lipolytic Enzymes:  Amylolytic enzymes: o Pancreatic amylase cleaves starches to sugars  End product of this digestion is disaccharides and trisaccharides, maltose, maltotriose and alpha-limit dextrins  Lipolytic enzymes: o Lipase → hydrolyzes triglycerides into free fatty acids and monoglycerides o Phospholipase A2 → hydrolyzes phospholipids into free fatty acids and lysophospholipids o Cholesterolesterase →hydrolyzes cholesterol-esters into free fatty acids and cholesterol  Some enzymes are secreted as active enzymes while others are secreted as inactive forms Lecture 5 recording 23: More on Pancreatic Secretions  Regulation of Pancreatic Juice Secretion:  Pancreatic juice secretion: o Primarily mediated by food and acid entering the SI o Cells in the epithelial layer of the duodenum:  S-cells → acid entering the duodenum from the stomach stimulates S- cells to produce the hormone secretin  Secretin → hormone released into the blood and finds its way to the pancreatic duct cells where it stimulates the release of HCO3-   I-cells → digested fats and protein are entering into the upper SI from the stomach stimulate I-cells to release the hormone cholecystokinin (CCK)  CCK → released into the blood and acts on the acinar cells in the pancreatic duct to stimulate the zymogen granules to release the digestive enzymes  Activity in parasympathetic nerves will also cause the release of digestive enzymes o When you are hungry and you smell food  CCK As an Example:  Fatty acids and amino acids in the SI trigger the secretion of CCK from cells in SI into the blood  CCK: o Stimulates the pancreas to increase the secretion of digestive enzymes o Stimulates the gallbladder to contract  Release of bile acids for fat breakdown  Sphincter of Oddi relaxes  As the fats and amino acids are absorbed, the stimuli for CCK release is removed, as it is the fats and amino acids themselves in the SI that trigger CCK secretion o A negative feedback control system  Secretin Regulation of Pancreatic HCO3- Secretion:  Acid entering the duodenum from the stomach stimulates secretin secretion from cells in the SI into the blood o Circulating secretin stimulates:  Pancreas (Duct cells) to increase HCO3- secretion  Liver (Duct cells) to increase HCO3- secretion o The stomach acid is neutralized and the stimulation of secretin release is stopped  A negative feedback control system  Secretin and CCK Influence on the Stomach:  Secretin and CCK both inhibit gastrin secretion o Results in reduced stomach motility (slows stomach emptying) and reduced acid secretion  The Phases of Pancreatic Secretion:  Cephalic phase → involves stimulation that is occurring in the brain o Sight, smell, and taste of food stimulate pancreatic secretion via the parasympathetic nerves  Gastric → distension of the stomach will stimulate the pancreatic secretion via the parasympathetic nerves  Intestinal phase → major regulatory phase of pancreatic secretion o Acid from the stomach in the duodenum stimulates secretin release and digested fat and protein in the duodenum stimulate CCK release  Pancreas and Cystic Fibrosis:  The Cl- channel involved in HCO3- secretion in the pancreas is the channel that is mutated in the disease cystic fibrosis   Cystic fibrosis: o A defective chloride channel is produced o Patients suffer from pancreatic insufficiency  Produce all of the digestive enzymes  HCO3- and water secretion is so minimal that these enzymes do not get flushed from the ducts and do not reach the intestines  The retained proteolytic enzymes, which break down proteins, can result in pancreatic autodigestion  The cystic ducts in the pancreas are fibrotic because of constant autodigestion and inflammation  Patients must receive supplements of digestive enzymes and antacids to allow for adequate nutrition Lecture 5 recording 24: The Liver  The Liver and Biliary System Components:  Gall bladder → a small sac located underneath a lobule of the liver  Bile ducts run from the liver and join to form the common hepatic duct, which then joins with the common bile duct  Main pancreatic duct and the common bile duct join and release their contents into the duodenum o Sphincter of Oddi controls the release of contents into the SI  Blood Flow in the Liver:  Liver: o Receives blood by 2 distinct circulatory routes: the systemic circulation and the hepatic portal circulation  Systemic supply = arterial blood  Hepatic artery contributes ~ 25% of the blood volume entering the liver  Blood → oxygen rich but nutrient poor  Hepatic portal circulation = venous blood  Hepatic portal vein brings blood from the stomach, spleen, pancreas and intestines Contributes ~ 75% of the blood volume to the liver Blood → nutrient rich, oxygen poor o As blood flows into the liver, there is mixing of the venous and arterial blood  Hepatic and Lobule Structure:  Hepatic lobule: o Functional unit of the liver o Hexagonal structure with a central vein running through the centre and a portal triad in each corner  More Detailed Structure of a Lobule:  Portal triad: o Consists of a hepatic artery, a hepatic portal vein, and a bile duct  Hepatocytes:  o Epithelial cells of the liver o Form tube like structures called canalicular networks  Canalicular networks conduct bile produced by hepatocytes  Join together until they form bile ducts  Venous blood of the hepatic portal system and arterial blood are mixed within hepatic sinusoids and then flows slowly toward the central vein  Microanatomy:  Bile components produced by the hepatocytes are put into the canalicular networks  Bile components flow towards the bile ducts  Blood flow occurs on the other surface of the hepatocyte Lecture 5 recording 25: Functions of the Liver and Bile  Major Functions of the Liver:  Liver: o Exocrine gland  Formation and secretion of bile  Bile → breakdown of fat o Metabolizing and storing nutrients  Matching supply to demand o Deactivation and detoxification o Producing circulating proteins  Eg. Blood coagulation factors and lipoproteins  Constituents of Bile:  Bile contains 6 major components o Bile acids → made within the hepatocyte from cholesterol  Emulsification of fats  Chemicals that are amphipathic that are important for allowing other enzymes to digest the fat o Cholesterol o Salts (sodium, potassium and bicarbonate) and water o Phospholipids  Important for the breakdown of fat o Bile pigments  Bilirubin → breakdown product of heme o Trace metals  Role of Bile in Fat Digestion:  Bile works with the pancreatic enzyme lipase o Pancreatic lipase is a water-soluble enzyme and can only work on the surface of the lipid droplets o Large lipid droplets need to be made smaller so that pancreatic lipase can access them  This process is called emulsification  Emulsification requires: o Mechanical disruption to make the lipid droplets smaller  o Emulsifying agent to prevent droplets from re-aggregating  2 things contained in bile that do this: amphipathic bile acids and phospholipids  Role of Bile in Fat Digestion:  Micelle: o Polar head groups facing the outside in contact with the aqueous solution and nonpolar groups facing the inside o Composed of only a single layer  Bile acids also form “mixed micelles” with phospholipids and products of lipase digestion (Free fatty acids and monoglycerides) o Soluble clusters of amphipathic molecules  Micelle Function:  Fatty acids and monoglycerides are very insoluble in water o A few molecules exist in solution and are free to diffuse into the enterocyte o Free monoglycerides and the fatty acids can diffuse into the intestinal epithelial cells o The majority of the breakdown products of fat digestion are held in micelles which keep the monoglycerides and fatty acids in small soluble aggregates o Fatty acids and monoglycerides in the micelles are in equilibrium with the small amount of fatty acids and monoglycerides free in solution  The micelle is broken down and reformed; small amounts of free fatty acids and monoglycerides can be absorbed by the SI by diffusion across the SI epithelium  An emulsion droplet is held in solution and not allowed to re-aggregate with other droplets due to the bile salts and phospholipids o Increases the surface area for the water soluble pancreatic lipase to have access to these fat droplets o Lipase breaks down the triglycerides into monoglycerides and fatty acids o A small number of monoglycerides and fatty acids can exist in an aqueous solution but are rapidly absorbed by the SI epithelium while the majority of them exist in micelles o As micelles break down and reform, some of the monoglycerides and fatty acids are released and this allows their absorption  Formation of Bile:  Hepatocytes: o Produce and secrete bile acids o Secrete phospholipids, cholesterol and bile pigments into the bile canaliculi  Bile duct cells: o Add bicarbonate and other salts and water to the bile  Gallbladder is important for storing and concentrating bile between meals and releasing it when chyme enters the duodenum Lecture 6 recording 26: Bile Acids  Enterohepatic Circulation of Bile Acids:   Bile acids: o Conserved by the body o Recycling of bile acids occurs through the enterohepatic circulation o Produced by hepatocytes in the liver o Secreted into canalicular networks o Bile components are stored in the gallbladder or are directly secreted into the intestine  In the intestine, bile components will act on the meal and move from the duodenum, to the jejunum and to the ileum o Ileum → reabsorption of bile acids back into the portal circulation o Portal vein carries the bile components back to the liver o Allows the secretion rate to greatly exceed the synthesis rate  Steps for Bile Acid Recycling:  Bile acids are released by the liver/gallbladder into the duodenum for fat digestion  Bile acids are reabsorbed across the small intestine (Ileum) into the portal circulation  Bile acids are transported back into hepatocytes  Step 1: Transport of Bile Acids from Hepatocyte to Bile:  Bile acids are synthesized within the hepatocyte and move across the apical surface of the hepatocyte o Bile acids are transported across the apical surface by a primary active transport pathway into the canalicular networks (requires ATP) o Canalicular networks drain into bile ducts and then enter gallbladder or directly into the SI  Step 2: Bile Acids Reabsorption from the Ileum:  In the small intestine: o Bile acids enter the small intestine lumen, digest the food and move through the SI to the terminal portion called the ileum o In the ileum, the bile acids move back into the portal circulation o Bile acids are absorbed across the epithelial cell (enterocyte) through a Na+- dependent secondary active transport pathway  Secondary active transport process is required to allow the bile acids to move from a region that is dilute, which is the intestinal lumen, across the apical membrane to a region that is more concentrated, which is the enterocyte o Bile acids then move by facilitated transport across the basolateral surface of the enterocyte into the portal blood  Step 3: Transport of Bile Acids from Blood into Hepatocyte:  Bile acids are in the portal blood and are carried into the hepatocyte predominantly through a secondary active transporter  The cycle can start over again with the transport of bile acids from the hepatocyte into the bile through a primary active transport pathway  Summary of Bile Acid Recycling:  (This slide puts all the steps together) Lecture 6 recording 27: More on the Liver  More About Enterohepatic Circulation:  Bile acids are made of cholesterol o May reduce cholesterol by preventing the reabsorption of bile acids  Oatmeal and other foods high in fiber will bind with bile acids so they are excreted in the feces  Drugs and toxins can enter the hepatic circulation  Regulation of Hepatobiliary Secretion During Intestinal Phase:  Regulated predominantly during the intestinal phase  By bile salts: o As more bile salts are absorbed from the ileum and return to the liver, more will be secreted back into the bile o Bile salt synthesis is reduced when the enterohepatic circulation is working well  By secretin: o Controls bicarbonate production not only in the pancreas but also in the liver o Produced and released by the S-cells in the duodenum  Its prod