NPB 114 MT #3 notes - Google Docs PDF

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Gastric secretion, gastric acid production, states of stimulation, pepsinogen secretion, injuries and inflammation, pancreas, pancreatic trypsin inhibitor, isotonic, components, small intestine morphology, villi, absorption process across the enterocytes, digestive enzymes on apical membrane, protei...

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Thursday 7/22/21: GASTRIC SECRETIONS (two functions) ● Protective (protects the mucosa of stomach from being destroyed by digestive secretion) ○ Mucus (mucins polymerizing themselves into mucus) + watery bicarb solution (forming a thin film under mucus to protect the stomach by parietal and chief cells) ● Digestive - damaging and can hurt cells ○ Hydrocholic acid (does not destroy proteins, fats, or carbs.. We need it to reduce bonds) we are getting rid of secondary, tertiary, and quaternary folds. It doesn’t break covalent bonds, it just hydrolizes weak/hydrogen bonds => this makes is easy to digest because it increases the surface area ○ Pepsin (protein digestion) - we don’t produce any enzymes to digest fats or cabs in the stomach ○ Intrinsic factor is secreted by the stomach and binds to vit b12 (IF to b12) is then absorbed in small intestine - it needs to be produced or else we get b12 deficiency 1. Gastric mucosa (where most secretions are coming from) a. Gastric pits found throguh out the entire region, mainly in body and fundus of stomach i. From a lateral perspective layer of stomach we find a deep tube (envaginations) w/ branches coming off of it ii. Linned w surface mucous cells 1. Produce bicarb and mucus (a very thin layer of bicarb on the surface of mucus cells and differectly above that is a thin layer of mucus) it serves as a protective layer. These could die soon so they need to be turned over every 1-3 days. iii. Interior of pit are neck mucous cells 1. Precursor cells that replace the linned surface mucous cells that are being removed 2. High mitosis rates - worried for lots of cell division because it can be transformed if its exposed to weird stuff (ulcerations, carcinogens, = cancer) iv. Parietal cells (2 different shapes) 1. Produces hydrochloric acid 2. Intrinsic factor (IF3) - binding to b12 v. Chief cells 1. Produce digestive enzyme - pepsinogen (precursor to pepsin the digestive enzyme) vi. G cells 1. Producing gastrin vii. Heterochromatin cell (ECL cell) 1. Produces histamine

2. Gastric acid production by parietal cell (histamine + gastrin is what allows us to produce acid) a. Apical membrane - faces the lumen of the GI pit where the acid is being secreted out of i. Rested state: 1. Has small invaginations known as canaliculi (little cannal) 2. Vesicles are close to apical membrane which have enzymes that are responsible for acid secretion and channels as well (storing the acid secreting machinery)

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Stimulated state 1. Vesicles fuse w/ apical membrane then translocates the acid -secreting machinery into the apical membrane ( Signals will make Vesicles are now fusing to the apical membrane which places the transport proteins at the apical membrane -> translocate the acid secreting machinery (channel and enzyme) into the apical membrane) 2. Hcl can now be secreted, so protons and chlorides are going to come out

Food associated stimuli will produce this (producing acid is exhaustive so we only do it when it’s absolutely necessary) -> it take about 10 min secretion of hcl Controllers that are mediating this response is: gastrin (+), histamine (+), and PNS (+) through acetylcholine (Ach)

GASTRIC ACID PRODUCTION

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Co2 + H2o H2Co3 H+ Hco3Exactly what goes on in the salivary gland except in the salivary gland we want the bicarb but in the stomach we want the proton Parietal cell: carbon dioxide comes out of the blood and react it w/ water which causes a dissociation of H2Co3 and bicarb is pumped out into the blood stream at the same time the chloride is being pumped into the cell and move through it’s channel into the lumen (half of Hcl) ● We want to take the proton and move it into the lumen. The mechanism is a :proton pump (like the salivary glands) H+ channel that moves H into the lumen is moving K+ into the cell. H+/K+ ATPase (stored in the membrane of the vesicle in conjunction w the chloride channel. When the signal is given and the vesicles fuse thats whats going to translocate all transporters to apical membrane, this puts lots of membrane in there which lets canaliculi to get longer and longer) ● There is a K+ channel right next to it which allows the K+ to just circle in and out of the cell The bicarb that is in the blood is most likely making the blood more alkaline. This can be a bad thing (lots vomiting means they are vomiting out the stomach acid = alkalosis so the pH of blood is >7.4 so we need to correct it through the pancreas) We used to think that the H and K pump was NHE but it’s not because the pharmacological treatments are not targeting NHE, they are targeting the pump that moves K and H (the actual proton pump)

1. Low secretory rates (BASAL SECRETIONS) - Isotonic

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Non-parietal secretion to maintain the integrity of epithelium we just need a bit of moisture a. In the absence of food stimuli i. At low secretory rates: high [Na], low [cl-] , same through out [k] no protons seen ii. At high secretory rates: low [Na], high [cl-] , same throughout and then gets a bit higher [k] protons match cl- level b. In blood/plasma i. Higher [Na], about the same [K+], about the same [cl-] no protons in blood b/c pH is at 7.4 in normal blood

2. High secretory rates a. Na+ drops b. K+ just slightly (sometimes we can’t measure) c. H+ and Cl- increases in stimulated state (forms hydrochloric acid) - Large volume - Slightly hypotonic: as we digest the food in the stomach we need to dilute the concentration w/ this solution before we empty it out. (parietal secretions) STATES OF STIMULATION for acid secretion ( we don’t want to induce this unless it’s absolutely necessary) 1. Cephalic phase of acid secretion - about 30% of acid production a. Sight, smell, taste, thinking and talking. (this has to be desirable) - stimuli b. Pns control (primary pathway downstream coming from the brain downstream that is inducing this is PNS control) vagal efferents are coming out - Input is coming into the nervous system into the brain stem. From the BS we are going to PNS pathways. There is an output (theory #1) pre ganglion neuron on post ganglionic that will synapse upon an enteric secreto motor neuron that is being activated (extrinsic pathway), this will talk to the parietal cell which will produce HCl in response.

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Pathway #2: there is a G cell (produces gastrin, g17 in response to food stimuli in a short path life of about 30 mis. and g34) gastrin is being released intot he blood stream and into the parietal cell which will allows us to have some gastrin to come out but there is also en enteric pathway by enteric endocrine effert (telling gcell to produce hormoone) and an inter neuron w some neg control that is not shutting it off but slightly inhibiting it. - Background inhibition that is occurring at low secretory rates (or at least its only inducing us to produce g34 and not 17 - g17 is allowing us to maintain the ____ of the GI system) (yellow) A #3 pathway is tuingin on an inhibitory interneuron by PNS which will inhibit the other inhibitory interneurons and as a result it removes the inhibition of (pink) the efferent endocrine g cell -> then there is positive

In regards to how gastrin (produced by g cell) is working 1. Making the vesicles fuse, gastrin will travel distance to bind a receptor on parietal cell and produce acid 2. Gastrin goes in the bloodstream and into an ECL to activate it. The ECL will then produce histamine. Histamine will bind to its receptor (H2 receptor) on the parietal cell and produce acid

We don’t produce acid as food is going down the esophagus b/c its not really stimulatory 2. Gastric phase - 50-70% of total response of acid secretion a. Food stimuli is in stomach i. Stretches and increases in lumen amino acids (and lumenal proteins (whole proteins are poor in inducing response. Single AA are better)) - all sensed by our sensory neurons ● Activate stretch receptors: both vagal and and the ones in the stomach cells ○ Vagoefferent sends input into the BS and then activates PNS efferents into the pathway (does the same mechanism/pathway as in the cephalic phase except this is done by the stomach) ○ Enteric nervous system efferents will induce an intrinsic reflex using intraneurons ■ Stretch sensory IPAN is talking to an interneurons (maybe gcells ) and then stimulate gastrin. ■ The gastrin can be stimulating the parietal cells directly or the gastrin that comes out can stimualte the ECL cell to produce histamine and then produce response

Both cephalic and gastric phase feature negative feedback

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If there is adrop in the pH, it will be detected by afferents and signal will go to gastric d-cell (also associated w/ the pit although we don’t see as many of these in comparison to g-cells) ■ D-cells produce somatostatin by The afferents will be the IPANs that interact w interneurons and the interneurons will talk to enteric endocrine efferent cells to activate the D-cell. ■ Somatostatin goes into the blood which will influence cells: g cells and ECL. as somatostatin is signaling it’s actigin to inhibit the g cells and ECL so they reduce the activating of gastrin and histamine. If there is a drop of pH there is a sign that we are making too much acid and we need to shut it down. Protons that get into acid by hcl that is produced by the parietal cell is being buffered out by the stuff that we are eating.

3. Intestinal phase a. Inhibitory to acid production and secretion (acid is never stored in the parietal cells, it will be secreted) b. Chyme enters small intestine => results to be very acidic pH 2-5 and distends the SI because its pushing on the sides of the wall (stretch and acidity we are detecting) c. We don’t know what signals are coming out of the chyme entering the SI through the antrum. Not sure what is causign the negative feedback but this phase is mainly inhibitory.

PEPSINOGEN SECRETION ● Regulated by the cephalic and gastric phase (seen very similar to acid production) probably in response to the same stimuli for both phases ● Pepsinogen is the Precursor to pepsin (a digestive protease) ○ Pepsinogen is cleaved into pepsin (active form) by HCL. pepsin will target dietary proteins and will begin the first significant step of protein digestion. ○ Pepsin can come back and autocatalyze sich that it will target pepsinogen and create pepsin. ○ Pepsin is only active in acidic environments (bc it needs HCL) when its taken in neutral (pH 7) its activity is basically stopped. pH of 3.0 is prime but begins at about 5.0.

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Combining fed motor activity followed by this has allowed us to become omnimover diets

INJURIES AND INFLAMMATION (related to GERD) - Acid induced damage - Usually repaired quite easily such that pt are asx (healed yourself by the systems already set in place by the GI tract) - Prolonged injuries will results in diseases 1. Helicobacter pylori (H.pylori)

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In USA in adults 60 yr or older (stomach ulcerations were due to bacteria proved by tx pt w/ sx w/ abx) 50% prevalence in infection (½ will have bacteria in stomach and some may present sx or not) due to fecal contamination of food (not washing veggies from store, it’s better to grow your own veggies) (how it causes ulcerations) Invades the mucus / bicarb (alkaline) layer h.pylori wants to live under the layer. H.pylori Produces urease - Urea ----(urease)----> ammonia (cuts through everything (this is what is creating the whole in the mucus) + co2 = which eats away at the mucus (the whole may also allow HCL to go into it) Most pt’s have erosion caused by HCL -> repaired and resolved easily or -> worsening of erosion/damage that are not healing properly which can create an ulcer and increase stomach cancer risk Tx: abx is the best. (for H.pylori - arythromyocins) - Pepto bismol (coats ulcers and smoothens bacteria)

2. NSAIDs (non-steroidal anti inflammatory drugs) - Aspirin (low dose used to treat hypertension), ibu, naproxen: help tx inflammation by decreasing production of prostaglandins (important overall inflammatory response. Necessary for recruitment blood flow to injury region, recurit immune cells and are needed for healing) - tylenol/acetaminophen is not an NSAID - Prostaglandins are needed for mucus production (if a person is taking these drugs, they are decreasing mucus production and at increase for stomach ulceration) - 30-60% of pt who take NSAIDs chronically show gastric erosions or ulcerations

3. Diet components - holy trinity of undergrad ○ High salt (dehydrate mucus and reduces integrity) ○ High nitrates (hot dogs, preserved foods, dried meat like beef jerky) ○ Alcohol ( ● Tx ○ Eliminate noxious molecules (salts, nitrates, etc) ○ Reduce use of NSAIDs ○ Pepto bismol ○ Histamine R-blockers (okay to take daily) ○ Proton-pump inhibitors (can’t take every day needs to be taken q 3-4 months) ○ Rolaids and tums antacids - (in the past, they would give pt a vagotomy and cut the vagus innervation and pt’s would feel better w/o sx) spicy food does not cause ulcerations, it induces bicarb production at the pancreas. PANCREAS - Produces exocrine and hormonal secretions - Pancreas tissue is very flimsy (looks like fat) - Common bile duct and main pancreatic duct drain into the small intestine - Primarily exocrine cells produce secretions going into the GI tracts - Endocrine cells - Produce insulin, glucagon, pancreatic somatostatin - Has a duct and an acinar cells and the contents coming out of the acinar cells are dumping into the deudanum

1. Acinar cells : enzymes (primary function as either precursors or active form) a. Pancreatic amylase i. Secreted in active form and loves pH is neutral ii. Targets alpha 1,4 glycosidic bonds in starches 1. carbons can be placed in a line just like cellulose (except the bond is in the oposite end b-14 glycosidic linkage which we cant break down) iii. Produces maltose (2 glucose) and maltotriose (3 glucose linked) iv. We find two different components in the starches: 1. Amylose: linear alpha 1,4 glycosidic linkages 2. Amylopeptine: has alwpha 1,4 glucosidyc linkages and an alpha 1,6 linkage which allows for branching and our body can not target that. Wehn we try to digest this it needs a lof of space and can’t target the end of starches. a. When amylase targets amylopetine we result in maltose, maltotriose + alpha limit dextrins w/ alpha 1,4 and 1,6 linkages. - This is the problem w amylase it doesnt completely break down starcehs into monomeric single glucose molecules. We still busted apart into smaller molecules but it’s not digested just started.

b. Pancreatic proteases (4 total including trypsin) i. Neutral pH of about 7 ii. Main protease: trypsin (first produced as precursor of trypsinogen) 1. Trypsinogen is activated by enzyme (enterokinase) to trypsin (active) by cleaving off a part 2. Trypsin can autocatalyze itself iii. Enterokinase is living on the apical surface of an epithelial cells (enterocytes). Enterokinase is responsible to convert trypsinogen into it’s active form trypsin. iv. Activated trypsin can target digestive proteins by cleavage.

I. II. III.

Chymotrypsinogen(precursor) converted into active form chymotrypsin by trypsin. Proelastase (precursor) converted into active form elastase by trypsin. Procarboxypeptidase (precursor) converted into active forms carboxypeptidase A or B by trypsin. Trypsin is the key to activate these enzymes and it’s also important for shutting them off. Most of the enzymes are proteins. Trypsin targets proteins. Shuts them off by: elactase (active form) to inactivated enzyme form by trypsin. (same steps but backwards)

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c. Pancreatic “lipases” -> esteraces (term b/c it targets the fat soluble things we eat) i. Pancreatic lipase targets triglycerides and is active 1. Triglycerides are steriphied to fatty acids when lipase is acting on it we cleave off number 1 and 3 fatty acids creating 2 monoglycerides + 2 FFA Pancreatic lipase is secreted in its active form and bc non of cell membranes are made up of triglycerides so its okay to store and then secrete in active form The prooteases we must hold them in their inactive form or else they would digest membrane proteins

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Pancreatic phospholipase (targets phospholipids 1. Stored as a precursor 2. Trypsin activates the enzyme t 3. Loans neural pH Phosphate group is added to the 3rd carbon and FFA 1 is cleaved off so we result w/ FFA on carbon 2 and on #3 carbon there is a phosphate group still on tehre b/c phospholypase is unable to cleave off that. The final compound made is a lysophospholipid + 1 FFA. Usually excists as a salt in solution.

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d. Pancreatic cholesterol esterase i. Stored and secreted in active form ii. loves neutral pH (does its job once we neutralize all the chyme thats coming from the stomach) iii. Targets esterified of cholesterol Esterified cholesterol (cholesterol w/ a carbon chain added to it) gets cleaved by Cholesterol esterase into cholesterol + 1 FFA. All of these enzymes need to have a neutral place.

PANCREATIC TRYPSIN INHIBITOR (inhibitor of digestion that is not secreted, it stays within the pancreas) ● Remains in the pancreas ○ Purpose: neutralizes trypsin inside the pancreas (sometimes, trypsinogen sometimes gets activated into trypsin inside the pancreas even in the absence of enterokinase and this trypsin can begin to destroy pancreas) ○ Can destroy the pancreas -> pancreatitis ■ So we want the trypsin inhibitor inside the pancreas to bind to the trypsin and prevent pancreatitis and protect the pancreas.

Tuesday 7/27/21:

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We want chyme to be around pH of 3(more acidic)-5(neutrality) -> stimulate bicarb secretion We need to crank bicarb secretion Sodium stays identical to what we would see in the blood (150 mM) K+ remains unchanged In pancreatic solution there is an increase in enzymes and volume but also bicarb is high inlow secretroy rates and then in high it continues to climb but int he blood the bicarb is low (meaning bicarb cells are being made by central acinar and ductal cells) Cl- concentration decreases at high secretory rates and in blood its high although not as high as sodium Relatively isotonic: we are trying to neutralize the acidity not change the tonicity. Relay on gastric secretions that are bringing the tonicity back to normal

ISOTONIC

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Central acinar cells in transition spot between duct cells and acinar cells. Central and duct cells are responsible for producing bicarb

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Acinar cells are responsible for producing enzyme Blood delivers carbon dioxide into duct cells ○ Co2 + water -> h2co3 (carbonic acid) -> dissociates into H+ and Hco3○ We want to get the bicarb into the duct from the ductal cells through a transporter working in conjunction to a chloride channel. ■ Chloride is able to cycle into and out of the cell through the transporter and channel (cl channel is identical to channel in the salivary gland) (someitems the cl cant be pushed out as quickly as its being pulled into the cell) = lowers [cl-] that is within the pancreatic secretion ■ THIS IS WHAT ALLOWS US TO PUMP BICARB PUMPED INTO THE LUMEN ■ Bicarb neutralizes what is in the duodenum NHE(?): sodium hydrogen exchanger will take H+ that was inteh cell into the blood. This proton is what accounts for the bicarb that was placed intothe blood by the parietal cell (when producing acid) The proton that is made by the duct cells in the pancreas will match it one on one. This is how we ensure that we have pH balance. (vominting pt case placing themselves in alkalosis b/c they are vominting out acid and the acid is not activated to produce bicarb) Regulation of [Hco3-] secretin: (stimuli in the duodenum) decreases pH in duodenum Inducing response are hormones and neuronal regulation ○ Secretin (released...