Gastric and Intestinal secretion

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2 Gastric and Intestinal secretion OBJECTIVES: 1. Describe the various types of gastric cells and the secretion of each cell type. 2. Mention the components of gastric juice and the function of each component. 3. Describe the different mechanisms involved in the control of gastric secretion (mechanical, chemical, and neural). 4. Explain the cellular steps involved in acid secretion in the stomach. 5. Discuss the interaction between neural, hormonal and paracrine regulatory mechanisms regulating acid secretion at different phases of a meal. 6. Indicate the role of Brunner s glands secretion in duodenum. 7. Mention component of intestinal secretion and its control. 8. Describe the regulation of intestinal secretion. This sheet contains the entire slides and past year questions. The lecture is a bit long but very easy to understand and memorize. Note: Anything in italics is from outside the lecture just to clarify some points. There are two main types of tubular exocrine gastric glands found in our stomach mucosa. Exocrine: glands which secrete their products through ducts opening on to an epithelium rather than directly into the blood. Tubular: Tube shaped like structures. 1. The oxyntic glands Make up 80% of gastric glands and are found in the body and fundus of the stomach. Basically all over the stomach except in the antrum area. 1 P a g e

3 2. The pyloric glands Make up 20% of gastric glands and are found in the antrum of the stomach. There are 6 main types of gastric cells: 1. Mucous Neck cells 3. ECL cells 2. Surface epithelial cells 4. Parietal cells 5. Chief cells 6. G-cells In the Oxyntic gland you have the following gastric cells: 1. Mucous Neck cells: Cells which mainly secrets mucus. 2. Parietal cells: Also called Oxyntic cells. Cells which secrete HCL and Intrinsic Factor. 3. Entero-chromaffin like cells (ECL): Cells which secrete histamine. Remember that mast cells also secrete histamine. 4. Chief cells : Which secrete pepsinogen (digestive enzyme) 2 P a g e

4 Oxyntic Gland The different gastric cells are distributed throughout the gland. Surface mucous cells align the surface of the stomach between the glands and secrete viscid mucous that is alkaline (bicarbonate). Mucous cells secrete thin watery mucus. Similar to the mucus secreted by our salivary glands. Mucous neck cells are labelled stem cell compartment because they differentiate upwards and downwards. In the Pyloric gland you have the following gastric cells: 1. Surface epithelial cells: Cells which secrete mucus. Although the doctor didn t mention them as part of pyloric glands, the picture shows that they are embedded deep into the gland so I added them here. 2. Mucous neck cells: Cells which mainly secrete mucus. 3. Chief cells: Cells which secrete pepsinogen. 4. G-cells: Cells which secrete the hormone gastrin. Since gastrin is a hormone, it is first secreted by the cells into the blood and from the blood they will migrate to the stomach and act locally. Pyloric Gland There are few chief cells present. 3 P a g e

5 There is another type of gastric cells known as D-cells (secrete somastatin), but we will talk about them later in the lecture. Remember that there are no pareital cells in the pyloric glands and few chief cells present. Both chief cells and pareital cells are present in the oxyntic glands, Both glands have mucous neck cells. Now we will consider the different components of gastric juices and the functions they serve. Approximatly 2 L of gastric juice is secreted per day. This number is obviously an estimate because secretions may vary depending on many factors for instance food intake. The secretion is isotonic, ph 2-3 (in stomach lumen). However, the HCL that is directly secreted by the pareital cells is actually 0.8. In the lumen this HCL is mixed with the food allowing the overall ph to slightly increase. Note: Usually the stomach is sterlie. No bacteria or virus present. Gastric secretion and function: 1. Intrinsic factor: Secreted from pareital cells. a. Needed for vitamin B12 uptake in lower small intestine (ileum). Terminal illeum to be more specific. b. It is an indispensable substance in gastric juice. It s absence leads to pernicious anemia (megaloblastic anemia). 2. Mucus: a. Protects gastric epithelium. Since the ph enviroment is low enough to burn through the epithelium of the stomach. b. It adheres to gastric surface and prevents H+ and pepsin eroding the mucosa; failure of this process leads to gastric ulceration. 3. HCl: From parietal (oxyntic) cells (Functions of Gastric acid): a. To kill microgorganisms. However, H. pylori can survive by making ammonia (alkaline) from urea using urease enzyme. 4 P a g e

6 b. Activates pepsinogen (cleaved to form pepsin). It is very important that the inactive from be realesed from the gland (pepsinogen), otherwise the active form may digest the gland itself. c. Pepsin: initiates protein digestion. Pepsin has proteolytic destructive factors. d. Breaks down connective tissue in food. e. Denatures protein. f. Keep iron in soluble ferrous state. Since the ferric form is not very soluble. Either way iron isnt very soluble but the preffered state is ferrous. 4. Pepsinogen: from chief (peptic) cells a. Conversion to pepsin (active enzyme) requires low ph. b. Pepsin initiates protein digestion; optimum ph 1-2. If the ph of the stomach increases to 4-5, pepsin will not be able to perform its actions. Mucosal Protection of gastric epithelium: Remember that there are two types of mucus in the stomach. The viscid thick mucus released by surface eptithelial cells lining the stomach and the second watery mucus released by mucousal neck cells. Mucus layer on gastric surface forms a mucosal barrier against damage to gastric epithelium 1. a gel about 1 mm thick. 2. secreted by neck cells and surface epithelium 3. release is stimulated by acetylcholine from nerve endings (parasympetheitc fibers). 4. also rich in bicarbonate (released by the epethilial cells) a. HCO3- content creates a "micro-environment" around surface cells to prevent acid damage. b. HCO3- secretion is inhibited by adrenergic input (prominent in stress!) Prostoglandins: An important protective agent that increases mucus productions and blood flow. 5 P a g e

7 Arachidonic acid is converted to prostogladin by COX1. So the inhibition of COX1 would prevent PG from forming, removing the protective function of PG and causing peptic ulcers. Inhibition of enzymes involved in prostaglandin production (cyclooxygenase 1 =COX1) by NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen, etc. results in gastric damage. The surface epithelial cells of the stomach secrete thick insoluble, unstirred mucus that lines the surface of the stomach. Unstirred means it does not move. If we replaced this mucus with the same mucus that is in our nose and mouth it would be continuously moving. This mucus contains glycoproteins that form an almost gelatinous coating which contains relatively high concentrations of bicarbonate ion. This coating protects the stomach epithelium from gastric acid and pepsin. Glycosylation of mucin makes it relatively resistant to proteolysis.. Mucus layer lining the gastric mucosa is for protection 1. Lumen about 2 ph 2. Epithelium almost 7 not effected due to bicarbonates. 3. Adherent to epithelium (protective) A second type of mucus (soluble) is secreted along with the gastric juice from the gastric pits to lubricate the food bolus and facilitate mixing. Soluble mucus restricts the access of gastric juice to the gastric pit epithelial cells. 6 P a g e

8 Parietal cells secrete HCL and intrinsic factor 1. HCL is found in the canaliculi and not inside the cells (that would kill them). HCL will be pushed into the lumen. Parietal cells and its receptors In order for Parietal cells to produce HCL, they need H+ and Cl-. So we need to bring H+ and Cl- from the extracellular fluid and push it to the canaliculi of the parietal cells. To release hydrogen, we need a special carrier known as H+/K+ ATPase. These carriers are scattered all over the inside of the parietal cell. 7 P a g e

9 When the parietal cell is stimulated, H+/K+ ATPase will be moved into the canaliculi where they will act and perform their action. Their action (from the name), will push H+ to the canaliculi (to the lumen) and get K+ inside the parietal cell. There are three important factors stimulating parietal cells. 1. Acetylcholine. Released from Cholinergic nerve fibers and enteric system. (parasympathetic) Will act on muscarinic receptors of M3 type. 2. Histamine. Coming from ECL. Will act on histamine receptors. Remember we have two types of histamine receptors H1 and H2. In the stomach we only have H2 receptors. (Activate adenylyl cyclase enzyme). Inhibited by H2 receptor antagonists (Cimetidine). 3. Gastrin. Coming from G-cells. Gastrin will act on G-cell-receptors If the parietal cell is stimulated by one or all three of these receptors the H+/K+ ATPase will insert themselves to the canaliculi and perform their action (pumping hydrogen outside and bringing potassium inside). Notice the picture. Each one of these stimulants potentiates the effect of the other. In other words, the action of one stimulus will be increased by the action of another stimulus. Effect of parietal stimulation by the three stimulants are: More H+/K+-ATPase insertion in the membrane. More Cl- channels insertion. 8 P a g e

10 1. ECL are stimulated by gastrin and acetylcholine. 2. Histamine stimulates H2 receptors. Paracrine hormones and HCL release in the gastric phase of secretion. Histamine is released from ECL cells by either Gastrin or Acetylcholine and acts directly on parietal cells to produce HCL. If you want to decrease the HCL secretion, block the H2 receptors. (H2 receptor antagonist) This is what we do when we treat peptic ulcers. We have a special type of hormone called somatostatin. Produced by cells called D-cells. Somatostatin is inhibitory to gastrin. It will decrease the HCL secretion. Somatostatin: Released from D-cells in gastric epithelium by direct action of H+ (at lumen ph < 2). Somatostatin is released by D-cells when the ph of the lumen is less than 2. Which shows it is protective because if the parietal cells are stimulated continuously by the three stimuli the HCL will increase the acidity more than normal. Doctor corrected the slide and said not by the gastric epithelium but by the gastric cells found in the glands Reduced gastrin release reduced HCL secretion Very important to note that the inhibitory effect of somatostatin is indirect since it inhibits the g-cells which in turn inhibits the other two stimulants (Acetylcholine and Histamine). 9 P a g e

11 So to answer the question, what alters the acid secretion by Parietal cells in the stomach? 4 things: 1. Acetylcholine (Stimulates) 2. Histamine (Stimulates) 3. Gastrin (Stimulates) 4. Somatostatin (Inhibits) Do we have any other inhibitors of gastric secretion? Yes, but they don t come from the stomach. They come from the duodenum. We have three types: 1. Secretin (the most important) 2. Hyperosmotic Chyme fatty acids This figure shows the relationship between D-cells and G-cells. 10 P a g e

12 When hydrogen concentration is increased too much this will stimulate D-cells to produce somatostatin which inhibit G-cells from producing gastrin. Therefore, HCL concentration is decreased. This next figure shows the interactions between the different factors that regulate HCL secretion. Histamine Histamine release is stimulated by 1. Ach 2. Gastrin Gastrin secretion is stimulated by: 1. Peptides 2. Gastrin-releasing peptides released from intrinsic nerve Comments on figure: 1. In the presence of food, especially amino-acids, or a less acidic environment will stimulate g-cells. 2. In addition to that the intrinsic nerves from the myenteric plexus and submucosal plexus produce certain transmitters called gastrin 11 P a g e

13 releasing peptides which will act on G-cells that will produce gastrin which will go to the blood and stimulate parietal cells. 3. So we can say that G-cells can be stimulated by food or by gastrin releasing peptides released from gastric nerve fibers. 4. G-cells are inhibited by high acidity. 5. As gastrin moves through the blood it will reach the parietal cell and bind to receptors at the same time gastrin is stimulating ECL to produce histamine. 6. Vagus nerve which produces acetylcholine that will bind to M3 and stimulate ECL cells to produce histamine. Comments on the previous figure: Here you can see vagal nerves stimulating several different cells by releasing acetylcholine. 1. Stimulates chief cells to release pepsinogen. 2. Stimulates Parietal cell to release HCL. 3. Stimulates ECL cell to release histamine. 4. Acetylcholine will also stimulate the enteric nervous system to release gastrin releasing peptides that will stimulate G-cells to release gastrin into the blood. Now we will look into the mechanism of forming HCL 12 P a g e

14 How do we get the H+ and how do we get the Cl-? 1. CO2 diffuses out of the blood and into the extracellular fluid and into the parietal cell. 2. Under the effect of carbonic anhydrase, CO2 and H2O will react to form Carbonic acid H2CO3. Without carbonic anhydrase this process would be very slow. 3. Carbonic acid will then disassociate to give H+ and bicarbonate HCO H+ ions are pumped into gastric lumen by K+ /H+ pump. This pump is very powerful because it pushes H+ outside against a very large concentration gradient that will push K+ inside as H+ is being pushed outside. (H + /K + -ATPase (i.e. proton pump), located in the luminal membrane of parietal cells) 5. As for bicarbonate, it will be pushed outside of the parietal cells into the blood and in exchange, Cl- will be pushed inside the cell. 6. Cl moves out (by diffusion) of parietal cell into lumen through electrical gradients. Note: Cl- will exchange with bicarbonate by an anti-porter. An antiporter (also called exchanger or counter-transporter) is a cotransporter and integral membrane protein involved in secondary active transport of two or more different molecules or ions across a phospholipid membrane such as the plasma membrane in opposite directions. 13 P a g e

15 So to recap, H+ will be made inside the parietal cell by dissociation of carbonic acid. While Cl- will move inside the cell from the blood as bicarbonate is pushed out. This is considered a simplified version of the process. (Poor choice of words) Another version of the process comes from Guyton. 1. Hydrogen ions are formed from the dissociation of water molecules. 2. The enzyme carbonic anhydrase facilitates the reaction of carbon dioxide and water forming carbonic acid which dissociates into a bicarbonate ion (HCO3 ) and a hydrogen ion (H+). 3. The bicarbonate ion (HCO3 ) diffuses out in exchange with chloride ion (Cl ) which diffuses inside. The doctor added here that according to Guyton the Cl- will move by active transport. 4. Potassium (K+) ions diffuse into the canaliculi. 5. Hydrogen ions are pumped out of the cell into the canaliculi in exchange for potassium ions, via the H+/K+ ATPase. Extra points regarding HCL formation (because why not) During active secretion of HCL after a meal, the ph of the blood drained from the stomach is elevated (due to secretion of HCO3 ions). This increase in ph of the venous blood leaving the stomach is referred to as the alkaline tide. It raises the ph of systemic blood and makes urine alkaline (postprandial alkaline tide). 14 P a g e

16 The K + /H + pump is very powerful and requires an appreciable amount of energy because H + is pumped against more than concentration gradient (ph 7 to ph 1) It can concentrate H+ more than 3 million times (Plasma = meq/l, while gastric Juice =150 meq/l). Inhibition of this pump by drugs called proton pump inhibitors (Omeprazole) helps in reducing the amount of HCL secretion. The ph of parietal cell secretion into canaliculi is very low (about 0.8). Remember the ph of the gastric lumen is about 2. Regulation of pepsinogen secretion 1. Stimulation of chief cells by acetylcholine released from: a. Vagus nerve endings. b. Gastric enteric nervous plexus. In other words by parasympathetic innervation. 2. Presence of acid in the stomach: through eliciting enteric reflexes. Absence or less acid secretion will cause less pepsinogen formation. Phases of gastric secretion We have three main gastric secretion phases. 1. Cephalic phase: This is the phase where you are seeing, smelling, or even thinking of food. Way before the food has reached the stomach. Occurs before food enters stomach ~30% of total secretion Direct vagal stimulation + gastrin release 2. Gastric phase: Occurs while food is in stomach >60% of total secretion Involvement of: vagal and enteric nerves 15 P a g e

17 Involvement of: Paracrine (local) hormones (histamine) Involvement of: Endocrine hormones (gastrin) Gastrin secretion is inhibited at lumen ph <2 3. Intestinal phase: Occurs after food enters small intestine (when chime enters the small intestine) Largely hormonal: - Stimulatory effects (gastrin) some gastrin is produced when food is in the intestine. - Inhibitory effects (secretin, GIP (gastric inhibitory peptide), cholecystokinin) Cephalic Phase of gastric secretion 16 P a g e

18 1. The taste or smell of food, tactile sensations of food in the mouth, or even thoughts of food stimulate the medulla oblongata (green arrow) via stimulation of appetite center of hypothalamus and amygdala. 2. Parasympathetic action potentials are carried by the vagus nerves to the stomach (pink arrow). 3. Parasympathetic vagus nerve fibers stimulate enteric plexus of the stomach. 4. Postganglionic neurons stimulate secretion by parietal and chief cells and stimulate gastrin secretion by endocrine cells. 5. Gastrin is carried through the circulation back to the stomach (purple arrow), where it stimulates secretion by parietal and chief. Gastric Phase of gastric secretion 1. Distention of the stomach activates a parasympathetic reflex. Action potentials are carried by the vagus nerves to the medulla oblongata (green 17 P a g e

19 arrow). This is called the Vago-vagal reflex because both sensory and motor stimulation are by the vagus nerves. One carries information (sensory) and the other action (motor). 2. The medulla oblongata stimulates stomach secretions (pink arrow). 3. Distention of the stomach also activates local reflexes that increase stomach secretions (purple arrow). 4. Peptides in stomach cause secretion of gastrin. Intestinal phase of secretion Occurs when chyme enters small intestine. Largely hormonal: 1. Some gastrin secretion released from duodenum causes slight secretion. 2. Feedback inhibitory effects (secretin, gastric-inhibitory-polypeptide) Chyme in the duodenum with a ph less than 2 or containing fat digestion products (lipids) inhibits gastric secretions by three mechanisms: 1. Sensory vagal action potentials to the medulla oblongata (green arrow) inhibit motor action potentials from the medulla oblongata (pink arrow). 2. Local reflexes inhibit gastric secretion (orange arrows) this called reverse entrogastric reflex. 18 P a g e

20 3. Acid, fat, protein breakdown products, hyperosmotic or hypo-osmotic or any irritating factor in duodenum and upper small intestine cause secretion of Secretin, gastric inhibitory polypeptide, and cholecystokinin produced by the duodenum (brown arrows) inhibit gastric secretions in the stomach. Secretin has more powerful inhibitory effect than other factors. Secretion from other parts of GIT 19 P a g e

21 Notes by doctor about slides above: 1. The protective mechanism by the esophagus is not very protective. If there is continuous reflex of gastric content to the esophagus the 20 P a g e

22 end result would be burning of the esophagus since the mucus of the esophagus is not like the stomach. 2. Since the stomach is acidic, the chyme coming to the duodenum is also acidic. We need a very important protective mechanism. The Bile and pancreatic secretions which are alkaline will cancel the acidity however they are not secreted in the beginning of the duodenum, just a few centimeters below the pylorus. So the area between the pyloris and Ampulla of Vater needs to be protected from the acidity of the stomach secretions. A special group of glands called Brunner's gland offer the protection. Brunner's gland produce mostly mucus. 3. Brunner's gland is inhibited by Sympathetic stimulation which may cause duodenal ulcers. Past year Questions HCL secretion by the stomach is increased by all of the following factors EXCEPT: Answer: somatostatin Which of the following statements regarding the mucous covering the epithelium of the stomach is correct: Answer: its secretion is increased by prostaglandin Regarding cells in the stomach and their products, which of the following is correctly paired? Answer: D cells somatostatin. Release of which ONE of the following increase the PH of duodenal contents? Answer: Secretin..And that s it ^_^ 21 P a g e