Gastric Secretion

Summarise the gastric phase and acid secretion

So overall you have stimulation of the antral G cells to produce more gastrin. Gastrin increases the parietal cells to produce more acid. Gastrin also stimulates ECL cells to release histamine and this gives the parietal cells and extra boost to produce more acid. You then have the D cells across the stomach. THe d cell dampens down Antral D cells via somatostatin (and SST receptors), so there's less gastrin and less acid. D cells also dampen down parietal cells directly via somatostatin. H. pylori affects the D cells - so there's less dampining down, more acid, more spill over and duodenal ulcers • If you have an infection in the top, however, the inflammation switches off the parietal cells and youget gastric ulcers and eventually gastric cancer as you're pre-disposed.

So what causes gastrin secretion generally?

• Distention of stomach • Amino acids/peptides - proteins • Low acidity (Buffering by food)

What are tubulovesicles?

• Within the parietal cell, there are structures called tubulovesicles - which contain dormant proton pumps. When the parietal cell becomes activates, these pumps are brought to the membrane surface of the canaliculus.

Name a disease where you produce too little stomach stuff?

Autoimmune gastritis (PA) Atrophic gastritic - H.pylori VIPoma

Out of the three stages which are neural, endocrine and paracrine?

Cephalic Neural Gastric Endocrine Intestinal Paracrine

What are chief cells?

Chief cells - produces pepsinogen, secreted into the acid stomach, then once it's in the acid pepsinogen gets converted to pepsin. Helps a little bit in breaking down peptides. Doesn't do a lot.

Gastric glands - what are these, where do they sit? What cells are part of them? What cells make up the majority of the gland?

Each of the folds in the stomach is covered in hundreds of gastric pits. At the base of these pits sits a gastric gland. It secretes pepsinogen from chief cells and hydrochloric acid (HCl) from parietal cells. Chief cells make up the majority of the cells of the gland, but we are more interested in the parietal cells - as acid is far more important.

What cells produce HCl, pepsin and mucous?

HCL - Parietal cell Pepsin - Chief cell Mucous - Goblet cel

What is mucous made up of?

Mucins and glycoproteins

What causes gastrin inhibition?

Once you have reached max acidity you want to switch it off. When it's too acidic, you get a feedback loop.

How would rinitidine work?

Well it would block this booster mechanism via ECL cells. It's not brilliant cos you can still make acid via the normal mechanism.

Name a disease where you produce too much stomach acid

Zollinger-Ellison syndrome H.pylori Retained gastric antrum syndrome

What is the basolateral membrane of the parietal cell exposed to?

• The basolateral membrane of the parietal cell is exposed to extracellular fluid. Hormones can diffuse out of blood capillaries into this fluid, and therefore come into contact with the membrane. Critically, the receptors for gastrin, histamine and acetylcholine sit in this membrane.

Describe the cephalic stage of acid secretion

• The first stage is the cephalic stage, and this is controlled by the brain. • When you think about food, look at food, smell food, or you're hungry or enjoying a good meal... the brain will ensure the stomach starts acid secretion. • This is done via the vagus nerve and AcH receptors. • The shortest phase • Assisted by chemoreceptors and mechnoreceptors in the toungue, mouth and nasal cavity

How does the mucosal lining change throughout the stomach? This is in terms of cell type and stretch and acidity

• The mucosal lining of the stomach can stretch in size with feeding. • The greater curvature of the undistended stomach has thick folds or rugae. • The mucosa of the upper two-thirds of the stomach contains parietal cells, which secrete hydrochloric acid, and chief cells, which secrete pepsinogen (which initiates proteolysis). • There is often a colour change at the junction between the body and the antrum of the stomach, which can be seen macroscopically and confirmed by measuring surface pH.

What are parietal cells? Are they shaped? What organelle is prevalent in the parietal cell?

• The parietal cells are convoluted (folded) membrane-lined channel openings into the lumen of the gastric gland. This channel is called the canaliculus. • It's packed full of mitochondria as the pumps involved require ATP. Within the cell there are also shit loads of mitochondria. These provide an energy supply as molecules of ATP, which gives energy as it breaks down to ADP.

What drives the production of acid in this stage?

There are two indirect vagal mechanisms of parietal cell stimulation: • The release of the antral hormone, gastrin, from G cells following vagal stimulation by means of gastrin releasing peptide. The gastrin diffuses into the venous system and is delivered via the heart and arterial system to stimulate the parietal cells of the stomach (an endocrine mechanism). • The release of histamine from enterochromaffin-like cells as a result of the action of acetylcholine released from postganglionic vagal nerves, and by the action of gastrin. - Histamine diffuses from the enterochromaffin-like cells through the tissue fluid to stimulate the parietal cells (a paracrine mechanism).

What stimulates secretion in this stage?

• Gastrin - hormone. Acts on CCK-B receptor • Endocrine in delivery (by blood) • Produced by G cells found in the gastric antrum • It's also a trophic hormone - making cells grow larger in number, particularly in cancer. • When the stomach is distended, mechanoreceptors are triggered in the body or antrum, causing a reflex leading to acetylcholine to be released locally, the neurotransmitter responsible for activating gastric parietal cells. • G cells are sensitive to amino acids and peptides and so when they are present, G cells stimulate parietal cells with gastrin. Gastrin also has some effect on ECL cells causing them to release histamine. • Amino acids and peptides also trigger vagal chemoreceptors, causing the release of acetylcholine, which in turn triggers parietal cells.

What stimulates histamine production?

• Histamine is an organic hydrophyllic amine which acts on the parietal cell H2 receptors • "Paracrine" ie. Locally active hormone acts on these receptors • Produced by enterochromaffin-like (ECL) cells. • Gastrin stimulates ECL cell histamine release • Essentially it's gastrin from the antral G cells, not only working on parietal cells, but also working on the ECL cells on the right. This causes Histamine release, which in a paracrine way acts on the histamine receptors. • It's like an extra boost of acid production from gastrin. • It's not great, cos of you block the H2 receptors acid is still produced in the usual way.

How is this phase triggered? (This is quite confusing!)

• Inhibitory- acid with a pH less than 2 in the stomach, and distension of it causes somatostatin to be released from D cells in the stomach. If the D cells are in the antrum then they inhibit the release of gastrin by G cells and if they are in the body they inhibit secretion of stomach acid directly by acting on parietal cells. Somatostatin is a paracrine hormone acting only on surrounding cells. There are also other mediators active in this phase such as secretin, (which inhibits gastrin release and parietal cell response to gastrin, and is mediated primarily by strong acidity), and Gastric inhibitory polypeptide (GIP) and cholecystokinin (CCK). The latter two are released when fatty acids are detected in the duodenum and proximal jejunum. GIP and CCK both suppress parietal cell production of HCL and also suppress gastrin release. • Excitatory- amino aids and chyme (the mulched up food from the stomach) triggers receptors in the duodenum and causes intestinal gastrin to be released. This is then carried in the blood to the stomach. Intestinal stimuli only produces around 5-10% of total gastric acid produced during a meal

What stimulates acetylcholine?

• It is stimulated by the vagus nerve (Xth cranial) • Parasympathetic control system • Autonomic nervous control

Give an overview of the gastric mucosa's protective mechanisms

• Mucous • The surface cells secreting HCO3- • The surface membranes of the jucosal cells o Tight junctions and the ability to forma fibrin coat to protect the cells • Prostaglandins o E and I series o Inhibits acid secretion by enhancing blood flow to the mucosa and encouraging mucous production

Name the different things the gastric mucosa produces, and what cells produce it and brief function

• Resting juice o Isotonic juice secreted by the surface cells o A higher concentration of bicarbonate and an alkaline pH • Mucous o Secreted by goblet cells (MAYBE NOT: Foveolar cell instead?) o Thick sticky, alkaline mucopolysaccharide o Adheres to the side of the stomach lumen • Pepsin o Chief cells o Pepsinogen - pepsin by HCL • Lipase o Starts the process of converting TAGs to fatty acids and glycerol • Intrinsic factor o Produced in the parietal cells of the stomch o Absorption of B12 • Hydrochloric acid o Produced by parietal cells

How is pepsinogen secreted?

• Similar method to gastric acid secretion • The major mediator is Ach from vagal nerves acting on muscarinic receptors in the peptic cell during the cephalic and gastric stage • Other actions also take place

What controls the proton pumps and the amount of ions moving across the membrane?

• So the protein pump, pups ions of H+ across the membrane into the canaliculus and into the lumen of the gastric gland • Critically, at the bottom of the gastric gland there are three main receptors. These are critical for the stimulation of acid (and pepsinogen) secretion. • These are for acetylcholine (ACh), histamine (H) and gastrin (G). The histamine receptor is a particular type called H2 receptor. • When one or more type of receptor is stimulated, they signal to the proton pumps to become active and hence activate more proton pumps to pump out more protons

What is the canalicular membrane, what structures lay inside?

• So, there are structures in the canalicular membrane, and one of the most important is the proton pump. • This structure pumps hydrogen ions out of the cell into the canalicular lumen. Protons are exchanged for potassium ions. This is to keep the pump iso-electric. • Chloride ions diffuse passively across the membrane and so out of the parietal cell. These join the hydrogen ions in the fluid within the canaliculus - thus forming HCL. • The H/K uses the ATPase enzyme and ATP to do this. Hence the high levels of mitochondria.

What type of cells does the antral mucosal have? What stuff do antral mucosal cells produce?

• The antral mucosa secretes bicarbonate and contains mucus-secreting cells and G cells, which secrete gastrin, stimulating acid production. • There are two major forms of gastrin, G17 and G34, depending on the number of amino-acid residues. G17 is the major form found in the antrum. • Somatostatin, a suppressant of acid secretion, is also produced by specialized antral cells (D cells).

What is somatostatin? What does it do?

• This is an inhibitory peptide hormone • It acts on the SST receptors • Again, this acts in a paracrine way • It is produced by the D-cells in the stomach • It acts on the antrum, with the G-cells - inhibiting gastrin (and inhibiting parietal cells too)

What is the intestinal phase?

• This is less important in terms of gastric secretion (doesn't secrete much here!) • This phase is not very well understood. • Lots of theories suggested, but basically there's gastric acid secretion of acid once food passes from the stomach to the duodenum. A small spike in pH.

What happens in the gastric stage of acid secretion?

• This is the second phase, and the longest phase. • It's main function is to increase acidity after a food buffer. • Initiated by having food in the stomach • Causes the largest amount of gastric acid to be produced.