Diarrhea Flashcards
What is the chloride channel on crypt cells sensitive to?
intracellular calcium levels
How do chloride channels on crypt cells open?
calcium is released from intracellular stores in the cytosol
How do post-ganglionic parasympathetic or ENS fibers trigger the release of intracellular calcium?
post-ganglionic parasympathetic or ENS fibers release ACH to act on muscarinic receptors which cause the second messenger cyclic GMP to increase in the cell which triggers an intracellular Ca to rise
Normally, when are crypt cells stimulated to secrete chloride?
to get sodium to the villus when it is needed to absorb dietary components
What are the three types of diarrhea?
secretory, malabsorptive, and osmotic
What occurs to the gut in secretory diarrhea cases?
excessive chloride secreting activity of crypt cells, reduced activity of villus cells, excessive secretion of water from the cells
Explain the mechanisms that lead to increased Cl and water secretion in secretory diarrhea.
certain toxins cause production of free radicals which damage tissues resulting prostaglandin E2 and I2 production by cells in mucosa and submucosa. Prostaglandins E2 and I2 bind to Pg receptors on crypt cells and activate adenyl cyclase which increases cyclic AMP in the cells. Increased cyclic AMP will cause a rise in intracellular Ca from intracellular stores which binds to calmodulin and initiates the opening of Cl channels; Na and water will follow into the lumen.
What is the alternative pathway for Ca release in the ER during secretory diarrhea?
prostaglandins activate phospholipase A which tells IP3 to open Ca channels in the ER
What are some toxins that cause secretory diarrhea?
salmonella, cholera, and enterotoxigenic e-coli
How does salmonella cause secretory diarrhea?
white blood cells and cells damaged by salmonella within the lamina propria release prostaglandins (PGE2) which not only stimulates the secretion of Cl but also stimulates mucous secretion by goblet cells
What can slow the production of PGE2?
glucocorticoids and NSAIDs
How does salmonella use extracellular calcium to cause secretory diarrhea?
bacterial toxins have been found to cause secretion of serotonin from enteroendocrine cells, serotonin causes calcium channels in adjacent cell basolateral membranes to open which raises intracellular calcium and stimulates secretion of chloride
How does inflammation lead to hypersecretion in secretory diarrhea?
TNF-alpha and other cytokine can bind to receptors on crypt cells and activate adenyl cyclase which activates cyclic AMP which activates secretion of intracellular calcium stores
What mechanism does cholera use to cause secretory diarrhea?
it secretes enterotoxin which binds to specific receptors on enterocytes of the small intestine only linked to guanylate cyclase activity
How does the enterotoxin that cholera secretes cause secretory diarrhea?
it raises levels of intracellular calcium to rise, mostly from intracellular calcium stores, through extracellular calcium can also serve as a source; Cl leaves, Na and H2O follows
What are the two types of toxins that e-coli secrete?
ST-toxin and LT-toxin
How does ST toxin work?
it is heat stable and activates cyclic GMP just like cholera toxin
How does LT toxin work?
it is heat labile and activates adenylate cyclase via its own g-protein coupled receptor which raises intracellular cAMP which then raises intracellular calcium increasing the secretion of chloride
Why does the secretory diarrhea associated with LT toxin last until the cells slough off?
because it irreversibly binds to the receptors
How does secretory diarrhea effect villus cells?
it blocks Na coupled to Cl entery across the apical membrane so more Na and Cl stays in the gut
What does secretory diarrhea not block in villi cells?
Na absorption coupled to sugars or amino acids
What generally occurs to the gut due to malabsorptive diarrhea?
loss of villous cells or villous enzymes, loss of tight junctions, loss of plasma proteins that would normally be absorbed by lymphatics
What are some toxins that cause malabsorptive diarrhea?
Johne’s disease, rota virus, transmissable gastroenteritis coronavirus, coccidiosis, cryptosporidosis, panleiukopenia, parvo