This page gathers together information about clinical examples where epithelial transport plays an important role.
Cystic fibrosis is a genetic disease that is due to mutations that reduce or eliminate function of the protein CFTR. As you have learned, the movement of Cl- ions through the CFTR channel (located on the apical membrane) is the rate-limiting and regulated step for fluid secretion by many epithelia (see Epithelial Transport).
Although most people think of cystic fibrosis as a lung disorder, it affects secretion in the GI tract and thus causes digestive system pathologies. In the intestines, the lack of fluid secretion can cause intestinal blockage. For instance, some infants with cystic fibrosis present with meconium ileus, which is the failure to pass meconium (meconium refers to the first tarry stool produced by newborns).
In the pancreas, pancreatic duct cells utilize a CFTR-dependent mechanism to secrete fluid (and also bicarbonate ions). The pancreas produces zymogens (inactive precursors to digestive enzymes), and the fluid secretion is necessary to ensure that the zymogens flow out of the pancreatic ducts and into the small intestine before being activated. In patients with cystic fibrosis, the lack of secretion by pancreatic duct cells can lead to chronic pancreatitis, when inappropriate zymogen activation leads to inflammation and damage to pancreatic tissue.
The most common digestive system pathology affecting patients with cystic fibrosis is pancreatic insufficiency. This occurs because blocked ducts and tissue damage in the pancreas will prevent release of adequate amounts of digestive enzymes into the small intestine. If severe enough, pancreatic insufficiency causes malnourishment--for instance in an infant, it might cause a failure to thrive. Pancreatic insufficiency is treated with digestive enzyme supplements.
Finally, because chronic pancreatitis causes generalized tissue
damage in the pancreas, there may also be damage to endocrine
tissue in the pancreas. When cystic fibrosis-associated
pancreatitis damages the beta cells in the pancreatic islets
of Langerhans, this causes insulin deficiency and diabetes
mellitus. CFTR-related diabetes mellitus is treated
with insulin replacement.
In the lungs, the defect in CFTR changes the environment in the airways so that they are much more prone to infection by pathogens. One hypothesis is that a lack of fluid secretion causes insufficient hydration of mucus. As a result, the mucus becomes very thick. Normally mucus is moved up out of the lungs by the beating of cilia present on the surface of airway epithelial cells. The thick mucus is not easily cleared, and is conducive to bacterial and fungal growth. This causes a cycle of infection, inflammation, and tissue damage in the upper airways, which leads to further problems in clearing the mucus. However, the situation in the lungs is complex, and other changes caused by CFTR dysfunction may be contributing to pathology in the lungs.
By contrast to cystic fibrosis in which there is a lack of secretion due to a lack of CFTR function, cholera causes unregulated and excessive activity of CFTR.
The regulation of intestinal secretion involves a regulatory molecule binding to a G-protein coupled receptor. As shown in the figure, this leads to G-alpha stimulating adenylyl cyclase to form cAMP, which activates protein kinase A (PKA), the enzyme that phosphorylates CFTR.
Cholera is the disease that results from infection with toxic strains of the bacterium Vibrio cholerae. Toxic strains of the bacteria produce cholera toxin, which contains an enzyme that modifies the alpha subunit of the G-protein (G-alpha), destroying its GTP hydrolyzing (GTPase) activity. GTP hydrolysis is the way that G-alpha inactivates to terminate the signal from the GPCR. With its GTPase activity destroyed, the G-alpha subunit continuously activates adenylyl cyclase to produce excessive levels of cAMP, PKA stimulation, and CFTR channel opening. The resulting excessive secretion leads to watery diarrhea and loss of extracellular fluid to cause dangerously low ECF volume (severe hypovolemia).
The main treatment for cholera involves fluid replacement. As we shall learn when we study kidney physiology, the amount of Na+ in the body is the main determinant of the extracellular fluid (ECF) volume. Thus, to restore the ECF volume in a patient with cholera, it is important to provide not just water, but also Na+ ions. A mainstay of treatment for cholera (particularly in resource-poor locations) is oral rehydration solution. Oral rehydration solution is a mixture that contains both Na+ and glucose, because the major protein that transports Na+ across the apical membrane of the intestinal epithelium is the sodium-glucose cotransporter. Glucose is necessary because this protein requires both Na+ and glucose to bind in order for transport to occur.