Question

What are the Systemic implications of defects in the CFTR channel ?

Answer 1

CFTR (cystic fibrosis transmembrane conductance regulator) is the protein that forms CFTR channels in apical membrane of epithelial cells in organs such as lungs and pancreas. The CFTR channels are involved in transport of chloride from cytoplasm of epithelial cells to the extracellular medium. Chloride ions accumulate within epithelial cells due to actions of anion exchanged and NBC present in basolateral membrane of the epithelial cells. CFTR transport of Cl- ions will cause sodium ions to also move out of the cell. Sodium ions move along with water via a paracellular pathway from blood into the epithelial lumen. Water can also move into extracellular lumen via aquaporin channels. The sodium chloride and water will cause mucus to be diluted in extracellular lumen. Although CFTR can also transport bicarbonate ions, its major role is to transport chloride. Dilution of mucus will maintain its viscosity. Mutation in CFTR will cause defective CFTR channels will leads to mucus being concentrated and less viscous. This leads to clogging of pancreatic ducts and the lungs (respiratory tract). Hence, these cystic fibrosis individuals will have defects in lung function and digestion. Other organs involved are gastrointestinal system, sinuses, liver and reproductive system.

Systemic implications are the effects of CFTR defects (CF) seen in the body. Effects on the lungs can cause systemic inflammation due to production of cytokines. Mucus that is produced in CF patients will cause blockage of bronchioles, resulting in obstructive lung disease. Such conditions are ideal for bacterial infection within the airways. In CF lungs, Inflammation may result due to production of neutrophil IL-8. This neutrophil IL-8 is produced by the epithelial cells and is known to increase mucus secretion. Thus, a positive feedback loop occurs which may lead to further inflammation and tissue damage. If chronic inflammation is combined with bacterial infection of lungs, there may be bronchiectasis and even death due to lung failure.

Thickened mucus will block the pancreatic ducts, thereby inhibiting the secretion of pancreatic enzymes into the lumen of the small intestine. As CFTR also excretes bicarbonate ions, the pancreatic secretion have low pH. Hence, there is lesser neutralization of chyme in the acidic stomach. The Chyme that has slow pH will also degrade pancreatic enzymes that reach the small intestine. All these effects lead to greasy stools, abdominal pain and also less nutrient absorption, especially of vitamin A, D, K and E. Faulty CFTR channels affect the large intestine causing increased fluid absorption. This may lead to constipation as well. Inflammation can also result due to obstruction of the intestine.

Pancreatitis may also result, due to effects of pancreatic enzyme that remain behind on the pancreas. These enzymes may autotarget the pancreas itself. Islets of Langerhans cells can be targeted by these enzymes and are digested, that may result in conditions like type I diabetes.

Hepatic and biliary systems are also affected in CF. Mucus plugging of these biliary ducts can cause Obstructive cirrhosis and post-hepatic hyperbilirubinemia. In case of hepatic portal vein plugging, there may be hypersplenism and splenomegaly seen.

Sweat glands normally transport chloride from extracellular surface to intracellular surface by CFTR (reverse). Hence, CFTR mutation effect on sweat glands leads to fluid loss on skin due to loss of sodium as well. Hence, in CF patients, salty skin is observed.

CF is known to affect male fertility as well. There is congenital absence of vas deferens and it leads to azoospermia (no sperm count). Other effects include oligospermia, asthenospermia etc. CFTR is required for bicarbonate transport in the sperm, which is required for sperm capacitation (attainment of hyperactive motility). CFTR is also expressed in germ cells of the testis and thus, involved in spermatogenesis. It is expressed by sertoli cells of the testis that maintain the testis-blood barrier. It is involved in ion transport in these cells, which is essential for germ cell maturation. CFTR is also required for sperm maturation in the epididymis. Thus, CFTR defects will cause male infertility. In female, the cervix will show thickened mucus, which inhibits the transport of sperm for fertilization.