CYSTIC FIBROSIS

Marc E. Tischler, PhD; University of Arizona

CYSTIC FIBROSIS: RELEVANT FACTS

defective gene = cystic fibrosis transmembrane conductance regulator (CFTR) CFTR protein C p o e is s a chloride c o de ion o channel c a e defective chloride channel affects lungs (Fig 1), liver (Fig 2), pancreas and intestine (Fig 3) and sweat glands (Fig 4) defect generally leads to mucus formation likely because of dehydration of the fluid surrounding affected cells

LUNGS NORMAL DISEASE

Chloride (Cl-) Sodium (Na+) (-1 charge) (+1 charge)

Cl- trapped in cell due to channel deficiency

Na+ trapped in cell to keep charge balance

ClChloride ion channel h l

Na+

LUNG FLUID

Excess mucus formation in lung fluid fl id

Figure 1. Chloride (Cl-) is moved out of lung cells into the surrounding fluid through the chloride ion channel that is the product of the CFTR gene (see slide 2). Because Cl- is negatively charged, a positively charged sodium ion (Na+) accompanies the Cl- to maintain a balance of charges (left). In cystic fibrosis, the chloride ion channel is defective (X) causing both chloride and sodium ions (X) to be trapped in the cell. Lower amounts of ions leaving the cell leads to less water in the lung fluid and results in mucus formation. Mucus buildup leads to inflammation. Bacteria trapped in the mucus grow out of control often leading to pneumonia.

LIVER NORMAL
Chloride (Cl-) Sodium (Na+) (-1 charge) (+1 charge)

DISEASE

Cl- trapped in cell due to channel deficiency

Na+ trapped in cell to keep charge balance

X
ClChloride ion channel h l

Na+
BILE DUCT

thickened secretions block bile duct

Figure 2. Chloride (Cl-) is moved out of liver cells into the bile duct through the chloride ion channel and is accompanied by sodium ion (Na+) to balance the charge (left). In cystic fibrosis, the chloride ion channel is defective (X) causing both chloride and sodium ions (X) to be trapped in the cell. Lower amounts of ions leaving the cell leads to less water in the bile duct and results in thickened secretions that block the bile duct. Consequently bile salts are trapped in the liver causing tissue damage that potentially leads to development of biliary cirrhosis.

NORMAL

PANCREAS DISEASE
Cl- trapped in Na+ trapped cell due to in cell to keep channel charge deficiency balance Digestive enzymes trapped in cell

Chloride (Cl-) Sodium (Na+) (-1 charge) (+1 charge) Digestive enzymes

INTESTINE

ClChloride ion channel

Na+

Digestive enzymes

Digestive enzymes for processing dietary fats

XX X
thickened secretions

PANCREATIC DUCT

Figure 3. Chloride (Cl-) is moved out of pancreatic cells into the pancreatic duct through the chloride ion channel and is accompanied by sodium ion (Na+) to balance the charge (left). Digestive enzymes also move into the pancreatic duct for delivery to the intestine. In cystic fibrosis, the chloride ion channel is defective (X) causing both chloride and sodium ions (X) to be trapped in the cell. Lower amounts of ions leaving the cell leads to less water in the pancreatic duct and results in thickened secretions that block the duct. Consequently digestive enzymes are trapped in the pancreas (X) causing tissue damage that leads to pancreatitis. The lack of digestive enzymes prevents processing of dietary fats leading to malabsorption of fats (also fat-soluble vitamins), so that fats are excreted causing fatty diarrhea (steatorrhea).

SWEAT GLANDS NORMAL

Chloride (Cl-) Sodium (Na+) taken into sweat taken into sweat gland for storage gland for storage

DISEASE

Sodium and chloride not taken leading into gland g g to measurable excess salt in the sweat

ClChloride ion channel

Na+

Excess salt excreted in sweat

Cl- trapped in duct

Na+ trapped in duct

SWEAT DUCT Figure 4. Chloride moves into sweat glands from the sweat ducts through the chloride ion channel and is accompanied by sodium ion (Na+) to balance the charge (left). In this way salt is stored in the glands to be released as needed to lose water (sweating) as a means of regulating body temperature. In cystic fibrosis, the chloride ion channel is defective (X) causing both chloride and sodium ions (X) to remain in the sweat ducts leading to excess salt in the sweat. This excess salt is measurable as a means of distinguishing between those with disease and those who are simply carriers of the disease. High levels of salt in the sweat test can also be used as a diagnostic tool though false positives are possible. (Cl-)