Inheritence pattern in CF
autosomal recessive
Channel defect in CF
CFTR
ATP-gated Cl- channel
Membrane spanning of CFTR
12 membrane-spanning domains
Regulation modalities of CFTR protein
NBD: nucleotide binding domain
–> ATP binds, must have 2 sites occupied to open
R domain: phophorylated via PKA
–> protein kinase A
What activates phosphorylation of R domain?
cAMP buildup
cAMP activates PKA
PKA phosphorylates R domain
CFTR chromosome
chromosome 7 long arm
Most common CFTR mutation
F508del (deletion of Phe508)
mutation in NBD
(binding site of ATP)
⇒ gating defect
⇒ protein folding defect
Polarity of CFTR in
lung
pancreas
liver
lung: Cl- outward movement
pancreas: Cl- outward movement
liver: Cl- outward movement
skin: Cl- inward movement
CFTR mutation
lung manifestation
pathophysiology
Cl- and HCO3- not secreted into airway
→ decreased airway surface liquid volume
→ expansion of mucin not completed by HCO3-
Airway damage in CF
inflammation due to inability to clear secretions/bacteria
activation of inflammatory pathways
LPS → TLR4 → MyD88 → NF-kB
inflammatory mediators: TNF-α
neutrophil recruitment
Neutrophil airway damage mechanism
elastase release
damage of CFTR
DAMPs → furthur damage
Common infection in CF patients
Pseudomonas aeruginosa
Long-term pulmonary damage in CF
bronchiectasis
Tx of CF classically
N-acetylcysteine
⇒ cleaves disulfide bonds in mucus
dornase alfa
⇒ DNAse, clears leukocytic debris
Pancreatic duct CFTR mutation
HCO3- not secreted by epithelial cells lining pancreatic duct
blockage of pancreatic duct by secreted protein plugs
leakage of proteolytic enzymes
inflammatory damage
Pancreatic damange manifestations
inability to absorb lipids, fat-soluble vitamins
CF-associated diabetes
⇒ from collateral inflammatory damage
Intestine CFTR mutation manifestations
crypt cells of intestinal epithelium
cannot secrete H2O that follows Cl-
⇒ obstruction
⇒ inability to absorb proteins, fats
Long-term GI risk in CF
colon cancer
more colonoscopies for screening
Liver CF manifestations
HCO3- normally neutalizes bile acids
retention of bile acids
→ MCP1 synthesis
→ hepatic stellate cell and fibrogenic myofibroblast acitvation
→ collagen, fibrogenesis
⇒ cirrhosis or portal HTN
CF and fertility
vas deferens absent in almost all males
absorbed in featus or infancy
Sweat glands CF
opposite polarity of other areas
Cl- brought in from interstitium
→ high Cl- in sweat
→ basis for sweat test
Ivacaftor
MOA
TU
MOA: keeps CFTR channel in open position longer
TU: G551D and F508del mutation, NBD mutation
Ataluren
MOA
TU
MOA: allows ribosome to read through stop codons
TU: G542X mutation, premature stop codon
Lumacaftor
MOA
TU
MOA: promotes trafficing of CFTR to membrane instead of degradation
TU: F508del mutation