Cystic Fibrosis 3

• CFTR


  Cystic Fibrosis Transmembrane Conductance Regulator - a protein that functions as a chloride channel in the cell membrane
• CFTR in normal bronchial epithelium

  • Expressed in large airways (bronchi)
  • Secretes chloride ions at apical membrane into airway lumen
  • Channel is activated by phosphorylation
  • Increases in cAMP activate protein kinase A which phosphorylates CFTR
  • Secretion also occurs through alternate chloride channels, although most is through active CFTR
  • Negatively regulates epithelial sodium channel (ENaC) and suppresses its activity, limiting sodium uptake
• Chloride ion transport in normal bronchial epithelium

  1. Chloride ions transported into cell via Na/K/Cl co-transporter at basal membrane

  2. Electrochemical gradients push chloride out through CFTR

  3. Sodium flows between cells to neutralize chloride ions secreted via CFTR

  4. Water follows movement of salt
• CFTR expression in normal airway epithelial cells

  • Expressed in surface epithelium and more predominantly in submucosal glands
  • Determines volume and composition of airway fluid
  • Salt secretion mainly due to chloride ion secretion through CFTR
  • Negative regulatory effect on epithelial sodium channels (ENaC) limits sodium uptake and water reabsorption
  • Sodium reabsorption mainly by passive diffusion of sodium down concentration gradients into cell through ENaC
  • Intracellular sodium concentration maintained low by Na/K pump activity
  • Epithelium is secretory, with net movement of water into airway to produce watery fluid lining
  • Fluid layer permits synchronous beating of cilia
• CFTR in CF bronchial epithelium

  • CFTR absent or defective, leading to reduced chloride secretion
  • Removes negative regulatory effect on ENaC, leading to massive increase in sodium absorption (10x normal)
  • Compensatory increase in Na/K pump activity
  • Primary electrophysiological defect is in sodium channel activity
  • Overall epithelium is absorptive, with chloride ions flowing between cells to neutralize excess sodium uptake
• Defective CFTR in CF airways

  Leads to dehydrated, retained secretions that invite infection and inflammation
• Bacterial pathogens in CF airway

  • Staphylococcus aureus
  • Haemophilus influenzae
  • Pseudomonas aeruginosa
  • Burkholderia cepacia complex
  • Stenotrophomonas maltophilia
• Events leading to chronic infection in CF

  1. Normal airway: Thin mucus layer, normal epithelial oxygen consumption

  2. CF epithelium: Depletion of periciliary fluid, increased oxygen consumption

  3. Continued mucus secretion increases mucus layer height and oxygen gradients

  4. Pseudomonas penetrates into hypoxic zones, adapts with increased alginate production and macrocolony formation

  5. Macrocolonies resist secondary defences, setting stage for chronic infection
• Production of neutrophil chemoattractant IL-8 in normal airway

  • Pulmonary macrophages initiate host response to bacterial infection
  • Neutrophils recruited in response to IL-8 concentration gradients
  • IL-8 produced by airway cells in response to bacterial toxins like LPS
  • Cytokines can have autocrine or paracrine effects
• Production of neutrophil chemoattractant IL-8 in hyperinflammatory CF airway


  • IL-8 levels orders of magnitude higher than normal
  • Absence of IL-10 and high protease levels contribute
  • Activated neutrophils release elastase which stimulates more IL-8 synthesis
  • Neutrophils are also a direct source of IL-8, creating a self-amplifying cycle
  • Inflammatory response fails to clear bacteria but causes tissue damage
  • Defects in CFTR trafficking may also contribute to inflammatory state
• Neutrophil phagocytosis and bacterial killing

  • Neutrophils have primary, secondary and tertiary granules containing antimicrobial proteins
  • Phagocytosis involves complement and immunoglobulin receptors
  • Granule contents released into phagosome to kill bacteria
  • Proteases, defensins, BPI, and reactive oxygen species are antimicrobial mechanisms
• Neutrophils attempt to phagocytose Pseudomonas, become activated and release elastase, MMPs, reactive oxygen and MPO into the tissue, damaging the tissue they should protect
• Pseudomonas evades the immune system by growing in large colonies covered in alginate, which also prevents antibiotics from working