Cellular Pathophysiology of Cystic Fibrosis

Cellular Pathophysiology of Cystic Fibrosis

Submitted by Terry White

Outside the cell:

Accurso 2-fold Increased PMNs, even in BAL from asymptomatic 2.4 month old infants. 10-20 fold increase in lactoferrin
(probably from PMNs) by 5 years, 3 fold increase in lysozyme (from PMNs and epithelial cells) by 5 years (7 fold after 5 years). No significant difference in SLPI before 5 years.
Noah Increased IL8 (which would result in increased ICAM
production in the CF or neighboring cell?)
Fiedler Increased TNF-alpha (from PMNs, I think) leads to a drop
in IkB in cytoplasm and therefore increased NFkB in nucleus, which induces more IL8 production. Blocking NFkB completely, however, leads to apoptosis.
Prince Increased asialoGM1, which binds increased amounts of
Weiss Phospholipase A2 (which kills gram-positive bacteria) is
increased in inflammatory fluids – CF-specific data not
Bals Human beta defensin 2 shows reduced expression or
secretion in (and external to) epithelial cells
Brogen Anionic peptides were present at 0.78 mm in CF BAL and
1.3 mM in normal BAL (significantly lower in CF). Should be present in alveolar epithelial cells, but this isn’t true in
CF – instead, it s mostly present in bronchiolar

  Inside the cell:

Author Reference Symptoms
Kelley Absence of iNOS results in a decrease in NO, which
normally makes guanylate cyclase which makes cGMP, which inhibits phosphodiesterase III from dephosphorylating CFTR. Therefore, decreased NO should decrease CFTR activity. Milrinone and IBMX inhibit PDEIII and therefore should increase CFTR activity.
Prince Stress response, due to increased mutant CFTR protein in
ER. Increased IL8 due to increases in NFkB expression
(blocking release of intracellular calcium prevents IL8
increase, as does blocking NFkB release from NFkB-IkB
complexes). Increased NFkB (which may also increase
apoptosis) (Ibuprofen decreases NFkB)
McCray Human beta defensin 1 and 2 present in both CF and normal epithelial and submucosal gland cells. IL1 can induce hBD2 in both CF and normal cells.