Cellular Pathophysiology of Cystic Fibrosis
Submitted by Terry White
Outside the cell:
| Author Reference |
Symptoms |
|---|---|
| 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 Pseudomonas |
| Weiss | Phospholipase A2 (which kills gram-positive bacteria) is increased in inflammatory fluids – CF-specific data not discussed. |
| 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 epithelium. |
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. |