Inflammation in cystic fibrosis airways: relationship to increased bacterial adherence

Abstract

It is unclear whether in¯ammation in the cystic ®brosis (CF) lung relates predominantly to bacterial infection, or occurs as a direct consequence of mutant cystic ®brosis transmembrane conductance regulator (CFTR) protein.Interleukin (IL)-8 secretion from CF and non-CF cell lines, and from CF and non-CF human primary nasal epithelial cells incubated with or without Pseudomonas aeruginosa, was measured. Activation of nuclear factor-kB (NF-kB) in unstimulated CF and non-CF nasal epithelial cells, cell lines and murine tissues was measured by gelshift assays.No signi®cant difference in basal IL-8 production or NF-kB activation was observed between CF and non-CF primary nasal cells. However, CF cells exhibited a signi®cantly (p<0.01) increased IL-8 secretion following P. aeruginosa stimulation. Equalization of the increased P. aeruginosa adherence observed in CF cells, to non-CF levels, resulted in comparable IL-8 secretion. Further, IL-8 production did not differ with mutations which result in either correctly localized CFTR, or in partial/total mislocalization of this protein. Similar levels of NF-kB activation were observed in a number of organs of wildtype and CF mice. Finally, IL-8 secretion and NF-kB activity were not consistently increased in CF cell lines. Cos-7 cell transfection with plasmids expressing DF508 or G551D mutant CFTR protein resulted in increased activation of a p50-containing NFkB complex, but IL-8 secretion was similar to wild-type cells.The authors conclude that the stimulus produced by Pseudomonas aeruginosa is the predominant in¯ammatory trigger in their models. Eur Respir J 2001; 17: 27±35.

CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-κB translocation

“…Bedard et al (36) finds no evidence for elevated production of IL-6, IL-8, or granulocyte͞macrophage colony-stimulating factor when using primary epithelial cell cultures from the lungs of CF patients. Finally, Scheid et al (37) report no difference in the basal levels of NF-B translocation and IL-8 production when comparing CF and non-CF primary nasal epithelial cells in culture, wt and transgenic CF mouse tissues, and wt and CF cell lines, although more prolonged interaction between CF cells and P. aeruginosa does lead to NF-B activation. Our observations reported here are consistent with the conclusion that CF epithelial cells do not constitutively translocate NF-B to the nucleus.…”

Anti-inflammatory gene therapy directed at the airway epithelium

“…Recently we have shown, that the degree of IL-8 stimulation in primary airway epithelial cells is directly related to the number of PA bound to the cell surface. 6 Cytokine secretion is predominantly regulated at the level of gene transcription. The transcription factor nuclear factor kappa B (NF B) is a central regulator of inflammatory and immune responses, 7,8 and belongs to the REL-family of transcription factors.…”

Airway surface pH in subjects with cystic fibrosis

“…CF cells express increased levels of asialoglycolipids, such as asialoGM1, a receptor for Pseudomonas aeruginosa and Staphylococcus aureus [4,5]. This increased bacterial adherence has been shown to lead to a proportionately increased release of proinflammatory cytokines [6], a characteristic hallmark of CF. Furthermore, secreted glycolipids and mucins are over-sulphated, the degree of which correlates with both CFTR mutations [7] and severity of lung disease [8].…”