It has been reported that exhaled nitric oxide levels are reduced in cystic fibrosis (CF) patients. We have examined the inducible isoform of nitric oxide synthase (iNOS) in the airways by immunostaining and found that iNOS is constitutively expressed in the airway epithelia of non-CF mouse and human tissues but essentially absent in the epithelium of CF airways. We explored potential consequences of lost iNOS expression and found that iNOS inhibition significantly increases mouse nasal trans-epithelial potential difference, and hindered the ability of excised mouse lungs to prevent growth of Pseudomonas aeruginosa. The absence of continuous nitric oxide production in epithelial cells of CF airways may play a role in two CF-associated characteristics: hyperabsorption of sodium and susceptibility to bacterial infections.
T J Kelley, M L Drumm
Submitter: Valerie M. Hudson | valerie_hudson@byu.edu
Brigham Young University
Published September 7, 2000
J Kelley and ML Drumm found that iNOS expression is reduced in cystic fibrosis human airway epithelial cells. The reason for this is unclear. However, a recent publication by G Chen, SH Wang, and TD Warner may provide a key. In their article, "Regulation of iNOS by mRNA levels in endothelial cells by glutathione, a double-edged sword." (Free Radic Res 2000 Mar; 32(3):223-34), they note that "appropriate concentrations of GSH and GSSG increase the expression of the iNOS gene. However, either GSH or GSSG at too high concentration inhibits its expression, indicating that the iNOS gene is fine tuned by the metabolites of the glutathione cycle." Couple that new finding with the long-standing observation of a systemic deficiency of GSH in CF (Roum et al, J Appl Physiol 75(6):2419-24, 1993 Dec), and the 1998 finding of P Linsdell and J Hanrahan that the CFTR channel is the primary efflux route of cellularly-produced GSH in cells without redundant anion channels (Am J Physiol – Cell Physiol 44(1): C323- 326, 1998 Jul), and an explanation of Kelly and Drumm's findings might be at hand. Might augmentation of GSH levels in CF patients rectify, among other things, reduced iNOS expression, thereby alleviating to some degree all the negative consequences of such reduction as outlined by Kelley and Drumm?