Hypertonic saline inhalation has become a cornerstone in the treatment of

Hypertonic saline inhalation has become a cornerstone in the treatment of cystic fibrosis (CF) but its effect on CF mucus is still not understood. similarity between the CF mucus in the ileum and airways. In the same type of system we investigated how hypertonic saline affects mucus thickness attachment and penetrability to fluorescent beads the size of bacteria in ileal explants from your cystic fibrosis transmembrane conductance regulator mutant (ΔF508) mouse in order to characterize how this common therapy affects mucus properties. Hypertonic saline (1.75-5%) detached the mucus from your epithelium but the mucus remained impenetrable to beads the size of bacteria. This approach might be used to test additional mucolytic interventions in CF. studies that suggest alternative mechanisms for the beneficial effect of this treatment.10-12 We have developed an experimental method where mucus can be studied and its properties evaluated after secretion from ileal explants.6 CF individuals commonly have Obatoclax mesylate intestinal problems including meconium ileus and distal intestinal obstruction syndrome. CF mice have a similar intestinal phenotype which can be controlled by adding salts and polyethylene glycol (a slight laxative) to the drinking water in conjunction with a liquid diet if required.13 We have previously shown that for proper unfolding of the MUC2 mucin the calcium and hydrogen ions bound to the mucin when packed in the goblet cell granule must be chelated on launch.14 This is accomplished by bicarbonate ions chelating calcium and increasing the pH. When this mechanism is definitely jeopardized as with CF the mucin is definitely insufficiently unfolded and is attached to the epithelium.6 Using normal homozygous wild-type (WT) and CF (ΔF508 = 3 green bar) and CF mice treated apically … Conversation Although the basis for CF is definitely a dysfunctional CFTR channel the relationship of this defect to actual CF disease manifestations has been controversial and there is still no uniform understanding of the reason for chronic lung infections. You will find two major and partly opposing models for the consequences of CFTR dysfunction one suggesting that this antibacterial peptides and proteins are less efficient and the other that this pericilliary liquid is usually decreased causing mucus to be caught in the cilia and entangled in the glycocalyx.18 19 The latter model was initially suggested to be caused by hyperabsorption of sodium but is more likely a result of decreased chloride and water efflux.19 20 More recently the gel-on-brush model Rabbit Polyclonal to PIAS2. was proposed indicating an Obatoclax mesylate electron-dense meshwork of transmembrane mucins between the cilia resulting in a double-layered system. Also this model suggests that the stagnant mucus characteristic of CF and COPD is a result of dehydration of mucus.21 22 Irrespective of aetiology the lungs of CF patients show poor bacterial clearance through the mucociliary system. Recently it was suggested that this mucus strands created from submucosal glands are attached in Cftr?/? but not Cftr+/+ piglets. This is extremely interesting because it suggests that there is a mucus phenotype before there is any sign of bacterial infection or inflammation in the lungs.23 Because the lungs are the main site of Obatoclax mesylate the severe and life-shortening CF problems less emphasis has been put on other organs. Among other hallmarks of CF are the salty sweat Obatoclax mesylate and plugged tubes of secretory organs such as the pancreas seminal ducts and biliary tree. Less attention has also been directed to the small intestine despite the high frequency of meconium ileus and distal obstruction syndrome. We have focused on this organ because the movement of mucus is usually slower and Obatoclax mesylate the main structural component is the MUC2 mucin and because mouse CF models both the full knock-out and ΔF508-Cftr have an intestinal pathology much like humans.13 Our previous studies have shown that in contrast to WT the CF small intestinal mucus is attached to the epithelium and that this a result of diminished unfolding of the intestinal MUC2 mucin. This was shown to be caused by insufficient concentrations of during mucin secretion.6 Hence the important ion in this context is not chloride but bicarbonate. We have also shown that selective CFTR inhibitors only cause 70% inhibition of the forskolin response in this set up and this level of inhibition is not sufficient to cause induction of the CF phenotype (i.e. attached mucus) in the ileal explants. However when the serosal answer was devoid of bicarbonate the WT.