Mechanism of Action of G-blocks: Is calcium involved?
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The mucus barrier coats the internal surfaces in the body and is one of nature?s success stories. Due to the physiological importance of it there has been extensive research on mucus and mucins for decades. Several mechanisms for mucus gelation have been proposed, but no consensus has been reached. Mucus is a very fine-tuned and complex system, where its different components act together to by different types of interactions to form the functional viscoelastic barrier.The ability of G-blocks from alginate to modify mucus rheology and barrier functions gives G-blocks a potential as a pharmaceutical mucus modifier, with applications in both the treatment and management in respiratory diseases like cystic fibrosis, and in drug delivery across mucosae. Calcium plays an important role in mucin packaging before granular release, and studies done on mucin-calcium interactions demonstrates that calcium increases the viscoelasticity of mucin in the concentrated regime and thus making the mucus network more impenetrable. In the dilute solution regime, where the number of mucin molecules is too low for intermolecular bonds, calcium compacts the mucin molecules and decreases the viscosity of the solution. This MSc thesis investigates the role played by calcium in mucin gelation and interactions, and the effect of G-blocks has on these interactions.The results from viscometry and rheometry in this master?s thesis show that calcium has a profound effect on the rheology of pig gastric mucin and mucus, and the presence of calcium in both purified pig gastric mucin and the native gastric mucus secretion indicates that calcium also plays a role in maintaining the gel network after granular release. The results from ITC further indicate an interaction between G-blocks and mucin in dilute solution. Given the complexity of the mucus gel and the mucin molecules, the mucolytic effect of G-blocks is most likely due to several types of interactions. By evaluating the results from this project, and the effect G-blocks has on both gastric and lung mucus as demonstrated by others, it seems possible that the mucin-mucin interactions that G-blocks affect is of a more universal nature than the specific acid induced interactions that has been proposed as being responsible for maintaining the gel network in gastric mucus.G-blocks bind calcium strongly, and together with the knowledge of the importance of calcium in mucus rheology, it is possible that the G-block effect linked to calcium. A possible explanation for the interaction is G-blocks interfering with the mucin-mucin bonds mediated by calcium, and that G-block-mucin bonds also could be mediated by calcium.