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Mechanisms of a sustained anti-inflammatory drug response in alveolar macrophages unraveled with mathematical modeling

By Elin Nyman, Maria Lindh, William Lövfors, Christian Simonsson, Alexander Persson, Daniel Eklund, Erica Bäckström, Markus Fridén, Gunnar Cedersund

Posted 14 Apr 2020
bioRxiv DOI: 10.1101/2020.04.13.031245 (published DOI: 10.1002/psp4.12568)

Both initiation and suppression of inflammation are hallmarks of the immune response. If not balanced, the inflammation may cause extensive tissue damage, which is associated with common diseases, e.g. asthma and atherosclerosis. Anti-inflammatory drugs often come with severe side effects driven by high and fluctuating drug concentrations. To remedy this, drugs with sustained anti-inflammatory responses are desirable. However, we still lack a quantitative mechanistic understanding of such sustained effects. Here, we study the anti-inflammatory response to a common glucocorticoid drug, Dexamethasone. We find a sustained response 22 hours after drug removal. With hypothesis testing using mathematical modeling, we unravel the underlying mechanism -- a slow release of Dexamethasone from the receptor-drug complex. The developed model is in agreement with time-resolved training and testing data, and is used to simulate hypothetical treatment schemes. This work opens up for a more knowledge-driven drug development, to find sustained anti-inflammatory responses and fewer side effects. ### Competing Interest Statement EB and MF are employees at AstraZeneca. ML contributed to this work as a thesis project with AstraZeneca. The rest of the authors declare that they have no conflict of interest.

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