RX-207, a Small Molecule Inhibitor of Protein Interaction with Glycosaminoglycans (SMIGs), Reduces Experimentally Induced Inflammation and Increases Survival Rate in Cecal Ligation and Puncture (CLP)-Induced Sepsis

Juhás, Štefan; Harris, Nicholas; Il'ková, Gabriela; Rehák, P; Zsila, Ferenc; Kogan, Faina Yurgenzon; Lahmy, Orly; Zhuk, R. A.; Gregor, Paul; Koppel, Juraj

doi:10.1007/s10753-017-0688-0

Cited by 8 publications

(1 citation statement)

References 34 publications

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“…Extending the investigations into endogenously produced pro-resolving lipid mediators, Ramon et al not only identified PCTR1, a member of the protectin family as a potent monocyte/macrophage agonist but also established the therapeutic potential of PCTR1 supplementation in resolving inflammation using microbial-induced peritonitis in mice [70]. Similarly, Juhas et al confirmed the ability of RX-207 to reduce neutrophil migration using thioglycollate-induced peritonitis [71]. These examples not only underscore the importance of developing a mathematical model based on experimental data from mouse peritonitis, but also provide the rationale and future application of such a model for evaluating and predicting outcomes to be validated by subsequent experimentation.…”

Section: Discussionmentioning

confidence: 99%

Identifying important parameters in the inflammatory process with a mathematical model of immune cell influx and macrophage polarization

et al. 2019

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In an inflammatory setting, macrophages can be polarized to an inflammatory M1 phenotype or to an anti-inflammatory M2 phenotype, as well as existing on a spectrum between these two extremes. Dysfunction of this phenotypic switch can result in a population imbalance that leads to chronic wounds or disease due to unresolved inflammation. Therapeutic interventions that target macrophages have therefore been proposed and implemented in diseases that feature chronic inflammation such as diabetes mellitus and atherosclerosis. We have developed a model for the sequential influx of immune cells in the peritoneal cavity in response to a bacterial stimulus that includes macrophage polarization, with the simplifying assumption that macrophages can be classified as M1 or M2. With this model, we were able to reproduce the expected timing of sequential influx of immune cells and mediators in a general inflammatory setting. We then fit this model to in vivo experimental data obtained from a mouse peritonitis model of inflammation, which is widely used to evaluate endogenous processes in response to an inflammatory stimulus. Model robustness is explored with local structural and practical identifiability of the proposed model a posteriori . Additionally, we perform sensitivity analysis that identifies the population of apoptotic neutrophils as a key driver of the inflammatory process. Finally, we simulate a selection of proposed therapies including points of intervention in the case of delayed neutrophil apoptosis, which our model predicts will result in a sustained inflammatory response. Our model can therefore provide hypothesis testing for therapeutic interventions that target macrophage phenotype and predict outcomes to be validated by subsequent experimentation.

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Section: Discussionmentioning

confidence: 99%