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Computational Identification of Mechanistic Factors That Determine the Timing and
Intensity of the Inflammatory Response
#MMPMID26633296
Nagaraja S
; Reifman J
; Mitrophanov AY
PLoS Comput Biol
2015[Dec]; 11
(12
): e1004460
PMID26633296
show ga
Timely resolution of inflammation is critical for the restoration of homeostasis
in injured or infected tissue. Chronic inflammation is often characterized by a
persistent increase in the concentrations of inflammatory cells and molecular
mediators, whose distinct amount and timing characteristics offer an opportunity
to identify effective therapeutic regulatory targets. Here, we used our recently
developed computational model of local inflammation to identify potential targets
for molecular interventions and to investigate the effects of individual and
combined inhibition of such targets. This was accomplished via the development
and application of computational strategies involving the simulation and analysis
of thousands of inflammatory scenarios. We found that modulation of macrophage
influx and efflux is an effective potential strategy to regulate the amount of
inflammatory cells and molecular mediators in both normal and chronic
inflammatory scenarios. We identified three molecular mediators - tumor necrosis
factor-? (TNF-?), transforming growth factor-? (TGF-?), and the chemokine CXCL8 -
as potential molecular targets whose individual or combined inhibition may
robustly regulate both the amount and timing properties of the kinetic
trajectories for neutrophils and macrophages in chronic inflammation. Modulation
of macrophage flux, as well as of the abundance of TNF-?, TGF-?, and CXCL8, may
improve the resolution of chronic inflammation.
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