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A mathematical model relates intracellular TLR4 oscillations to sepsis progression

By Razvan Costin Stan, Francisco Garcia Soriano and Maristela Martins de Camargo

Abstract

Abstract\ud \ud Objective\ud Oscillations of physiological parameters describe many biological processes and their modulation is determinant for various pathologies. In sepsis, toll-like receptor 4 (TLR4) is a key sensor for signaling the presence of Gram-negative bacteria. Its intracellular trafficking rates shift the equilibrium between the pro- and anti-inflammatory downstream signaling cascades, leading to either the physiological resolution of the bacterial stimulation or to sepsis. This study aimed to evaluate the effects of TLR4 increased expression and intracellular trafficking on the course and outcome of sepsis.\ud \ud \ud Results\ud Using a set of three differential equations, we defined the TLR4 fluxes between relevant cell organelles. We obtained three different regions in the phase space: (1) a limit-cycle describing unstimulated physiological oscillations, (2) a fixed-point attractor resulting from moderate LPS stimulation that is resolved and (3) a double-attractor resulting from sustained LPS stimulation that leads to sepsis. We used this model to describe available hospital data of sepsis patients and we correctly characterize the clinical outcome of these patients.This study was supported by CNPq (400662/2014-0 for RCS, 309041/2012-0 for MMDC), FAPESP (11/51778-6 for MMDC)

Topics: Sepsis, Infammation, Intracellular trafcking, Ordinary diferential equations, Oscillations
Publisher: BioMed Central
Year: 2018
DOI identifier: 10.1186/s13104-018-3561-9
OAI identifier: oai:www.producao.usp.br:BDPI/51652
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