Program
CTF2c | |
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Anna Ougrinovskaia | |
University of Sydney | |
Title | Modelling the inflammatory response in early stage atherosclerosis |
Abstract | Within the past decade, inflammation has been determined as a crucial factor in all stages of formation of atherosclerotic plaques. The inflammatory response is initiated by the appearance and modification of cholesterol-carrying Low Density Lipoproteins (LDL) in the intima. Monocyte-derived macrophages then bind modified LDL and internalize it, via a variety of scavenger receptors. Eventually they become laden with lipid and take on a foamy appearance. These macrophage foam cells become trapped in the intima, and, moreover, continue to proliferate, becoming the main constituent of early plaques. Macrophage proliferation and uptake of modified LDL are mediated by an array of factors, including pro- and anti-inflammatory cytokines, T-cells, and High Density Lipoproteins (HDL). HDL is thought to have an athero-protective role and to enable plaques to regress with time. We present a simplified ODE model based on the interactions of modified LDL and macrophages, and allow these interactions to be modified by the presence of T-cells and HDL. The model uses general kinetic functions, as the exact mechanisms of modified LDL uptake and HDL activity are still a subject of debate. We are able to perform a phase plane analysis of the system without relying on parameter estimation. Our results indicate that the underlying mechanisms of macrophage uptake of modified LDL can have a deep impact on the cellular dynamics in the lesion. We demonstrate that it is macrophage proliferation and constant signalling, rather than an increasing influx of modified LDL, that drives lesion instability. We also identify cholesterol efflux and possibility of foam cell emigration as the main pathways through which HDL stabilizes the system and reduces the foam cell content. |
Coauthors | Rosemary S. Thompson, Mary R. Myerscough |
Location | Friedman 153 |