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A quantitative model of thermal injury-induced acute inflammation.

ABSTRACT: Severe burns are among the most common causes of death from unintentional injury. The induction and resolution of the burn-induced systemic inflammatory response are mediated by a network of factors and regulatory proteins. Numerous mechanisms operate simultaneously, thus requiring a systems level approach to characterize their overall impact. Towards this goal, we propose an in silico semi-mechanistic model of burn-induced systemic inflammation using liver-specific gene expression from a rat burn model. Transcriptional responses are coupled with extracellular signals through a receptor mediated indirect response (IDR) and transit compartment model. The activation of the innate immune system in response to the burn stimulus involves the interaction between extracellular signals and critical receptors which triggers downstream signal transduction cascades leading to transcriptional changes. The resulting model consists of fifteen (15) coupled ordinary differential equations capturing key aspects of inflammation such as pro-inflammation, anti-inflammation and hypermetabolism. The model was then evaluated through a series of biologically relevant scenarios aiming at revealing the non-linear behavior of acute inflammation including: investigating the implication of effect of different severity of thermal injury; examining possible mechanistic dysregulation of IKK-NF-?B system which may reflect secondary effects that lead to potential malfunction of the response; and exploring the outcome of administration of receptor antagonist or anti-body to significant cytokines.

SUBMITTER: Yang Q

PROVIDER: S-EPMC3239409 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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A quantitative model of thermal injury-induced acute inflammation.

Yang Qian Q Berthiaume Francois F Androulakis Ioannis P IP

Mathematical biosciences 20100811 2

Severe burns are among the most common causes of death from unintentional injury. The induction and resolution of the burn-induced systemic inflammatory response are mediated by a network of factors and regulatory proteins. Numerous mechanisms operate simultaneously, thus requiring a systems level approach to characterize their overall impact. Towards this goal, we propose an in silico semi-mechanistic model of burn-induced systemic inflammation using liver-specific gene expression from a rat bu ...[more]

PMID: 20708022

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Project description:Alcohol liver disease (ALD) is a liver disease caused by long-term heavy drinking. Glucosamine (GLC) is an amino monosaccharide that plays a very important role in the synthesis of human and animal cartilage. GLC is commonly used in the treatment of mild to moderate osteoarthritis and has good anti-inflammatory and antioxidant properties. In this study, alcoholic injury models were constructed in mice and human normal hepatocyte L02 cells to explore the protective effect and mechanism of GLC on ALD. Mice were given GLC by gavage for 30 days. Liver injury models of both mice and L02 cells were produced by ethanol. Detecting the levels of liver injury biomarkers, lipid metabolism, oxidative stress biomarkers, and inflammatory factors through different reagent kits. Exploring oxidative and inflammatory pathways in mouse liver tissue through Western blot and RT-PCR. The results showed that GLC can significantly inhibit the abnormal increase of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), triglycerides (TG), total cholesterol (TC), very low density lipoprotein (VLDL), low-density lipoprotein cholesterol (LDL-C), and can significantly improve the level of high-density lipoprotein cholesterol (HDL-C). In addition, GLC intervention significantly improved alcohol induced hepatic oxidative stress by reducing the levels of malondialdehyde (MDA) and, increasing the levels of glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) in the liver. Further mechanisms suggest that GLC can inhibit the expression of ethanol metabolism enzyme cytochrome P4502E1 (CYP2E1), activate the antioxidant pathway Keap1/Nrf2/HO-1, down-regulate the phosphorylation of MAPK and NF-κB signaling pathways, and thus reduce the expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). Therefore, GLC may be a significant candidate functional food for attenuating alcohol induced acute liver injury.

Dataset Information

A quantitative model of thermal injury-induced acute inflammation.

Publications

A quantitative model of thermal injury-induced acute inflammation.

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