Accession Number : ADA586380


Title :   Modeling the Intra- and Extracellular Cytokine Signaling Pathway under Heat Stroke in the Liver


Descriptive Note : Journal article


Corporate Author : ARMY RESEARCH INST OF ENVIRONMENTAL MEDICINE NATICK MA THERMAL AND MOUNTAIN MEDICINE DIVISION


Personal Author(s) : Rodriguez-Fernandez, Maria ; Grosman, Benyamin ; Yuraszeck, Theresa M ; Helwig, Bryan G ; Leon, Lisa R ; Doyle, III, Francis J


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a586380.pdf


Report Date : 05 Sep 2013


Pagination or Media Count : 21


Abstract : Heat stroke (HS) is a life-threatening illness induced by prolonged exposure to a hot environment that causes central nervous system abnormalities and severe hyperthermia. Current data suggest that the pathophysiological responses to heat stroke may not only be due to the immediate effects of heat exposure per se but also the result of a systemic inflammatory response syndrome (SIRS). The observation that pro- (e.g., IL-1) and anti-inflammatory (e.g., IL-10) cytokines are elevated concomitantly during recovery suggests a complex network of interactions involved in the manifestation of heat-induced SIRS. In this study, we measured a set of circulating cytokine/soluble cytokine receptor proteins and liver cytokine and receptor mRNA accumulation in wild-type and tumor necrosis factor (TNF) receptor knockout mice to assess the effect of neutralization of TNF signaling on the SIRS following HS. Using a systems approach, we developed a computational model describing dynamic changes (intra- and extracellular events) in the cytokine signaling pathways in response to HS that was fitted to novel genomic (liver mRNA accumulation) and proteomic (circulating cytokines and receptors) data using global optimization. The model allows integration of relevant biological knowledge and formulation of new hypotheses regarding the molecular mechanisms behind the complex etiology of HS that may serve as future therapeutic targets. Moreover, using our unique modeling framework, we explored cytokine signaling pathways with three in silico experiments (e.g. by simulating different heat insult scenarios and responses in cytokine knockout strains in silico).


Descriptors :   *CYTOKINES , *HEAT STROKE , *LIVER , INFLAMMATION , NEOPLASMS , RIBONUCLEIC ACIDS , SYSTEMS BIOLOGY , TEMPERATURE


Subject Categories : Biochemistry
      Anatomy and Physiology
      Medicine and Medical Research
      Stress Physiology


Distribution Statement : APPROVED FOR PUBLIC RELEASE