The effect of therapeutic hypothermia on the expression of inflammatory response genes following moderate traumatic brain injury in the rat.
Traumatic brain injury (TBI) initiates a cascade of cellular and molecular responses including both pro- and anti-inflammatory. Although post-traumatic hypothermia has been shown to improve outcome in various models of brain injury, the underlying mechanisms responsible for these effects have not been clarified. In this study, inflammation cDNA arrays and semi-quantitative RT-PCR were used to detect genes that are differentially regulated after TBI. In addition, the effect of post-traumatic hypothermia on the expression of selective genes was also studied. Rats (n = 6-8 per group) underwent moderate fluid-percussion (F-P) brain injury with and without hypothermic treatment (33 degrees C/3 h). RNA from 3-h or 24-h survival was analyzed for the expression of IL1-beta, IL2, IL6, TGF-beta2, growth-regulated oncogene (GRO), migration inhibitory factor (MIF), and MCP (a transcription factor). The interleukins IL-1beta, IL-2, and IL-6 and TGF-beta and GRO were strongly upregulated early and transiently from 2- to 30-fold over sham at 3 h, with normalization by 24 h. In contrast, the expressions of MIF and MCP were both reduced by TBI compared to sham. Post-traumatic hypothermia had no significant effect on the acute expression of the majority of genes investigated. However, the expression of TGF-beta2 at 24 h was significantly reduced by temperature manipulation. The mechanism by which post-traumatic hypothermia is protective may not involve a general genetic response of the inflammatory genes. However, specific genes, including TGF-beta2, may be altered and effect cell death mechanisms after TBI. Hypothermia differentially regulates certain genes and may target more delayed responses underlying the secondary damage following TBI.
Truettner
Jessie S
JS
Department of Neurological Surgery, The Neurotrauma Research Center, The Miami Project to Cure Paralysis, University of Miami School of Medicine, Miami, FL 33136, USA.
Suzuki
Takamoto
T
Dietrich
W Dalton
WD
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D001930:Brain Injuries / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000235:genetics; D016207:Cytokines / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004660:Encephalitis / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D005786:Gene Expression Regulation / Q000235:genetics; D007036:Hypothermia, Induced; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics; D008297:Male; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000235:genetics; D053781:Transforming Growth Factor beta2
D015703:Antigens, CD; C497860:Cd46 protein, rat; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; D016207:Cytokines; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D007378:Interleukins; D008263:Macrophage Migration-Inhibitory Factors; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2