title: Regulation of Toll-like receptor 4 expression in the lung following hemorrhagic shock and lipopolysaccharide.
abstract: The Toll-like receptor 4 (TLR4) has recently been shown to function as the major upstream sensor for LPS. In this study, a rodent model of lung injury following resuscitated hemorrhagic shock was used to examine the regulation of TLR4 gene and protein expression in vivo and in vitro. Intratracheal LPS alone induced a rapid reduction in whole lung TLR4 mRNA, an effect which is also observed in recovered alveolar macrophages. This effect appeared to be due to a lowering of TLR4 mRNA stability by approximately 69%. By contrast, while shock/resuscitation alone had no effect on TLR4 mRNA levels, it markedly altered the response to LPS. Specifically, antecedent shock prevented the LPS-induced reduction in TLR4 mRNA levels. This reversal was explained by the ability of prior resuscitated shock both to prevent the destabilization of TLR4 mRNA by LPS and also to augment LPS-stimulated TLR4 gene transcription compared with LPS alone. Oxidant stress related to shock/resuscitation appeared to contribute to the regulation of TLR4 mRNA, because supplementation of the resuscitation fluid with the antioxidant N-acetylcysteine reversed the ability of shock/resuscitation to preserve TLR4 mRNA levels following LPS. TLR4 protein levels in whole lung mirrored the changes seen for TLR4 mRNA. Considered in aggregate, these data suggest that levels of tlr4 expression are controlled both transcriptionally as well as posttranscriptionally through altered mRNA stability and that antecedent shock/resuscitation, a form of global ischemia/reperfusion, might influence regulation of this gene.
authors: Department of Surgery, University Health Network, St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada.
authors: Jie
authors: J
authors: Fan
authors: Andras
authors: A
authors: Kapus
authors: Philip A
authors: PA
authors: Marsden
authors: Yue Hua
authors: YH
authors: Li
authors: George
authors: G
authors: Oreopoulos
authors: John C
authors: JC
authors: Marshall
authors: Stefan
authors: S
authors: Frantz
authors: Ralph A
authors: RA
authors: Kelly
authors: Ruslan
authors: R
authors: Medzhitov
authors: Ori D
authors: OD
authors: Rotstein
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D029721:Drosophila Proteins; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000276:immunology* / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology; D012771:Shock, Hemorrhagic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors