title: Double-Stranded RNA Interacts With Toll-Like Receptor 3 in Driving the Acute Inflammatory Response Following Lung Contusion.
abstract: OBJECTIVE
  Lung contusion is a major risk factor for the development of acute respiratory distress syndrome. We set to determine the role of toll-like receptor 3 and the binding of double-stranded RNA in the pathogenesis of sterile injury following lung contusion.
  
  
  METHODS
  Toll-like receptor 3 expression was analyzed in postmortem lung samples from patients with lung contusion. Unilateral lung contusion was induced in toll-like receptor 3 (-/-), TIR-domain-containing adapter-inducing interferon-β (-/-), and wild-type mice. Subsequently, lung injury and inflammation were evaluated. Apoptotic indices, phagocytic activity, and phenotypic characterization of the macrophages were determined. Double-stranded RNA in bronchoalveolar lavage and serum samples following lung contusion was measured. A toll-like receptor 3/double-stranded RNA ligand inhibitor was injected into wild-type mice prior to lung contusion.
  
  
  RESULTS
  Toll-like receptor 3 expression was higher in patients and wild-type mice with lung contusion. The degree of lung injury, inflammation, and macrophage apoptosis was reduced in toll-like receptor 3 (-/-), TIR-domain-containing adapter-inducing interferon-β (-/-), and wild-type mice with toll-like receptor 3 antibody neutralization. Alveolar macrophages from toll-like receptor 3 (-/-) mice had a lower early apoptotic index, a predominant M2 phenotype and increased surface translocation of toll-like receptor 3 from the endosome to the surface. When compared with viral activation pathways, lung injury in lung contusion demonstrated increased p38 mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 phosphorylation with inflammasome activation without a corresponding increase in nuclear factor-κB or type-1 interferon production. Additionally, pretreatment with toll-like receptor 3/double-stranded RNA ligand inhibitor led to a reduction in injury, inflammation, and macrophage apoptosis.
  
  
  CONCLUSIONS
  We conclude that the interaction of double-stranded RNA from injured cells with toll-like receptor 3 drives the acute inflammatory response following lung contusion.
authors: 1Department of Surgery, University of Michigan, Ann Arbor, MI. 2Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI. 3Department of Pathology, University of Michigan, Ann Arbor, MI. 4Department of Chemistry, University of Michigan, Ann Arbor, MI. 5Department of Medicine, Cedar Sinai Medical Center, Los Angeles, CA.
authors: Madathilparambil V
authors: MV
authors: Suresh
authors: Bivin
authors: B
authors: Thomas
authors: David
authors: D
authors: Machado-Aranda
authors: Vladislov A
authors: VA
authors: Dolgachev
authors: Sadeesh
authors: S
authors: Kumar Ramakrishnan
authors: Nicholas
authors: N
authors: Talarico
authors: Karen
authors: K
authors: Cavassani
authors: Matthew A
authors: MA
authors: Sherman
authors: Mark R
authors: MR
authors: Hemmila
authors: Steven L
authors: SL
authors: Kunkel
authors: Nils G
authors: NG
authors: Walter
authors: Cory M
authors: CM
authors: Hogaboam
authors: Krishnan
authors: K
authors: Raghavendran
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000418:Albumins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid; D003288:Contusions / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology; D016676:Macrophages, Alveolar / Q000473:pathology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010766:Phosphorylation; D012330:RNA, Double-Stranded / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000418:Albumins; D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D058847:Inflammasomes; D053594:Myeloid Differentiation Factor 88; D012330:RNA, Double-Stranded; D051196:Toll-Like Receptor 3; D048051:p38 Mitogen-Activated Protein Kinases; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C495344:TLR3 protein, human