Double-Stranded RNA Interacts With Toll-Like Receptor 3 in Driving the Acute Inflammatory Response Following Lung Contusion. Issue 11 (November 2016)

• Record Type: Journal Article
• Authors: Suresh, Madathilparambil V.; Thomas, Bivin; Machado-Aranda, David; Dolgachev, Vladislov A.; Kumar Ramakrishnan, Sadeesh; Talarico, Nicholas; Cavassani, Karen; Sherman, Matthew A.; Hemmila, Mark R.; Kunkel, Steven L.; Walter, Nils G.; Hogaboam, Cory M.; Raghavendran, Krishnan
• Is Part Of: Critical care medicine. Volume 44:Issue 11(2016)
• Publication Date: 2016-11
• Subjects: double-stranded ribonucleic acid -- lung contusion -- TIR-domain-containing adapter-inducing interferon-β -- toll-like receptor 3; Critical care medicine -- Periodicals; Soins intensifs -- Périodiques; 616.028
• DOI: 10.1097/CCM.0000000000001879
• Languages: English
• ISSNs: 0090-3493

Abstract

Abstract : Objectives: 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. Design: 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. Measurements and Main 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.