title: Toll-Like Receptor-9 (TLR9) is Requisite for Acute Inflammatory Response and Injury Following Lung Contusion.
abstract: Lung contusion (LC) is a significant risk factor for the development of acute respiratory distress syndrome. Toll-like receptor 9 (TLR9) recognizes specific unmethylated CpG motifs, which are prevalent in microbial but not vertebrate genomic DNA, leading to innate and acquired immune responses. TLR9 signaling has recently been implicated as a critical component of the inflammatory response following lung injury. The aim of the present study was to evaluate the contribution of TLR9 signaling to the acute physiologic changes following LC. Nonlethal unilateral closed-chest LC was induced in TLR9 (-/-) and wild-type (WT) mice. The mice were sacrificed at 5, 24, 48, and 72-h time points. The extent of injury was assessed by measuring bronchoalveolar lavage, cells (cytospin), albumin (permeability injury), and cytokines (inflammation). Following LC, only the TLR9 (-/-) mice showed significant reductions in the levels of albumin; release of pro-inflammatory cytokines IL-1β, IL-6, and Keratinocyte chemoattractant; production of macrophage chemoattractant protein 5; and recruitment of alveolar macrophages and neutrophil infiltration. Histological evaluation demonstrated significantly worse injury at all-time points for WT mice. Macrophages, isolated from TLR9 (-/-) mice, exhibited increased phagocytic activity at 24 h after LC compared with those isolated from WT mice. TLR9, therefore, appears to be functionally important in the development of progressive lung injury and inflammation following LC. Our findings provide a new framework for understanding the pathogenesis of lung injury and suggest blockade of TLR9 as a new therapeutic strategy for the treatment of LC-induced lung injury.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Madathilparambil V
authors.initials: MV
authors.lastname: Suresh
authors.forename: Bivin
authors.initials: B
authors.lastname: Thomas
authors.forename: Vladislav A
authors.initials: VA
authors.lastname: Dolgachev
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sherman
authors.forename: Rebecca
authors.initials: R
authors.lastname: Goldberg
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
authors.forename: Aulina
authors.initials: A
authors.lastname: Chowdhury
authors.forename: David
authors.initials: D
authors.lastname: Machado-Aranda
authors.forename: Krishnan
authors.initials: K
authors.lastname: Raghavendran
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D003288:Contusions / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055370:Lung Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051217:Toll-Like Receptor 9