title: Characterization of TLR-induced inflammatory responses in COPD and control lung tissue explants.
abstract: OBJECTIVE
  Viruses are a common cause of exacerbations in chronic obstructive pulmonary disease (COPD). They activate toll-like receptors (TLRs) 3, 7, and 8, leading to a pro-inflammatory response. We have characterized the responses of TLR3 and TLR7/8 in lung tissue explants from COPD patients and control smokers.
  
  
  METHODS
  We prepared lung whole tissue explants (WTEs) from patients undergoing surgery for confirmed or suspected lung cancer. In order to mimic the conditions of viral infection, we used poly(I:C) for TLR3 stimulation and R848 for TLR7/8 stimulation. These TLR ligands were used alone and in combination. The effects of tumor necrosis factor α (TNFα) neutralization and dexamethasone on TLR responses were examined. Inflammatory cytokine release was measured by enzyme-linked immunosorbent assay and gene expression by quantitative real-time polymerase chain reaction.
  
  
  RESULTS
  WTEs from COPD patients released higher levels of pro-inflammatory cytokines compared with WTEs from smokers. Activation of multiple TLRs led to a greater than additive release of TNFα and CCL5. TNFα neutralization and dexamethasone treatment decreased cytokine release.
  
  
  CONCLUSIONS
  This WTE model shows an enhanced response of COPD compared with controls, suggesting an increased response to viral infection. There was amplification of innate immune responses with multiple TLR stimulation.
authors.affiliation: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation Trust.
authors.forename: Anna
authors.initials: A
authors.lastname: Pomerenke
authors.affiliation: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation Trust.
authors.forename: Simon R
authors.initials: SR
authors.lastname: Lea
authors.affiliation: Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester.
authors.forename: Sarah
authors.initials: S
authors.lastname: Herrick
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lindsay
authors.affiliation: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation Trust.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
mesh_terms: D000368:Aged; D000906:Antibodies / Q000494:pharmacology; D016022:Case-Control Studies; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011070:Poly I-C / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction; D013997:Time Factors; D046509:Tissue Culture Techniques; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D007093:Imidazoles; D018836:Inflammation Mediators; C495344:TLR3 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D011070:Poly I-C; C402365:resiquimod
keywords: COPD; R848; cytokines; lung explant; poly(I:C)