title: Alloimmune lung injury induced by local innate immune activation through inhaled lipopolysaccharide.
abstract: BACKGROUND
  Alloimmune lung injury, characterized by perivascular lymphocytic inflammation, lymphocytic bronchiolitis (LB), and obliterative bronchiolitis (OB), causes substantial morbidity and mortality after lung transplantation and bone marrow transplantation (BMT), but little is known regarding its pathogenesis. We have developed and pursued the hypothesis that local activation of pulmonary innate immunity through toll-like receptor (TLR)-4 is critical to the development of posttransplant alloimmune lung injury.
  
  
  METHODS
  We developed a fully major histocompatibility complex-mismatched murine BMT model without systemic graft-versus-host disease, and challenged mice with aerosolized lipopolysaccharide (LPS), a prototypic TLR4 agonist, to determine the effect upon pulmonary alloimmune lung injury.
  
  
  RESULTS
  LPS-exposed allogeneic BMT recipient mice developed histological and biological features of LB and OB, which were not observed in non-LPS-exposed allogeneic controls or syngeneic LPS-exposed mice. LPS-induced lymphocytic lung inflammation was dependent upon intact TLR4 signaling in donor-derived hematopoietic cells but not recipient structural lung cells, demonstrating a distinct function for TLR4 on hematopoietic cells in mediating alloimmunity.
  
  
  CONCLUSIONS
  We demonstrate a critical role for localized, environmentally induced innate immune activation in promoting alloimmune lung injury. Local inhibition of TLR4 signaling in pulmonary resident hematopoietic cells represents a novel and potentially important therapeutic target to prevent posttransplant rejection.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27709, USA. garantziotis@hiehs.nih.gov
authors.forename: Stavros
authors.initials: S
authors.lastname: Garantziotis
authors.forename: Scott M
authors.initials: SM
authors.lastname: Palmer
authors.forename: Laurie D
authors.initials: LD
authors.lastname: Snyder
authors.forename: Tonya
authors.initials: T
authors.lastname: Ganous
authors.forename: Benny J
authors.initials: BJ
authors.lastname: Chen
authors.forename: Tie
authors.initials: T
authors.lastname: Wang
authors.forename: Donald N
authors.initials: DN
authors.lastname: Cook
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D018946:Chemokine CCL5 / Q000032:analysis; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology; D007113:Immunity, Innate; D001239:Inhalation; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D016040:Lung Transplantation; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D018946:Chemokine CCL5; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha