title: Local exposure of bone components to injured soft tissue induces Toll-like receptor 4-dependent systemic inflammation with acute lung injury.
abstract: Remote and systemic inflammatory responses after long bone fractures have been well described, but the mechanisms underlying these changes remain unexplained. We hypothesized that bone components locally exposed to injured soft tissue are capable of inducing a systemic inflammatory response associated with acute lung injury, and that this inflammatory cascade requires Toll-like receptor 4 (TLR-4) signaling. Accordingly, male C3H/HeOuJ (TLR-4-competent) and C3H/HeJ (TLR-4-mutant) mice were injected with various bone components (bone marrow cells, bone marrow supernatant, and bone suspension, respectively) in bilaterally injured thigh muscles and euthanized after 6 h. Serum TNF-alpha, IL-6, and IL-10 levels, and pulmonary myeloperoxidase activity was measured using specific enzyme-linked immunosorbent assay kits. Pulmonary permeability changes were assessed with bronchoalveolar lavage. Local exposure of bone components to injured soft tissue induced systemic inflammation and acute lung injury in TLR-4-competent, but not in TLR-4-mutant, animals. These findings suggest that bone components contribute to systemic inflammation and acute lung injury after long bone fractures via TLR-4 signaling and support the notion of a central role for TLR-4 in sensing tissue damage.
authors.affiliation: Department of Orthopaedic Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. kobbep@upmc.edu
authors.forename: Philipp
authors.initials: P
authors.lastname: Kobbe
authors.forename: David J
authors.initials: DJ
authors.lastname: Kaczorowski
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Tzioupis
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Mollen
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Hans-Christoph
authors.initials: HC
authors.lastname: Pape
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000276:immunology*; D000818:Animals; D005264:Femoral Fractures / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009195:Peroxidase / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D015850:Interleukin-6; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009195:Peroxidase