title: Alterations in the cardiac inflammatory response to burn trauma in mice lacking a functional Toll-like receptor 4 gene.
abstract: Our group and others have previously shown that Toll-like receptor 4 (TLR-4) inactivation prevents burn-induced myocardial contractile dysfunction; however, the molecular mechanisms that are involved in this cardioprotection are not well defined. This present study examines the involvement of TLR-4 in the cardiac inflammatory response to thermal insult. C3H/HeJ (TLR-4 mutant mice) and C3H/HeN wild-type (WT) mice were subjected to either a sham burn or 40% full-thickness burn injury and were fluid resuscitated with lactated Ringer using the Parkland formula. Mice (n = 7-9 per group) were killed at 2, 4, or 24 h postsham or burn, and heart tissue was harvested. Immunoblotting was performed to evaluate phosphorylated p38 mitogen-activated protein kinase (MAPK), nuclear p50, and cytoplasmic p50. Nuclear factor-kappaB was also characterized via electrophoretic mobility shift assay. Systemic and cardiac myocyte secretion of TNF-alpha, IL-1 beta, IL-6, and IL-10 were measured by enzyme-linked immunosorbent assay. Burn injury in WT mice promoted myocardial inflammatory signaling that included increased expression of phosphorylated p38 MAPK, nuclear p50, and increased cardiac myocyte secretion of cytokines. Systemic cytokines were also increased in WT animals, although not to the extent of the myocardial cytokine expression. Toll-like receptor 4 inactivation resulted in an attenuation of several burn-induced responses, including phosphorylation of p38 MAPK, nuclear translocation of nuclear factor-kappaB, and cytokine secretion. These data suggest that burn injury initiates an inflammatory response via Toll/IL-1 signaling in the heart, which contributes to cardiac injury and contractile dysfunction.
authors.affiliation: Department of Surgery, UT Southwestern Medical Center at Dallas, Texas 75390-9063, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Bruns
authors.forename: David
authors.initials: D
authors.lastname: Maass
authors.forename: Robert
authors.initials: R
authors.lastname: Barber
authors.forename: Jureta
authors.initials: J
authors.lastname: Horton
authors.forename: Deborah
authors.initials: D
authors.lastname: Carlson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002056:Burns / Q000276:immunology / Q000503:physiopathology*; D024202:Electrophoretic Mobility Shift Assay; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000737:chemistry / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases