title: Molecular or pharmacologic inhibition of the CD14 signaling pathway protects against burn-related myocardial inflammation and dysfunction.
abstract: Signaling through toll-like receptor 4 (TLR4) plays an obligate role in burn-related myocardial dysfunction. We hypothesized that signaling through CD14, a cellular receptor for endotoxin that lacks a transmembrane domain but is coupled to TLR4, also plays a role in postburn myocardial inflammation and dysfunction. Burn covering 40% total body surface area (or sham burn for controls) was produced in wild-type (WT) and CD14 knockout (KO) as well as vehicle-treated and geldanamycin-treated WT mice (1 microg/g body weight) to inhibit CD14 signaling. Groups included (1) WT shams, (2) CD14 KO sham, (3) WT burns, (4) CD14 KO burns, (5) vehicle-treated WT shams, (6) geldanamycin-treated WT shams, (7) vehicle-treated WT burns, and (8) geldanamycin-treated WT burns. Twenty-four hours after burn, cardiac function (Langendorff) and cardiomyocyte secretion of inflammatory cytokines TNF-alpha, IL-1 beta, and IL-6 (in pg/mL; 5 x 10(4) myocytes) were studied in all groups. Relative to sham WT controls, burn trauma in increased cardiac myocyte secretion of inflammatory cytokines (TNF-alpha, IL-1 beta, and IL-6 rose from 59 +/- 10 to 171 +/- 8; 6 +/- 0.2 to 78 +/- 1; and 88 +/- 3 to 170 +/- 12 pg/mL, respectively; P < 0.05) and produced robust cardiac contractile dysfunction (left ventricular pressure and +dP/dt fell from 105 +/- 4 to 73 +/- 5 mmHg and 2,400 +/- 73 to 1,803 +/- 90 mmHg/s; P < 0.05). Inability to signal through the CD14/TLR4 pathway (induced by CD14/KO or inhibition of CD14 expression by administration of geldanamycin) attenuated TNF-alpha, IL-1 beta, and IL-6 production in response to burn injury and improved postburn myocardial contractile function. Our data suggest that signaling through the CD14 pathway plays an obligate role in cardiac inflammation/dysfunction which occurs after major burn injury.
authors.affiliation: Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9160, USA. robert.barber@utsouthwestern.edu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Barber
authors.forename: David L
authors.initials: DL
authors.lastname: Maass
authors.forename: D Jean
authors.initials: DJ
authors.lastname: White
authors.forename: Ling-Yu E
authors.initials: LY
authors.lastname: Chang
authors.forename: Jureta W
authors.initials: JW
authors.lastname: Horton
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002056:Burns / Q000150:complications / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D012964:Sodium / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
chemical_list: D016227:Benzoquinones; D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D047029:Lactams, Macrocyclic; D018950:Lipopolysaccharide Receptors; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D012964:Sodium; D002118:Calcium; C001277:geldanamycin