Molecular or pharmacologic inhibition of the CD14 signaling pathway protects against burn-related myocardial inflammation and dysfunction

Robert C. Barber, David L. Maass, D. Jean White, Ling Yu E. Chang, Jureta W. Horton

Research output: Contribution to journalArticle

18 Scopus citations

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 bum for controls) was produced in wild-type (WT) and CD14 knockout (KO) as well as vehicle-treated and geldanamycin-treated WT mice (1 μg/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) vehicletreated WT burns, and (8) geldanamycin-treated WT burns. Twenty-four hours after burn, cardiac function (Langendorff) and cardiomyocyte secretion of inflammatory cytokines TNF-α, IL-1β, and IL-6 (in pg/mL; 5 × 104 myocytes) were studied in all groups. Relative to sham WT controls, bum trauma in increased cardiac myocyte secretion of inflammatory cytokines (TNF-α, IL-1β, 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-α, IL-1β, and IL-6 production in response to bum 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.

Original languageEnglish
Pages (from-to)705-713
Number of pages9
JournalShock
Volume30
Issue number6
DOIs
Publication statusPublished - 1 Dec 2008

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Keywords

  • Burn
  • CD14
  • Calcium
  • Cardiac function
  • Cardiomyocyte
  • Cytokines
  • Dysfunction
  • Geldanamycin
  • Inflammation
  • Knockout
  • Myocardial
  • Sodium
  • TLR4 signaling

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