Attenuation of responses to endotoxin by the triggering receptor expressed on myeloid cells-1 inhibitor LR12 in nonhuman primate

Anesthesiology. 2014 Apr;120(4):935-42. doi: 10.1097/ALN.0000000000000078.


Background: The triggering receptor expressed on myeloid cells-1 is an immunoreceptor that amplifies the inflammatory response mediated by toll-like receptors engagement. Triggering receptor expressed on myeloid cells-1 inhibitory peptides such LR12 have been shown to prevent hyperresponsiveness and death in several experimental models of septic shock.

Methods: Twelve adult male Cynomolgus (Macaca fascicularis) monkeys exposed to an intravenous bolus of endotoxin (10 μg/kg) were randomized to receive LR12 or placebo (n = 6 per group) as an initial intravenous bolus followed by an 8-h continuous intravenous infusion. An additional group of four only received vehicle infusion. Vital signs were monitored for 8 h. Blood was sampled at H0, 1, 2, 4, and 8 for analysis of clinical chemistries, leukocyte count, coagulation parameters, and cytokine plasma concentration.

Results: LR12 showed no effect on heart rate and body temperature. By contrast to the placebo group, which experienced a 25 to 40% blood pressure decrease after endotoxin administration, LR12-treated monkeys remained normotensive. Endotoxin induced leukopenia at 2 h (mean leukocyte count, 7.62 g/l vs. 21.1 at H0), which was attenuated by LR12. LR12 also attenuated cytokine production.

Conclusions: The triggering receptor expressed on myeloid cells-1 inhibitor LR12 is able to mitigate endotoxin-associated clinical and biological alterations, with no obvious side effects. This study paves the way for future phases Ia and Ib trials in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Disease Models, Animal
  • Endotoxins / blood
  • Injections, Intravenous
  • Lauric Acids / administration & dosage*
  • Lauric Acids / blood
  • Lauric Acids / pharmacokinetics
  • Leukopenia / blood
  • Leukopenia / chemically induced
  • Leukopenia / drug therapy*
  • Macaca fascicularis
  • Male
  • Myeloid Cells / metabolism*
  • Oligopeptides
  • Random Allocation
  • Rhodamines / administration & dosage*
  • Rhodamines / blood
  • Rhodamines / pharmacokinetics
  • Shock, Septic / blood
  • Shock, Septic / chemically induced*
  • Shock, Septic / drug therapy*


  • Endotoxins
  • Lauric Acids
  • Oligopeptides
  • Rhodamines
  • nangibotide