Effects of the Trem 1 Pathway Modulation During Hemorrhagic Shock in Rats

Abstract

The triggering receptor expressed on myeloid cells (TREM) 1, a receptor expressed on the surface of neutrophils and monocytes/macrophages, synergizes with the Toll-like receptors in amplifying the inflammatory response mediated by microbial components. Because the pathogenesis of severe blood loss-induced excessive inflammation and multiple organ failure implies leukocyte activation and bacterial translocation, we hypothesized that the TREM-1 pathway modulation would prove beneficial in this setting. Wistar rats were subjected to a 1-h period of hemorrhagic shock and then reperfused with shed blood and ringer lactate for 1 h. At the time of reperfusion, animals were administered with LP17 (a synthetic soluble TREM-1 decoy receptor), a control peptide, or a vehicle (isotonic sodium chloride solution). Plasma concentration of TNF-alpha, IL-6, and soluble TREM-1 were measured by enzyme-linked immunosorbent assay. Lung permeability was assessed by the weight-dry ratio and fluorescein isothiocyanate-labeled albumin lung-blood ratio. Organ dysfunction was appreciated by measuring plasma aspartate aminotransferase and urea concentrations. Bacterial translocation was estimated by blood, mesenteric lymph nodes, and spleens culture. Hemorrhagic shock associated with cardiovascular collapse, lactic acidosis, systemic inflammatory response, and organ dysfunction that was partly prevented by LP17 administration. Hemorrhagic shock induced a marked increase in lung permeability that was also prevented by TREM-1 modulation. Finally, LP17 improved survival. Thus, the early modulation of the TREM-1 pathway by means of a synthetic peptide may be useful during severe hemorrhagic shock in rats in preventing organ dysfunction and improving survival.

Effect of TREM-1 blockade and single nucleotide variants in experimental renal injury and kidney transplantation

“…Several studies have shown that treatment with TREM-1 inhibitors represents a therapeutic strategy to prevent excessive inflammation resulting in decreased pathology and mortality. The inhibitory peptide LP17 was shown to successfully reduce the inflammatory responses in the context of infection, mesenteric IR-induced injury, hemorrhagic shock, colitis, autoimmune arthritis and acute pancreatitis1220343536373839. In addition, TREM-1 fusion protein and LR12 reduced the disease severity in sepsis and in models of acute myocardial infarction132324404142.…”

Triggering receptor expressed on myeloid cells -1 as a new therapeutic target during inflammatory diseases

“…In a rat model of HS, the TREM-1 modulation by LP17 attenuated the haemodynamic compromise, the development of lactic acidosis, prevented form cytokine production, organ dysfunction and finally improved survival. 49 Ischemia-reperfusion. Acute mesenteric ischemia is a medicosurgical emergency associated with 60 to 90% mortality.…”

A novel ligand-independent peptide inhibitor of TREM-1 suppresses tumor growth in human lung cancer xenografts and prolongs survival of mice with lipopolysaccharide-induced septic shock

“…1A) [13, 15, 23–24]. While the natural TREM-1 ligand is not yet known, based on a new model of immune signaling, the signaling chain homooligomerization (SCHOOL) model [25], we have developed a novel, ligand-independent approach to TREM-1 inhibition (Fig.…”