Effects of the TREM-1 pathway modulation during mesenteric ischemia-reperfusion in rats.
OBJECTIVE
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 ischemia-reperfusion-induced gastrointestinal tissue injury and multiple organ failure implies leukocyte activation and bacterial translocation, we hypothesized that the TREM-1 pathway modulation would prove beneficial in this setting.


METHODS
Animal study.


METHODS
Research laboratory.


METHODS
Adult male Wistar rats (250-300 g).


METHODS
Rats were subjected to intestinal ischemia-reperfusion induced by occlusion of the superior mesenteric artery during 60 mins and reperfused for 180 mins. At the time of reperfusion, animals were administered with LP17 (a synthetic TREM-1 inhibitor), a control peptide, or a vehicle (normal saline). Plasma concentrations of tumor necrosis factor-alpha, interleukin-6, and soluble TREM-1 were measured by enzyme-linked immunosorbent assay. Hepatic activation of the transcriptional factor nuclear factor-kappaB was assessed by electrophoretic mobility shift assay. Hepatic oxidant-antioxidant balance was estimated by measurement of lipid peroxidation and catalase activity. Ileal mucosal permeability was estimated by fluorescein dextran-4 clearance and bacterial translocation by mesenteric lymph nodes culture.


RESULTS
Ischemia-reperfusion was associated with cardiovascular collapse, lactic acidosis, and systemic and hepatic inflammatory response that were partly prevented by LP17 administration. Liver lipid peroxidation and catalase depletion were attenuated by LP17. Ischemia-reperfusion induced a marked increase in ileal mucosal permeability and an associated bacterial translocation that was also prevented by TREM-1 modulation. LP17 delayed mortality.


CONCLUSIONS
The modulation of the TREM-1 pathway by the means of a synthetic peptide may be useful during acute mesenteric ischemia.
Gibot
Sébastien
S
Groupe Choc, Contrat AVENIR INSERM, U684, Faculté de Médecine, Nancy Université, Nancy, France. s.gibot@chu-nancy.fr
Massin
Frédéric
F
Alauzet
Corentine
C
Montemont
Chantal
C
Lozniewski
Alain
A
Bollaert
Pierre-Edouard
PE
Levy
Bruno
B
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D019344:Lactic Acid / Q000378:metabolism; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D017538:Mesenteric Artery, Superior; D008641:Mesenteric Vascular Occlusion / Q000150:complications / Q000378:metabolism / Q000628:therapy*; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000502:physiology; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
D016207:Cytokines; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D019344:Lactic Acid