Modulation of the triggering receptor expressed on the myeloid cell type 1 pathway in murine septic shock.
The triggering receptor expressed on myeloid cell type 1 (TREM-1) is a cell surface molecule that has been identified on both human and murine polymorphonuclear neutrophils and mature monocytes. The activation of TREM-1 in the presence of microbial components amplifies the inflammatory response and may be responsible for the hyperresponsiveness observed during the initial stage of sepsis. To investigate the effect of the modulation of the TREM-1 pathway during experimental murine sepsis, we used analogue synthetic peptides derived from the extracellular moiety of TREM-1. The TREM-1 ligand was expressed on both peritoneal and peripheral neutrophils during experimental peritonitis in mice. The TREM-1 peptides inhibited the recognition by TREM-1 of its ligand and protected endotoxinic mice from death. In septic rats, the TREM-1 peptides improved the hemodynamic status, attenuated the development of lactic acidosis, modulated the production of such proinflammatory cytokines as tumor necrosis factor alpha and interleukin-1beta, and improved survival. The protective effect of these peptides on arterial pressure could partly be explained by a decreased production of nitric oxide. These data suggest that in vivo modulation of TREM-1 might be a suitable therapeutic tool for the treatment of sepsis.
Gibot
Sébastien
S
Service de Réanimation Médicale, 29 bld du Maréchal de Lattre de Tassigny, Hôpital Central, 54035 Nancy, France. s.gibot@chu-nancy.fr
Buonsanti
Cecilia
C
Massin
Frédéric
F
Romano
Michele
M
Kolopp-Sarda
Marie-Nathalie
MN
Benigni
Fabio
F
Faure
Gilbert C
GC
Béné
Marie-Christine
MC
Panina-Bordignon
Paola
P
Passini
Nadia
N
Lévy
Bruno
B
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D006863:Hydrogen-Ion Concentration; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000502:physiology*; D012772:Shock, Septic / Q000276:immunology*; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C484963:Tyrobp protein, mouse; D009569:Nitric Oxide