Abstract
The triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently discovered cell surface molecule expressed on neutrophils, mature monocytes, and macrophages [1]. Activation of TREM-1 synergistically enhances proinflammatory cytokine production induced by toll-like receptor (TLR) stimulation [2]. A soluble form of TREM-1 has shown promise as a sensitive and specific biomarker for sepsis in humans [3-5]. Expression and function of TREM-1 in the dog has yet to be characterized. We hypothesize that the expression of canine TREM-1 will be upregulated after stimulation with TLR agonists. We assessed TREM-1 expression on canine neutrophils after exposure to TLR agonists in vitro and in vivo after i.v. LPS administration. In vitro, expression of TREM-1 on neutrophils is significantly upregulated by stimulation with microbe-derived agonists against TLR2/6 (Pam2CSK4), TLR1/2 (Pam3CSK4), and TLR4/MD2 (ultrapure LPS and wildtype LPS) (paired t test, P < 0.05). The TLR5 agonist flagellin did not significantly upregulate TREM-1 expression at any time point. See Figure Figure1.1. In contrast, i.v. administration of LPS to dogs resulted in a significant decrease in both TREM-1 expression and the percentage of TREM-1-positive neutrophils from 6 hours through 12 hours post LPS administration. See Figure Figure2.2. The disparity between in vitro and in vivo effects of LPS suggest other factors, such as systemic and local cytokine production and neutrophil turnover, may influence expression and shedding of TREM-1 on canine neutrophils. We suggest that naturally occurring sepsis in the dog represents the ideal model for defining diagnostic biomarkers and discovering efficacious therapeutics for use in human sepsis. Figure 1 Kinetics of TREM-1 expression after TLR agonist stimulation in vitro. Figure 2 Kinetics of TREM-1 expression post LPS administration in vivo.
Highlights
In 2002, the Surviving Sepsis Campaign defined a strategy that aimed to reduce the high mortality due to sepsis
For example at 5 μg/ml LPS, the expression of GIPR was reduced to 86% and INSR 72% of control in U937: while in HUH7 cells at 1 μg/ml LPS, the GIPR expression was decreased to 63%, GLP-1R 95% and INSR 89% compared with control (P
As a result of this study we have developed a standardized sepsis protocol to integrate into the AE triage pro forma, as well as a pathway to help instigate treatment earlier to those patients identified as septic on the wards
Summary
In 2002, the Surviving Sepsis Campaign defined a strategy that aimed to reduce the high mortality due to sepsis. Patients admitted to ICUs with severe sepsis have a 39.8% risk of death [2], and for each hour delay in antibiotic administration, a 7.6% increase in mortality [3]. The objective of the present study was to evaluate the impact of early fluid resuscitation on serial TNFα and IL-6 levels and its association with mortality in severe sepsis. Our laboratory has demonstrated in preliminary clinical studies among the various biomarkers of endothelial dysfunction that blood levels of endocan (ESM-1), a pulmonary vascular endothelial cell-specific molecule participating in the control of endothelial–leukocyte interactions, are associated with the severity and evolution of septic states. The objective, of our study was to predict the development of organ failure at 24 hours using only the data available from the first 4 hours post inoculation Methods This pneumonia-sepsis model included 19 sheep with ALI. The sera were analyzed through serological (IgM and IgG specific ELISA) and molecular (gel-based and real-time RT-PCR) testing
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