Abstract
Sepsis is a life threatening condition which produces multi-organ dysfunction with profound circulatory and cellular derangements. Administration of E.Coli endotoxin (LPS) produces systemic inflammatory effects of sepsis including disruption of endothelial barrier, and if severe enough death. Whole body periodic acceleration (pGz) is the headward-footward motion of the body. pGz has been shown to induce pulsatile shear stress to the endothelium, thereby releasing vascular and cardio protective mediators. The purpose of this study was to determine whether or not pGz performed as a pre-treatment or post-treatment strategy improves survival in a lethal murine endotoxin model.This study was designed as a prospective randomized controlled study in mice. pGz was performed in mice as pre-treatment (pGz-LPS, 3 days prior to LPS), post-treatment (LPS- pGz, 30 min after LPS) strategies or Control (LPS-CONT), in a lethal murine model of endotoxemia. Endotoxemia was induced with intraperitoneal injection of E.Coli LPS (40mg/kg). In a separate group of mice, a nonspecific nitric oxide synthase inhibitor (L-NAME) was provided in their drinking water and pGz-LPS and LPS-pGz performed to determine the effect of nitric oxide (NO) inhibition on survival. In another subset of mice, micro vascular leakage was determined. Behavioral scoring around the clock was performed in all mice at 30 min intervals after LPS administration, until 48 hrs. survival or death. LPS induced 100% mortality in LPS-CONT animals by 30 hrs. In contrast, survival to 48 hrs. occurred in 60% of pGz-LPS and 80% of LPS-pGz. L-NAME abolished the survival effects of pGz. Microvascular leakage was markedly reduced in both pre and post pGz treated animals and was associated with increased tyrosine kinase endothelial-enriched tunica interna endothelial cell kinase 2 (TIE2) receptor and its phosphorylation (p-TIE2). In a murine model of lethal endotoxemia, pGz performed as a pre or post treatment strategy significantly improved survival, and markedly reduced microvascular leakage. The effect was modulated, in part, by NO since a non-selective inhibitor of NO abolished the pGz survival effect.
Highlights
Sepsis is a life-threatening condition of multi-organ dysfunction caused by a dysregulated host response to infection
The protocol conforms to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication No 85–23, revised 1996) Protocol No 17-20-A-04
Survival for LNAME animals did not surpass 16 hrs. (Fig 1). pGz-LPS and LPS-pGz animals which survived beyond 48 hrs., appeared normal 14 days after completion of the study
Summary
Sepsis is a life-threatening condition of multi-organ dysfunction caused by a dysregulated host response to infection. Septic shock is a subset of sepsis in which profound circulatory cellular and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone [1]. Sepsis affects more than 1.5 million humans in the USA with mortality rates of 15–30% [2]. The economic burden of sepsis is highly significant. The Agency for Healthcare Research and Quality lists sepsis as the most expensive condition treated in U. S. hospitals, costing nearly $24 billion in 2013, and accounting for 6.2% of the aggregate costs for hospitalization in the USA [3]. Despite hundreds of treatment trials dating to the 1960s, interventions to improve survival from sepsis have not significantly lowered mortality
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