Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets lipoprotein receptors for degradation, thereby reducing hepatic lipid clearance. PCSK9 inhibition reduces mortality in septic mice, presumably through increased hepatic clearance of pathogen lipids due to increased lipoprotein receptor concentrations. However, PCSK9 overexpression in vivo has not been studied in sepsis. Therefore, this study aimed to evaluate the effects of differential PCSK9 expression on systemic infection, inflammation, and coagulation in sepsis. ⋯ These findings demonstrate that PCSK9 deficiency confers protection against systemic bacterial dissemination, organ pathology, and tissue inflammation, particularly in the lungs and liver, while PCSK9 overexpression exacerbates multi-organ pathology as well as the hypercoagulable and pro-inflammatory states in early sepsis.
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Crush syndrome is a devastating condition leading to multiple organ failure. The mechanisms by which local traumatic injuries affect distant organs remain unknown. ETS-GS is a novel water-soluble, stable anti-oxidative agent composed of vitamin E derivative. ⋯ Ex vivo imaging confirmed that ETS-GS treatment reduced ROS generation in both the lung and the muscle following crush injury. The administration of ETS-GS could suppress ROS generation, systemic inflammation, and the subsequent organ damage, thus improving survival in a rat model of crush injury. These findings suggest that ETS-GS can become a novel therapeutic agent against crush injury.
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Hypertonic sodium lactate (HTL) expands intravascular volume and may provide an alternative substrate for cellular metabolism in sepsis. We compared the effects of HTL, hypertonic saline (HTS), 0.9% ("normal") saline (NS) and Ringer's lactate (RL) on hemodynamics, sublingual and renal microcirculation, renal, mesenteric and brain perfusion, renal and cerebral metabolism, and survival in anesthetized, mechanically ventilated, adult female sheep. Animals (7 in each group) were randomized to receive a bolus (over 15-min) of 3 mL/kg 0.5 M HTL, 3 mL/kg 3% HTS, 10.8 mL/kg NS, or 10.8 mL/kg RL at 2, 6, and 10 h after induction of fecal peritonitis, followed by 2-h infusions of 1 mL/kg/h (HTL/HTS groups) or 3.6 mL/kg/h (NS/RL groups). ⋯ Median survival times were significantly shorter in the HTL (17 h) and NS (16 h) groups than in the HTS (22 h) or RL (20 h) groups (P = 0.0029). In conclusion, in an ovine model of septic shock, administration of HTL was associated with earlier onset impaired tissue perfusion and shorter survival time. These observations raise concerns about use of HTL in septic shock.