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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Vascular endothelial growth factor (VEGF) is a potent vascular permeability factor. The development of capillary leak is common in septic patients, and several sepsis-associated mediators may induce VEGF production. The potential role of VEGF during sepsis has not been studied to date. ⋯ These data show that plasma VEGF levels are elevated during severe sepsis. Furthermore, our data indicate that plasma VEGF levels are associated with disease severity and mortality. Further study of the potential role of VEGF in the development of sepsis-associated capillary leak is indicated.
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There is good evidence that endotoxemia, sepsis, and septic shock are associated with the generation and release of reactive oxygen species (ROS) such as superoxide anion (O2), indicating that oxygen-derived free radicals play an important role in the pathogenesis of sepsis/shock. Studies on the application of free oxygen radical scavengers to limit the damage to tissues and organs have been recently attempted. A stable piperidine nitroxide of low molecular weight (Tempol) can permeate biological membranes and scavenge O2 in vitro and in vivo. ⋯ Moreover, Tempol reduced the plasma NO. and interleukin-1beta and organ O2 levels in CLP-treated rats. In conclusion, Tempol prevented circulatory failure and attenuated organ dysfunction/injury as well as decreased the mortality rate in CLP-treated animals. These beneficial effects of Tempol may be attributed to inhibition of ROS formation (e.g., NO. and O2), suggesting antioxidant (e.g., Tempol) is a potential therapeutic agent in the treatment of intraperitoneal septic shock.
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Endotoxin tolerance has been characterized as diminished TNF-alpha expression after a second LPS stimulus and is dependent on new protein synthesis. LPS-induced expression of TNF-alpha is partly regulated by the p38 mitogen-activated protein (MAP) kinase, which post-transcriptionally stabilizes TNF-alpha mRNA. The dual-specific phosphatase, MKP-1, has been shown to negatively regulate p38 via dephosphorylation. ⋯ In the canonical and Ad-MKP-1-mediated tolerance models, decreased phospho-p38 activity was observed. MKP-1s role in mediating endotoxin tolerance was further confirmed by demonstrating the inability to fully tolerize peritoneal macrophages isolated from MKP-1 null mutant (vs. wild type) mice (24% vs. 72% reductions, respectively). These data demonstrate that the dual specific phosphatase MKP-1 is an important mediator of endotoxin tolerance via p38 regulation.
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Comparative Study
Association between the severity of sepsis and the changes in hemostatic molecular markers and vascular endothelial damage markers.
It is well known that disorders of coagulation and fibrinolysis play a major role in the development of organ dysfunction during sepsis. Furthermore, the importance of the early initiation of anticoagulation therapy for severe cases has been emphasized based on the success of recent clinical trials. The purpose of this study is to search for useful markers for predicting organ dysfunction. ⋯ The WBC and platelet counts were not different between the groups. In contrast, fibrin/fibrinogen degradation products, D-dimer, thrombin-antithrombin complex, plasmin alpha2-antiplasmin complex, soluble fibrin, and total plasminogen activator inhibitor-1 were significantly higher, and the antithrombin activity and protein C levels were lower in the patients with organ dysfunction. Thus, the changes in the hemostatic molecular markers were associated with organ dysfunction from an early stage of sepsis, and antithrombin and protein C activities were found to be the most reliable markers.
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Gadolinium chloride (GdCl3) reportedly inhibits Kupffer cell function including TNF-alpha production and thereby improves organ dysfunctions after LPS challenge, particularly in partially hepatectomized (PH) mice. In addition, TNF-alpha reportedly promotes the regeneration of hepatocytes after PH. However, we have frequently seen GdCl3 treatment increase the mortality of normal mice after LPS injection. ⋯ In marked contrast, the increased amount of TNF-alpha induced by GdCl3 improved the survival after LPS challenge in PH mice because TNF-alpha promoted hepatocyte mitosis/regeneration in PH liver as evidenced by the fact that the inhibition of TNF-alpha before PH suppressed hepatocyte regeneration and decreased survival after LPS challenge. In conclusion, GdCl3 depletes the superoxide-producing Kupffer cells but conversely enhances the function of TNF-alpha-producing Kupffer cells, which thereby leads to LPS-induced mortality. Meanwhile, the increased TNF-alpha production induced by GdCl3 supports liver regeneration and increases the survival after LPS challenge in PH mice.