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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Complex interactions of nitric oxide and other free radicals have been implicated in the pathogenesis of sepsis and organ dysfunction. We hypothesized that simultaneous inducible nitric oxide synthase inhibition (L-N6-[1-iminoethyl]-lysine [L-NIL]) and neutralization of superoxide (O2-) (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl [Tempol]) would protect from detrimental consequences of long-term, volume-resuscitated, hyperdynamic porcine bacteremia. In this prospective, randomized, controlled experimental study, 16 anesthetized, mechanically ventilated and instrumented pigs were exposed to 24 h of continuous infusion of live Pseudomonas aeruginosa. After 12 h of hyperdynamic sepsis, animals were randomized to receive either vehicle (control, n = 8) or combination of L-NIL and Tempol (n = 8). Systemic and hepatosplanchnic hemodynamics, oxygen exchange, metabolism, ileal mucosal microcirculation and tonometry, oxidative stress and coagulation parameters were assessed before, 12, 18, and 24 h of P. aeruginosa infusion. Combined treatment inhibited sepsis-induced increase in plasma nitrate/nitrite, 8-isoprostane, and thiobarbituric acid reactive species concentrations, prevented hypotension, and reversed hyperdynamic circulation. Despite lower intestinal macrocirculation, combined regimen attenuated the otherwise progressive deterioration in ileal mucosal microcirculation and prevented mucosal acidosis. Treatment substantially attenuated mesenteric and hepatic venous acidosis, preserved sepsis-induced impairment of hepatosplanchnic redox state, and prevented the development of renal dysfunction. Finally, coinfusion of L-NIL and Tempol largely attenuated the sepsis-induced rise in plasma von Willebrand factor and thrombin-antithrombin complexes. Thus, hemodynamic, microcirculatory, metabolic, renal, and coagulation data indicate that combining inducible inhibition with cell permeable O2(-) radical scavenger afforded significant protection in porcine sepsis, thus suggesting an important interactive role of O2(-) and nitric oxide in mediating organ dysfunction.
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PMID:Effects of combining inducible nitric oxide synthase inhibitor and radical scavenger during porcine bacteremia. 1717 82

We studied the state of ultra-large von Willebrand factor (ULVWF) proteolysis in 21 pediatric patients with severe sepsis and found that the overall group of patients had moderately reduced ADAMTS-13 activity, but 31% had severe enzymatic deficiency. The severe deficiency correlated with greater adhesion activity of von Willebrand factor, severity of thrombocytopenia and plasma levels of interleukin-6. It also correlated clinically with severity of illness and organ dysfunction. These results suggest that ULVWF proteolysis is insufficient in septic patients and severely deficient in a subgroup of patients. The deficiency may contribute to the development of thrombocytopenia and ischemic organ failure associated with sepsis.
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PMID:Acquired ADAMTS-13 deficiency in pediatric patients with severe sepsis. 1722 45

The effects of steroids on the outcome of sepsis are dose dependent. Low doses appear to be beneficial, but high doses do not improve outcome for reasons that are insufficiently understood. The effects of steroids on systemic inflammation as a function of dose have not previously been studied in humans. To determine the effects of increasing doses of prednisolone on inflammation and coagulation in humans exposed to LPS, 32 healthy males received prednisolone orally at doses of 0, 3, 10, or 30 mg (n = 8 per group) at 2 h before i.v. injection of Escherichia coli LPS (4 ng/kg). Prednisolone dose-dependently inhibited the LPS-induced release of cytokines (TNF-alpha and IL-6) and chemokines (IL-8 and MCP-1), while enhancing the release of the anti-inflammatory cytokine IL-10. Prednisolone attenuated neutrophil activation (plasma elastase levels) and endothelial cell activation (von Willebrand factor). Most remarkably, prednisolone did not inhibit LPS-induced coagulation activation, measured by plasma concentrations of thrombin-antithrombin complexes, prothrombin fragment F1+2, and soluble tissue factor. In addition, activation of the fibrinolytic pathway (tissue-type plasminogen activator and plasmin-alpha(2)-antiplasmin complexes) was dose-dependently enhanced by prednisolone. These data indicate that prednisolone dose-dependently and differentially influences the systemic activation of different host response pathways during human endotoxemia.
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PMID:Prednisolone dose-dependently influences inflammation and coagulation during human endotoxemia. 1723 35

Coagulation abnormalities have been implicated in the pathogenesis of sepsis and organ dysfunction. Nitric oxide (NO) is regarded as a critical mediator of many vascular pathologies, including sepsis. However, limited evidence is available to document a relationship between NO generated by inducible NO synthase (iNOS) and hemostatic abnormalities in sepsis. Therefore, we evaluated the effects of selective iNOS inhibition on markers of endothelial and coagulation homeostasis in a clinically relevant model of porcine bacteremia induced and maintained for 24 hours (h) with a continuous infusion of live P. aeruginosa. After 12 h of sepsis, animals received either vehicle (Control, n=7) or continuous infusion of selective iNOS inhibitor L-NIL (n=7). Before as well as 12, 18 and 24 h after starting P. aeruginosa following variables related to i) endothelial dysfunction (von Willebrand factor [vWf]; tissue plasminogen activator activity [t-PA]; ii) coagulation (thrombin-antithrombin complexes [TAT]; platelet count); iii) fibrinolysis (t-PA activity, activity of plasminogen activator inhibitor type 1 (PAI-1 act); and iv) oxidative/nitrosative stress (isoprostanes, nitrate/nitrite levels) were measured. L-NIL inhibited sepsis-induced increase in plasma nitrate/nitrite and isoprostanes concentrations, prevented hypotension and acidosis. L-NIL significantly attenuated sepsis-induced rise in plasma vWF and TAT. P. aeruginosa-induced drop in t-PA activity was blunted by iNOS inhibition, while increased PAI-1 and reduced platelet count were not reversed by the treatment. In conclusion, selective iNOS inhibition was associated with attenuation of sepsis-induced coagulation and endothelial dysfunction suggesting the interplay between mediators of vascular system and hemostatic balance. Reduction of oxidative stress probably contributes to the beneficial effects afforded by iNOS blockade.
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PMID:Coagulation and endothelial dysfunction during longterm hyperdynamic porcine bacteremia--effects of selective inducible nitric oxide synthase inhibition. 1726 61

Interleukin-11 (IL-11) is a cytokine which interacts with a variety of haemopoietic and non-haemopoietic cell types. Recombinant human IL-11 (rhIL-11; oprelvekin) is produced in Escherichia coli and differs from the naturally occurring protein only in the absence of the amino-terminal proline residue. In synergy with other factors, rhIL-11 stimulates the growth of myeloid, erythroid, and megakaryocyte progenitor cells in vitro. In vivo, rhIL-11 is active in mice, rats, dogs, guinea pigs, hamsters and non-human primates, where the principal activity measured was stimulation of megakaryocytopoiesis and thrombopoiesis. rhIL-11 has shown benefit in 2 clinical trials by significantly reducing severe chemotherapy-induced thrombocytopenia. In addition to its thrombopoietic activity, rhIL-11 has also shown activity in models of acute gastrointestinal mucosal damage. rhIL-11 enhanced survival in mice following cytoablative therapy and in a hamster model of chemotherapy-induced oral mucositis, where treatment with rhIL-11 was associated with decreased mucosal damage, accelerated healing and reduced numbers of deaths. rhIL-11 is currently in clinical trials for the treatment of chemotherapy-induced mucositis. In rat models of acute colonic injury and inflammatory bowel disease, rhIL-11 treatment reduced intestinal mucosal damage and alleviated clinical signs. rhIL-11 has direct effects on activated macrophages to reduce the production of pro-inflammatory mediators. In animal models of endotoxaemia, rhIL-11 treatment reduced serum levels of pro-inflammatory cytokines and blocked hypotension. rhIL-11 increased survival in models of Gram-negative sepsis and toxic shock. Based on these studies, rhIL-11 is currently in clinical trials for treatment of Crohn's disease. Other inflammatory conditions are being further evaluated. Mechanistically, rhIL-11 functions at many levels to control inflammation, ameliorate tissue damage and maintain haemostasis in the face of trauma or infection. rhIL-11 has direct effects on hepatocytes, inducing the production of acute phase reactant proteins, haem oxygenase and tissue inhibitor of metalloproteinase-1 (TIMP-1). TIMP-1 expression can also be induced in synoviocytes and chondrocytes by treatment with rhIL-11. rhIL-11 administration has been associated with increased plasma levels of von Willebrand factor and fibrinogen. rhIL-11 treatment potentially offers multiple benefits for cancer chemotherapy patients, such as prevention of thrombocytopenia, gastrointestinal epithelial protection and subsequent reduction of mucositis, and amelioration of inflammatory complications. In addition, rhIL-11 is being evaluated further in the treatment of inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis and sepsis.
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PMID:Interleukin-11. 1803 Nov 4

Sepsis is a systemic response to infection, and symptoms are produced by host defense systems rather than by the invading pathogens. Amongst the most prominent features of sepsis, contributing significantly to its outcome, is activation of coagulation with concurrent down-regulation of anticoagulant systems and fibrinolysis. Inflammation-induced coagulation on its turn contributes to inflammation. Another important feature of sepsis, associated with key symptoms such as hypovolemia and hypotension, is endothelial dysfunction. Under normal conditions, the endothelium provides for an anticoagulant surface, a property that is lost in sepsis. In this review, data about the interplay between inflammation and coagulation in sepsis are summarized with a special focus on the influence of the endothelium on inflammation-induced coagulation and vice versa. Possible procoagulant properties of the endothelium are described, such as expression of tissue factor (TF) and von Willebrand factor and interaction with platelets. Possible procoagulant roles of microparticles, circulating endothelial cells and endothelial apoptosis, are also discussed. Moreover, the important roles of the endothelium in down-regulating the anticoagulants TF pathway inhibitor, antithrombin, and the protein C (PC) system and inhibition of fibrinolysis are discussed. The influence of coagulation on its turn on inflammation and the endothelium is described with a special focus on protease-activated receptors (PARs). We conclude that the relationship between endothelium and coagulation in sepsis is tight and that further research is needed, for example, to better understand the role of activated PC signaling via PAR-1, the role of the endothelial PC receptor herein, and the role of the glycocalyx.
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PMID:Inflammation, endothelium, and coagulation in sepsis. 1803 92

In a prospective, longitudinal study, we investigated the association between decreased ADAMTS13 activity and impaired hemostasis, as well as organ dysfunctions in patients with systemic inflammation due to extracorporeal cardiopulmonary circuit or with severe sepsis. Similar to negative acute phase proteins, ADAMTS13 activity declined stepwise according to the extent of inflammatory responses. A marked imbalance between ADAMTS13 activity and VWF antigen level was associated with the appearance of ultra-large VWF multimers in plasma, with organ dysfunction and lethality. Our data support the view that systemic inflammation results in an ADAMTS13 deficiency which activates hemostasis.
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PMID:Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor. 1816 99

The Ashwell receptor, the major lectin of hepatocytes, rapidly clears from blood circulation glycoproteins bearing glycan ligands that include galactose and N-acetylgalactosamine. This asialoglycoprotein receptor activity remains a key factor in the development and administration of glycoprotein pharmaceuticals, yet a biological purpose of the Ashwell receptor has remained elusive. We have identified endogenous ligands of the Ashwell receptor as glycoproteins and regulatory components in blood coagulation and thrombosis that include von Willebrand factor (vWF) and platelets. The Ashwell receptor normally modulates vWF homeostasis and is responsible for thrombocytopenia during systemic Streptococcus pneumoniae infection by eliminating platelets desialylated by the bacterium's neuraminidase. Hemostatic adaptation by the Ashwell receptor moderates the onset and severity of disseminated intravascular coagulation during sepsis and improves the probability of host survival.
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PMID:The Ashwell receptor mitigates the lethal coagulopathy of sepsis. 1932 79

The coupled plasma filtration adsorption (CPFA) was developed as an adsorptive hemopurification method aimed at nonselective removal of circulating soluble mediators potentially involved in the pathogenesis of sepsis. We hypothesized that this nonselective hemopurification could protect from detrimental consequences of long-term, volume-resuscitated porcine septic shock. In 16 anesthetized, mechanically ventilated, and instrumented pigs, the hyperdynamic septic shock secondary to peritonitis was induced by intraperitoneally inoculating feces and maintained for 22 h with fluid resuscitation and norepinephrine infusion as needed to maintain MAP above 65 mmHg. After 12 h of peritonitis, animals were randomized to receive either supportive treatment (control, n = 8) or CPFA treatment (CPFA, n = 8). Systemic, hepatosplanchnic, and renal hemodynamics; oxygen exchange; energy metabolism (lactate/pyruvate and ketone body ratios); ileal mucosal and renal cortex microcirculation; systemic inflammation (TNF-alpha, IL-6); nitrosative/oxidative stress (thiobarbituric acid reactive species, nitrates + nitrites); and endothelial/coagulation dysfunction (asymmetric dimethylarginine, von Willebrand factor, thrombin-antithrombin complexes, platelet count) were assessed before and 12, 18, and 22 h of peritonitis. Coupled plasma filtration adsorption neither delayed the development of hypotension nor reduced the dose of norepinephrine. The treatment failed to attenuate sepsis-induced alterations in microcirculation, surrogate markers of cellular energetics, endothelial injury, and systemic inflammation. Similarly, CPFA did not protect from lung and liver dysfunction and even aggravated sepsis-induced disturbances in coagulation and oxidative/nitrosative stress. In this porcine model of septic shock, the early treatment with CPFA was not capable of reversing the sepsis-induced disturbances in various biological pathways and organ systems. Both the efficacy and safety of this method require further rigorous experimental validation in clinically relevant models.
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PMID:Coupled plasma filtration adsorption in experimental peritonitis-induced septic shock. 1882 47

Although surface sialic acid is considered a key determinant for the survival of circulating blood cells and glycoproteins, its role in platelet circulation lifetime is not fully clarified. We show that thrombocytopenia in mice deficient in the St3gal4 sialyltransferase gene (St3Gal-IV(-/-) mice) is caused by the recognition of terminal galactose residues exposed on the platelet surface in the absence of sialylation. This results in accelerated platelet clearance by asialoglycoprotein receptor-expressing scavenger cells, a mechanism that was recently shown to induce thrombocytopenia during Streptococcus pneumoniae sepsis. We now identify platelet GPIbalpha as a major counterreceptor on ST3Gal-IV(-/-) platelets for asialoglycoprotein receptors. Moreover, we report data that establish the importance of sialylation of the von Willebrand factor in its function.
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PMID:Role of sialic acid for platelet life span: exposure of beta-galactose results in the rapid clearance of platelets from the circulation by asialoglycoprotein receptor-expressing liver macrophages and hepatocytes. 1952 Aug 7


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