Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endotoxin from gram-negative bacteria consists of a molecule lipopolysaccharide (LPS) which can be shed by bacteria during antimicrobial therapy. A resulting syndrome, endotoxic shock, is a leading cause of death in the developed world. Thus, there is great interest in the development of antimicrobial agents which can reverse rather than promote sepsis, especially given the recent disappointing clinical performance of antiendotoxin therapies. We describe here two small cationic peptides, MBI-27 and MBI-28, which have both antiendotoxic and antibacterial activities in vitro and in vivo in animal models. We had previously demonstrated that these peptides bind to LPS with an affinity equivalent to that of polymyxin B. Consistent with this, the peptides blocked the ability of LPS and intact cells to induce the endotoxic shock mediator, tumor necrosis factor (TNF), upon incubation with the RAW 264.7 murine macrophage cell line. MBI-28 was equivalent to polymyxin B in its ability to block LPS induction of TNF by this cell line, even when added 60 min after the TNF stimulus. Furthermore, MBI-28 offered significant protection in a galactosamine-sensitized mouse model of lethal endotoxic shock. This protection correlated with the ability of MBI-28 to reduce LPS-induced circulating TNF by nearly 90% in this mouse model. Both MBI-27 and MBI-28 demonstrated antibacterial activity against gram-negative bacteria in vitro and in vivo against Pseudomonas aeruginosa infections in neutropenic mice.
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PMID:Antiendotoxin activity of cationic peptide antimicrobial agents. 894 27

Although studies have shown that endothelium-derived nitric oxide (NO) release is depressed during endotoxic shock or polymicrobial sepsis, it remains unknown whether the decreased release of endothelium-derived NO during the hyperdynamic stage of sepsis is due to downregulation of endothelial NO synthase. To study this, adult rats were subjected to sepsis by cecal ligation and puncture (CLP). At 10 h after CLP (i.e., hyperdynamic sepsis) or sham operation, the aorta was removed and a monoclonal antibody against endothelial (constitutive) NO synthase (E-NOS) was used to determine the immunohistochemical presence and electron microscopic localization of E-NOS in rat aortic endothelial cells. Image analysis was used to quantify aortic E-NOS. In additional groups of animals, the aorta was isolated at 10 h after CLP and the vascular responses to an endothelium-dependent vasodilator, acetylcholine, and an endothelium-independent vasodilator, nitroglycerine, were determined. The results indicate that the number of E-NOS negative endothelial cells increased from 7% in shams to 22% in septic animals. E-NOS densely labeled endothelial cells were significantly reduced from 20% to 8% at 10 h after CLP. The E-NOS positive area in aortic endothelial cells was reduced from 26.1 +/- 1.0 microm2/standard frame in sham to 22.3 +/- 0.9 microm2/standard frame in septic animals. Moreover, acetylcholine-induced but not nitroglycerine-induced vascular relaxation was significantly depressed at 10 h after the onset of sepsis. These results, taken together, indicate that the decreased E-NOS in the vascular endothelial cell is at least in part responsible for endothelial cell dysfunction (i.e., the reduced endothelium-derived NO release) observed during the early, hyperdynamic stage of polymicrobial sepsis.
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PMID:Endothelial nitric oxide synthase is downregulated during hyperdynamic sepsis. 913 55

Gram-negative sepsis and subsequent endotoxic shock remain major health problems in the United States. The present study examined the role of morphine in inducing sepsis. Mice administered morphine by the subcutaneous implantation of a slow-release pellet developed colonization of the liver, spleen, and peritoneal cavity with gram-negative and other enteric bacteria. In addition, the mice became hypersusceptible to sublethal endotoxin challenge. The effects were blocked by the simultaneous implantation of a pellet containing the opioid antagonist naltrexone. These findings show that morphine pellet implantation in mice results in the escape of gram-negative organisms from the gastrointestinal tract, leading to the hypothesis that morphine used postoperatively or chronically for analgesia may serve as a cofactor in the precipitation of sepsis and shock. In addition, morphine-induced sepsis may provide a physiologically relevant model of gram-negative sepsis and endotoxic shock.
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PMID:Morphine induces sepsis in mice. 920 65

Interfering with the endotoxin-mediated cytokine cascade is thought to be a promising approach to prevent septic complications in gram-negative infections. The synthetic lipid A analog SDZ MRL 953 has been shown to be protective against endotoxic shock and bacterial infection in preclinical in vivo models. As part of a trial of unspecific immunostimulation in cancer patients, we conducted a double-blind, randomized, vehicle-controlled phase I trial of SDZ MRL 953 to investigate, first, its biologic effects and safety of administration in humans and, second, its influence on reactions to a subsequent challenge of endotoxin (Salmonella abortus equi). Twenty patients were treated intravenously with escalating doses of SDZ MRL 953 or vehicle control, followed by an intravenous application of endotoxin (2 ng/kg of body weight [BW]). Administration of SDZ MRL 953 was safe and well-tolerated. SDZ MRL 953 itself increased granulocyte counts and serum levels of granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6), but not of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), IL-1beta, and IL-8. Compared with vehicle control, pretreatment with SDZ MRL 953 markedly reduced the release of TNF-alpha, IL-1beta, IL-8, IL-6, and G-CSF, but augmented the increase in granulocyte counts to endotoxin. Induction of tolerance to the endotoxin-mediated cascade of proinflammatory cytokines by pretreatment with SDZ MRL 953 in patients at risk may help to prevent complications of gram-negative sepsis.
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PMID:Downregulation of the proinflammatory cytokine response to endotoxin by pretreatment with the nontoxic lipid A analog SDZ MRL 953 in cancer patients. 926 88

Platelet-activating factor (PAF) is a potent vasoactive and inflammatory lipid mediator which has been implicated in the hemodynamic alterations of endotoxemia and sepsis. Different PAF receptor antagonists have been shown to attenuate the systemic and pulmonary disturbances of sepsis, but they were generally administered before the injection of endotoxin and their effects have not been consistent. To examine the effects of BB-882, a novel potent PAF receptor antagonist, on general hemodynamics and regional flow distribution in a canine endotoxic shock model, 14 anesthetized and ventilated dogs received 2 mg/kg of Escherichia coli endotoxin intravenously (i.v.) followed by generous fluid resuscitation. Thirty minutes later, the dogs received either BB-882 (n = 7) as a continuous i.v. infusion with hourly increasing doses (2, 5, and 10 mg/kg.h, respectively) or a corresponding amount of saline (n = 7). The administration of BB-882 resulted in a dose-dependent reduction in cardiac output and an increase in systemic and pulmonary vascular resistance. Mesenteric and renal flow were not different from control values whereas femoral blood flow progressively decreased. Another group of 7 dogs received 5 mg/kg i.v. bolus of BB-882 30 min before endotoxin. Pretreatment significantly increased mesenteric blood flow by about 50% but did not show any significant hemodynamic effects. This study demonstrates that the administration of a PAF receptor antagonist following endotoxic shock in fluid resuscitated dogs does not offer significant hemodynamic benefit. Pretreatment with BB-882 at the dose used only enhanced mesenteric perfusion. These findings do not support beneficial effects of PAF receptor antagonists in septic shock.
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PMID:Treatment with a platelet-activating factor antagonist has little protective effects during endotoxic shock in the dog. 937 67

A paracrine pathway for the regulation of cardiac contractile function by nonmuscle cells is documented in the heart. Coronary and endocardial endothelium release several diffusible agents, such as prostaglandins, endothelin-1, and nitric oxide, with an action on cardiac myocyte function. Cardiac diseases involving an immune or inflammatory mechanism, such as endotoxic shock, are now seen as conditions in which cross-talk between different cell types in the heart is clearly implicated. The potential biological relevance of inducible nitric oxide synthase in the myocardium, and the subsequent production of nitric oxide has been proposed as a mechanism of the cardiac depression observed in septic shock. In addition to cardiac myocytes, activated microvascular endothelial cells and cardiac endothelial cells may contribute to nitric oxide generation and, ultimately, to the depression of myocardial contractile activity during sepsis. This article reviews the local intercellular communication between cardiac myocytes and endothelial cells in the normal heart and discusses some of the mechanisms potentially claimed to depress heart function in sepsis.
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PMID:Paracrine regulation of cardiac myocytes in normal and septic heart. 955 26

CAP18 (an 18-kDa cationic antimicrobial protein) is a granulocyte-derived protein that can bind lipopolysaccharide (LPS) and inhibit various activities of LPS in vitro. The present study examined the protective effect of a synthetic 27-amino-acid peptide (CAP18(109-135)) from the LPS-binding domain of CAP18 against antibiotic-induced endotoxin shock, using highly LPS-sensitive D-(+)-galactosamine (D-GalN)-sensitized C3H/HeN mice. The antibiotic-induced endotoxin (CAZ-endotoxin) was prepared from the culture filtrate of Pseudomonas aeruginosa PAO1 exposed to ceftazidime (CAZ). Injection of CAP18(109-135) protected the mice injected with LPS or CAZ-endotoxin from death and lowered their tumor necrosis factor (TNF) levels in serum in a dose-dependent manner. Treatment with CAZ caused death of the D-GalN-sensitized P. aeruginosa PAO-infected mice within 48 h, while injection with CAP18(109-135) rescued the mice from death. In the mice rescued from death by injection with CAP18(109-135), endotoxin levels in plasma and TNF production by liver tissues were decreased but the numbers of viable infecting bacteria in their blood were not decreased significantly and remained at the levels in CAZ-treated mice. These results indicate that CAP18(109-135) is capable of preventing antibiotic-induced endotoxic shock in mice with septicemia and that the effect is due to its LPS-neutralizing activity rather than to its antibacterial activity.
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PMID:Protective effects of a human 18-kilodalton cationic antimicrobial protein (CAP18)-derived peptide against murine endotoxemia. 957 62

Chylomicrons (CM) can bind endotoxin (lipopolysaccharide [LPS]), forming CM-LPS complexes, and protect against endotoxic shock and death in rodent models of gram-negative sepsis. The liver appears to play a central role in this process, as demonstrated by the increased uptake of LPS by this organ. We examined the effect of CM on the uptake and cellular response to injected 125I-LPS by hepatocytes and hepatic nonparenchymal cells. Whereas CM increased the uptake of LPS by both hepatocytes and Kupffer cells, the increase was proportionately greater in hepatocytes than Kupffer cells. Importantly, CM-LPS complexes inhibited inducible nitric oxide synthase (iNOS) mRNA expression and NO production in Kupffer cells and endothelial cells, reducing mRNA levels by 45% to 50% as compared with LPS alone. CM-bound LPS also reduced NO production by hepatocytes in response to cytokine stimulation. Lastly, CM-LPS complexes yielded a concentration-dependent inhibition of LPS-induced tumor necrosis factor alpha (TNF-alpha) production by Kupffer cells in vitro. These data indicate that the mechanism by which CM protect against endotoxicity may involve an increased uptake of LPS by hepatocytes. Moreover, uptake of CM-bound LPS by liver cells attenuates the capacity of these cells to respond to proinflammatory stimulation. These results highlight important anti-inflammatory properties of CM.
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PMID:Chylomicrons alter the hepatic distribution and cellular response to endotoxin in rats. 958 89

Although cardiac function is depressed during endotoxic shock, it remains controversial whether the ventricular contractility and structure are altered during sepsis. To resolve this issue, rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). At 2, 5, and 10 h after CLP (i.e., the early, hyperdynamic stage of sepsis) or 20 h after CLP (the late, hypodynamic stage of sepsis, based on the depressed tissue perfusion), in vivo left ventricular contractility parameters such as maximal rate of the left ventricular pressure increase (+dP/dtmax) and decrease (-dP/dtmax), maximal rate of "pressure-normalized" change in ventricular pressure (dP/dtmax/P), and ventricular peak systemic pressure were determined using a Digi-Med Heart Performance Analyzer. In additional groups of animals, ultrastructure of the cardiac muscle in the left ventricle was examined at 5, 10, or 20 h after CLP, using a transmission electron microscope. The results indicate that +dP/dtmax and dP/dtmax/P increased significantly at 2-10 h after CLP. The values of -dP/dtmax and ventricular peak systemic pressure increased significantly at 2 and 5 h after the onset of sepsis, respectively. These in vivo ventricular contractility parameters, however, were not significantly different from shams at 20 h after CLP. Ultrastructural examination showed that enlarged T-tubules were prominent during the hyperdynamic stage of sepsis, which was correlated with the increased cardiac contractility. Although focal and moderate hypertrophy as well as expanded intermyocyte junctions could be observed occasionally, myocardial cells did not appear to be compromised at 20 h after CLP. Thus, the transition from the hyperdynamic to hypodynamic circulation during sepsis does not appear to be due to any depression in myocardial function because cardiac contractility and structure are not compromised even during the late, hypodynamic stage of sepsis. However, further investigation is required to determine whether cardiac function is depressed at the terminal stage of polymicrobial sepsis.
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PMID:Cardiac contractility and structure are not significantly compromised even during the late, hypodynamic stage of sepsis. 992 20

Endotoxic shock with multiorgan dysfunction syndrome (MODS) is fatal in more than 80% of cases and is the leading cause of death in patients admitted to intensive care units. The incidence has increased to more then 100% in the last 10 years and there has been no significant decreases in its morbidity and mortality. The systemic inflammatory response to infection, e.g. sepsis, develops when the endotoxins activate various cascade systems. The activation of the cascade systems triggers further release of various active substances and cytokines. The progress may result in consumption coagulopathy, which may further generate an acute septic shock, disseminated intravascular coagulation, and MODS. When more than 3 organs are involved, the risk of fatal outcome exceeds 80%. The use of plasma exchange may be a beneficial adjunct to therapy during a progressive septic shock with MODS, when the patient does not respond to classical intensive care unit therapy. The beneficial effect, recently reported for plasma exchange procedures in patients with sepsis, may be due to the removal of various toxins and waste products from the blood, and administration of plasma from healthy subjects.
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PMID:Therapeutic plasma exchange in severe sepsis or septic shock. 968 1


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